Thursday, December 31, 2009

GMO bacteria as a cure for IBD?

Bacteria Wins First Round Against Inflammatory Bowel Disease
December 31, 2009 By Ann Perry

ARS microbiologist Terry Whitehead is part of a team that found and altered a microbe so it might one day help treat inflammatory bowel disease and other chronic intestinal diseases in people.

( -- A group of British scientists and their Agricultural Research Service (ARS) colleague used a benign bacterium from the human gut to develop a microbe that someday might help treat inflammatory bowel disease (IBD) and other chronic intestinal diseases.

IBD erodes the delicate lining of the intestine, and its symptoms—often severe—include cramping, abdominal pain and other gastrointestinal discomfort. IBD cannot be cured, and current treatments can have adverse side effects. Medical practitioners and patients are anxious for the development of more effective therapies, particularly protocols that deliver drugs directly to the intestine.

So ARS microbiologist Terry Whitehead, who works at the National Center for Agricultural Utilization Research in Peoria, Ill., and his partners began searching for a solution. Simon Carding, who works at the Institute of Food Research and the University of East Anglia in Norwich, Great Britain, led the research project with Zaed Hamady, who works at the University of Leeds in Great Britain and St. James University Hospital, also in Leeds.

The group focused on the bacterium Bacteroides ovatus (B. ovatus), which is one of an assortment of intestinal microflora in humans. B. ovatus thrives in the oxygen-free environment of the large intestine, where it breaks down xylan—a fiber found in plants—and other sugars for energy and growth.

The team created a strain of B. ovatus that used xylan to induce secretion of human keratinocyte growth factor, a protein that helps repair and restore the intestine’s delicate lining. This increased the ability of the intestine to repair IBD-inflicted damage.

The researchers found that IBD-affected mice treated with oral doses of xylan and the engineered strain of B. ovatus had intestinal tissues that healed more rapidly. This group of mice also lost less weight and had lower levels of rectal bleeding. In addition, dosing mice with B. ovatus provided protection from induced IBD and limited the development of subsequent intestinal inflammation.

An abstract of this research was published online in the journal Gut.
Provided by USDA Agricultural Research Service

Autoimmune disease can no longer be lumped together

From the beginning of this blog, I have maintained that what works to help one autoimmune disease ought to help many if not all other autoimmune diseases. It appears I was wrong.

I based my views on the following facts. I knew that the tendency for autoimmune disease runs in families. I also knew that once a person is diagnosed with one autoimmune disease that person is often likely to get diagnosed with more autoimmune diseases. For instance my youngest son, Paul, has three autoimmune diagnosis.

I thought an autoimmune disease is an autoimmune disease is an autoimmune disease and it was time to stop dividing the community of autoimmune sufferers into separate camps. Each camp pursuing its own agenda. I thought all the various groups should join together in one focused attempt to solve all autoimmune disease. But I was at least partly wrong if Stanford researchers are correct with their latest research findings.

Researchers at Stanford have looked at genetics of various autoimmune diseases and found that instead of all the genes falling into one category, they seem to lump together in at least two groups. One group of genetically similar autoimmune disease lumps the following together: multiple sclerosis, Type I diabetes, autoimmune thyroid disease. Let's call that group A.

The other group seems to be rheumatoid arthritis and Ankylosing Spondylitis (AS) and likely psoriatic arthritis (PsA) due to similar drugs helping PsA as help RA. If PsA is in the group than psoriasis is probably there as well. Call this group B.

Patients with PsA and psoriasis were not genetically screened by the researchers, so this is just my educated guess at the moment. It is NOT the conclusion of the Stanford researchers.

Hopefully this research will begin to give the NIH scientific justification to allow clinical trials of several autoimmune diseases at once. Perhaps all of Group A autoimmune diseases could be tested in one clinical trial and if the new therapy worked for all, then FDA could approve the drug for multiple autoimmune diseases at the same time. Clinical trials would also be streamlined giving us new meds faster.

When a new medical breakthrough for RA in Group B is discovered, this breakthrough could be tested on AS and PsA patients at the same time. If it worked for all three, then the FDA could approve it for all at once rather than forcing the company that developed the therapy to do a completely different, time consuming and costly tests for each autoimmune disease separately.

Let's hope more research confirms what Stanford researchers seem to have found. This is the kind of basic research that brings us closer to cures.
Personal note: My two antibiotics that my hypersensitive immune system is barely tolerating (incredible itching even with H1 and H2 antihistamines) seem to be failing at controlling the infection in my right nostril.

The infection is an incredibly resistant micro-organism. I go to a doctor on Monday who says he can desensitize anyone to any chemical. We will see.

I imagine he will say it takes at least several months. Sadly I do not seem to have that much time on my current regime. I am having red blood drainage from nostril today, first time since I started the oral antibiotic Zyvox, twelve days ago.

Zyvox is top of the line restricted antibiotic, so it is very strange it is beginning to fail. It worked pretty good at the beginning and cleared my sinuses of mucus.

We really need new and truly novel antibiotics. Where is Big Pharma? Hundreds of millions to bribe "opinion makers' on radio and cable 'news' organizations to stop universal health insurance and millions more to 'lobby' Joe Liberman and others in the Senate to kill the last bits of insurance reform, but nothing for research into new antibiotics? Should we ask if our current system of drug development is setting the right agendas?
Here is the article:

Genomic Toggle Switches Divide Autoimmune Diseases Into Distinct Clusters,
Stanford Study Shows
31 Dec 2009

Genomic switches can predispose an individual to one set of autoimmune disorders but protect the same person against another set of them, scientists at Stanford University School of Medicine have found.

"Maybe we should stop considering all autoimmune diseases in one lumped category," said Atul Butte, MD, PhD, assistant professor of pediatrics and of biomedical informatics and director of the Center for Pediatric Bioinformatics at Lucile Packard Children's Hospital. "It looks as if there may be at least two different kinds."

Pairs of autoimmune diseases have been linked in clinical practice, Butte said. People with type-1 diabetes are routinely screened for autoimmune thyroid disease, for which they are known to be at heightened risk. But no one has ever known why.

A study published online Dec. 24 in PLoS-Genetics provides a genetic basis for this clustering effect, while extending it to show how two such clusters tend to be mutually exclusive. Butte, who is the study's senior author, and his colleagues looked at data from several large genome-wide association studies of single-nucleotide polymorphisms, or SNPs: tiny genomic variations that constitute the genetic underpinning for inter-individual human differences from eye color to nose shape to personality quirks.

The human genome can be thought of as a 3-billion-unit-long sequence, with each unit consisting of one of four different chemical residues. At almost every specific location along two different people's genomes, the resident chemical unit is the same. But at about one or two out of every 1,000 positions, the first person's genome may boast one variety of chemical unit, while the second's hosts another type. This single-unit difference is a SNP (pronounced "snip").

There are several million SNPs in the human genome, making for a gigantic number of possible different versions of a human being, said the study's lead author, Marina Sirota, a fourth-year PhD student under Butte's supervision in Stanford's Biomedical Informatics Program. In so-called genome-wide association studies, SNPs linked to disease susceptibility are found by assessing genomes from two large groups of people, one composed of patients with, say, rheumatoid arthritis or heart disease and another of people without the condition. If, at a given SNP location, the frequency of one particular chemical unit is significantly greater or smaller among the diseased people than in the healthy ones, that SNP is presumed to lie close to or within a biologically important genomic region that increases or diminishes genetic susceptibility to the disease, Sirota said.

In the past few years the industrial-scale characterization of SNPs has been hugely enhanced by sophisticated electronic devices called gene chips, pioneered at Stanford about a decade ago. Gene chips can quickly scan an individual's genome to identify the chemical unit occupying each of more than a million SNP locations.

"More than 400 genome-wide association studies have been published since gene-chip technology took off a few years ago," said Butte. From these published studies, Sirota, Butte and their colleagues culled about a half-dozen that had been conducted on patients with or without autoimmune diseases including type-1 diabetes, rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease and a spinal condition called ankylosing spondylitis. The investigators restricted their attention to SNPs that were examined in all the studies they were focusing on.

That worked out to 573 SNPs. Of those, the researchers found 15 SNPs for which having a particular chemical unit at that site predisposed an individual to several autoimmune diseases.

That wasn't surprising, said Sirota. "We had started out looking for just such similarities. What was surprising was our finding that at nine locations generally associated with autoimmunity risk, where a particular chemical unit conferred a heightened risk of certain autoimmune diseases, but reduced risk of getting certain others."

For instance, a particular chemical unit at a SNP site shown to predispose people to multiple sclerosis also rendered them, as a group, more likely to have autoimmune thyroid disease, while the alternative chemical unit at the same site predisposed them to rheumatoid arthritis and ankylosing spondylitis. Most intriguing of all, people predisposed to one pair of diseases were protected against the other.

The scenario is akin to switches controlling banks of Christmas-tree lights. In addition to a master on/off switch that determines whether electricity (a general predisposition to autoimmune disease) will flow through the circuit, a second set of toggle switches determines whether, say, red or blue lights (one versus another autoimmune-disease cluster) will be on.

"As more genomic information becomes available on increasingly advanced platforms, this sort of analysis can be done on more diseases, possibly hundreds of them. Plus, the original set of 573 common SNPs we were able to inspect will grow much larger. So we'll be able to find more relationships like these," Sirota said.

Butte said finding SNPs predisposing people to one or another cluster of autoimmune diseases may help catch the onset of a disease earlier. "And if a patient has a particular autoimmune disease, this might help us know what else to screen that patient for, or guess whether a drug that works well in a different autoimmune disorder could be useful in treating this patient."

It might also help guide drug development, he added. "Several of these nine interesting SNPs we've found are located in or near genes that code for molecules found on cell surfaces, which makes them potentially easier targets for the drugs pharmaceutical researchers are best at producing."

Other Stanford co-authors were PhD student Marc Schaub and associate professor Serafim Batzoglou, PhD, of the computer science department, and William Robinson, MD, PhD, assistant professor of immunology and rheumatology. The study was funded by the Lucile Packard Foundation for Children's Health, National Institute of General Medical Sciences, National Library of Medicine, Howard Hughes Medical Institute and Pharmaceutical Research and Manufacturers of America Foundation.

Bruce Goldman
Stanford University Medical Center

Wednesday, December 30, 2009

Zinc fingers may give us gene therapy after all

Zinc fingers are one way to modify our DNA and the products our DNA produces for us.

The zinc fingers techniques is part of a larger field of study called epigenetics. This science studies how our DNA code is modified to produce more or less of certain gene products. Zinc fingers seems to be a leading candidate for the first success in targeting and modifying specific genes.

Certain genetic diseases are caused when too much of a gene product is produced. Many others like cystic fibrosis are caused when too little or no product is made. Hopefully the manipulation of our DNA with techniques like these zinc fingers will one day lead to cures or permanent long term fixes for many now intractable genetic diseases.

Read the following for more info on zinc fingers:

December 29, 2009
In New Way to Edit DNA, Hope for Treating Disease

Only one man seems to have ever been cured of AIDS, a patient who also had leukemia. To treat the leukemia, he received a bone marrow transplant in Berlin from a donor who, as luck would have it, was naturally immune to the AIDS virus.

If that natural mutation could be mimicked in human blood cells, patients could be endowed with immunity to the deadly virus. But there is no effective way of making precise alterations in human DNA.

That may be about to change, if a powerful new technique for editing the genetic text proves to be safe and effective. At the University of Pennsylvania, Dr. Carl June and colleagues have used the technique to disrupt a gene in patients’ T cells, the type attacked by the AIDS virus. They have then infused those cells back into the body. A clinical trial is now under way to see if the treated cells will reconstitute a patient’s immune system and defeat the virus.

The technique, which depends on natural agents called zinc fingers, may revive the lagging fortunes of gene therapy because it overcomes the inability to insert new genes at a chosen site. Other researchers plan to use the zinc finger technique to provide genetic treatments for diseases like bubble-boy disease, hemophilia and sickle-cell anemia.

In principle, the zinc finger approach should work on almost any site on any chromosome of any plant or animal. If so, it would provide a general method for generating new crop plants, treating many human diseases, and even making inheritable changes in human sperm or eggs, should such interventions ever be regarded as ethically justifiable.

Zinc fingers are essential components of proteins used by living cells to turn genes on and off. Their name derives from the atom of zinc that holds two loops of protein together to form a “finger.” Because the fingers recognize specific sequences of DNA, they guide the control proteins to the exact site where their target gene begins.

After many years of development, biologists have learned how to modify nature’s DNA recognition system into a general system for manipulating genes. Each natural zinc finger recognizes a set of three letters, or bases, on the DNA molecule. By stringing three or four fingers together, researchers can generate artificial proteins that match a particular site.

The new system has been developed by a small biotech company, Sangamo BioSciences of Richmond, Calif., and, to some degree separately, by academic researchers who belong to the Zinc Finger Consortium.

Sangamo was founded in 1995 by Edward O. Lanphier II, a former executive with a gene therapy company. Reading an article by Aaron Klug, the British crystallographer who discovered the zinc finger design, he saw the technique’s potential for genetic manipulation. He bought a company Dr. Klug had founded and worked with him and researchers like Carl O. Pabo to improve the technique and develop combinations of zinc fingers to match any sequence of DNA letters.

“We now have a full alphabet of zinc fingers,” Mr. Lanphier said, “but when we started the company it was like typing a novel with two fingers.”

Zinc finger proteins have many potential uses. One is to link them to agents that turn on or turn off the gene at the site recognized by the fingers.

More powerfully, the zinc fingers can be deployed as a word processing system for cutting and pasting genetic text. Two sets of zinc fingers are attached to a protein that cuts the DNA in between the two sites matched by the fingers. The cell quickly repairs the break but sometimes in a way that disrupts the gene. This is the approach used in destroying the gene for the receptor used by the AIDS virus to gain entry to white blood cells.

Or, if DNA for a new gene is inserted into a cell at the same time as the zinc fingers that scissor the DNA, the new gene will be incorporated by the cell’s repair system into the DNA at the break site. Most gene therapy techniques use a virus to carry new genes into a cell but cannot direct the virus to insert genes at a specific site.

“I think it’s a broadly applicable technology which has already allowed experiments that would not have been possible before,” said J. Keith Joung, a biologist who designs zinc finger proteins at the Massachusetts General Hospital.

Daniel F. Voytas, a plant geneticist at the University of Minnesota, said the zinc finger technique would allow breeders to change the oil composition of any plant, the types of carbohydrates produced or the way carbon dioxide is captured. “We can go in and make any change we want to any plant species,” Dr. Voytas said.

Zinc fingers can also be used for “trait stacking,” the positioning of several beneficial genes at a single site. This avoids heavy regulatory costs because genetically altered plants must be tested for safety for each site that is modified.
The zinc finger technology has taken many years to prepare because of the difficulty of designing the fingers and also of preventing them from cutting the genome in the wrong places. Only a handful of laboratories are currently using the technique, but proponents expect to see rapid growth.

The Zinc Finger Consortium, founded by Dr. Joung and Dr. Voytas, makes the method available free, and researchers need only pay for materials. But there are some 200 steps in Dr. Joung’s recipe for making zinc fingers, and it takes time and dedication to do them all correctly.

The alternative is to buy zinc fingers. Sangamo has a commanding patent position and has licensed Sigma-Aldrich, a large life science company in St. Louis, to make zinc finger proteins for researchers. Sigma-Aldrich’s charge for a zinc finger protein that cuts the genome at the site of your choice is $39,000, with a discount for academic researchers. Zinc fingers that cut well-known human genes cost $12,000. Sigma-Aldrich has used the technology to generate rats with genetic defects that mimic human disease. A schizophrenic rat can be had for $100.

David Smoller, president of Sigma-Aldrich’s biotechnology unit, licensed the technology from Sangamo in 2006 when he felt the company had proved it worked. “This technology is just amazing,” Dr. Smoller said. “It’s a game changer.”

Sangamo has licensed the use of zinc fingers to Dow Agrosciences for creating new crop plants, and has reserved medical uses for itself. It has four Phase 2 clinical trials in progress, including treatments for diabetic neuropathy and amyotrophic lateral sclerosis.

In an ambitious effort to cure AIDS, Sangamo and the University of Pennsylvania started a clinical trial in February.

The AIDS virus enters the T cells of the immune system by latching on to a receptor called CCR5, but about 10 percent of Europeans have a mutation that disables the CCR5 gene. People who inherit two disabled copies of the gene do not have CCR5 on the surface of their T cells, so the AIDS virus has nothing to grab. These people are highly resistant to H.I.V.

In the zinc finger approach, the patient’s T cells are removed, and zinc finger scissors are used to disable the CCR5 gene. The treated cells are allowed to multiply, then reinjected into the patient. In experiments with mice, the treated cells turned out to have a strong natural advantage over the untreated ones, since those are under constant attack by the AIDS virus.

Whether or not zinc fingers will make gene therapy practical remains to be seen. “It’s a little too early to know since clinical trials are in their early stages,” said Dr. Katherine A. High, a hemophilia expert at the University of Pennsylvania.

Dr. Matthew H. Porteus, a pediatric geneticist at the University of Texas, said, “I think it has the potential to solve a lot of the problems that have plagued the gene therapy field.” But Dr. Porteus noted that even the most carefully designed zinc fingers seemed to do some snipping away from their target site, a potentially serious safety problem.

Zinc fingers could be the gift that stem cell researchers have been waiting for. Stem cells taken from a patient may need to be genetically corrected before use, but until now there had been no way of doing so.

Dr. Rudolf Jaenisch, a stem cell expert at the Whitehead Institute in Cambridge, Mass., reported in August that he had successfully singled out three genes in induced embryonic stem cells with the help of zinc finger scissors designed by Sangamo. “This is a really important tool for human embryonic stem cells,” Dr. Jaenisch said. The technology has not yet reached perfection. Some of the zinc fingers Sangamo provided “worked beautifully,” he said, but some did not.

Zinc fingers may also make technically possible a morally fraught procedure that has been merely a theoretical possibility — the alteration of the human germ line, meaning the egg or sperm cells. Genetic changes made in current gene therapy are to body cells, and they would die with the individual. But changes made to the germ line would be inherited. Many ethicists and others say this is a bridge that should not be crossed, since altering the germ line, even if justifiable for medical reasons, would lower the barrier to other kinds of change.

Several scientists were reluctant to discuss the issue, or dismissed it by saying that even zinc fingers did not meet the error-free standards that would be required for germ-line engineering. But zinc finger scissors are so efficient that only 5 to 10 embryos need be treated to get one with the desired result. This could make it practical to alter the germ line.

Since the germ lines of rats and zebra fish have already been altered with zinc finger scissors, “in principle there is no reason why a similar strategy could not be used to modify the human germ line,” Dr. Porteus said. The kind of disease that might be better treated in the germ line, if ethically acceptable, is cystic fibrosis, which affects many different tissues.
The disease could be corrected in unfertilized eggs, using the zinc finger technique, Dr. Porteus said. But he added, “I don’t think our society is ready for someone to propose this.”

Monday, December 28, 2009

MIT's BIG News--novel delivery of Gene Silencing--siRNA seems ready for "the show"

Researchers at the Massachusetts Institute of Technology have perfected a delivery technique that appears to make gene silencing therapy ready for clinical trials. This is big news for a lot of genetic conditions possibly including autoimmune disease.

If malfunctioning immune genes could be ‘silenced’ for a time then our out of control immune systems might be able to be brought under control.

Gene silencing techniques have been available for last eight or ten years, but were not practical due to delivery problems. MIT researchers seem to have solved the problem by wrapping the gene silencing materials (siRNA) in a special coating of a fat like molecule that is readily absorbed by cells. Once inside the cell the silencing RNA is released to turn off the defective genes.

Sounds promising to me, but I have been disappointed before. Can you say Prochymal from Osiris?

I think this particular technique is a much more likely to work than not. MIT researchers have reputations to protect. Let’s hope they get funding for the quick development of effective treatments and cures for so many diseases, now untreatable.
Personal note: I am still fighting a resistant bacterial infection of my right nostril. At present I seem to be losing both sides of the battle. My immune system itches more and more with the top of the line restricted antibiotic (Zyvox) each time I take it and sadly the bacteria seems to be less and less affected by the Zyvox. Initially it died nicely. Not as good as the sulfa drug killed it but very nicely.

This morning’s dose of Zyvox barely affected the bacteria. I felt the rush of Zyvox hit me about an hour and half after ingesting the pill at 7am. Within minutes I felt a few of the scabs losing up and coming off as the bacteria were killed. But most scabs and sores were unaffected. Pain in the bones around my eye and cheekbones are increasing.

I am taking the maximum dose of Zyvox so the doctor also prescribed mupirocin spray and ointment in combination with the Zyvox. Sadly mupirocin also has lost its power over these bacteria. Originally it seemed that it alone would kill them. Now they act like it does not bother them at all to be drenched in the stuff. yet my immune system reacts in violent itching which I try to control with pre treatment of H1 and H2 antihistamine blockers (Zyrtec, Chlortrimeton, and Zantac)

I see the ear nose and throat guy tomorrow. He could try IV antibiotics, but it is unlikely that my immune system would tolerate them for as long a time as I would need to kill the bacteria.

Hypersensitivity reactions are life threatening and often treated as a joke on TV with someone swollen up or covered with hives being used for a punchline to a gag. However, when there is a systemic (whole body) malfunction of the immune system, like swelling (angioedema) or hives, that is not a joke. It is very often a medical emergency.

The odds were stacked against me when I acquired the infection and have gotten worse as either I reacted to medications like sulfa or the bacteria fought off the medication like Avelox. This country and the world desperately need new and completely novel antibiotics.

All Big Pharma ever seems to give us are the same old antibiotics just with new chemical side groups and other minor tweeks that allow the companies to market as a “new” antibiotic, a very similar one to what we already had.

Unless something positive happens quickly, things look a bit bleak for me. But hopefully the new gene silencing delivery system from MIT will make a difference for cures for you and for my son, Paul. Sure wish there were a gene silencing technique for hypersensitivity genes right about now.

New RNA interference technique can silence up to 5 genes
December 28, 2009

Researchers at MIT and Alnylam Pharmaceuticals report this week that they have successfully used RNA interference to turn off multiple genes in the livers of mice, an advance that could lead to new treatments for diseases of the liver and other organs.

Since the 1998 discovery of RNA interference — the naturally occurring phenomenon in which the flow of genetic information from a cell's nucleus to the protein-building machinery of the cell is disrupted — scientists have been pursuing the tantalizing ability to shut off any gene in the body. Specifically, they have been trying to silence malfunctioning genes that cause diseases such as cancer.

The new delivery method, described in the Proceedings of the National Academy of Sciences, is orders of magnitude more effective than previous methods, says Daniel Anderson, senior author of the paper and a biomedical engineer at the David H. Koch Institute for Integrative Cancer Research at MIT.

"This greatly improved efficacy allows us to dramatically decrease the dose levels, and also opens the door to formulations that can simultaneously inhibit multiple genes or pathways," says Anderson.

The key to success with RNA interference is finding a safe and effective way to deliver the short strands of RNA that can bind with and destroy messenger RNA, which carries instructions from the nucleus.

Anderson and his colleagues believe the best way to do that is to wrap short interfering RNA (siRNA) in a layer of fat-like molecules called lipidoids, which can cross cells' fatty outer membrane. Using one such lipidoid, the researchers were able to successfully deliver five snippets of RNA at once, and Anderson believes the lipidoids have the potential to deliver as many as 20.

How they did it: The team at MIT, along with Alnylam researchers, have developed methods to rapidly produce, assemble and screen a variety of different lipidoids, allowing them to pick out the most effective ones.

In a previous study, the researchers created more than 1,000 lipidoids. For their latest study, they picked out one of the most effective and used a novel chemical reaction to create a new library of 126 similar molecules. The team focused on one that appeared the most promising, dubbed C12-200.

Using C12-200, the researchers achieved effective gene silencing with a dose of less than 0.01 milligrams of siRNA per kilogram of solution, and 0.01 milligrams per kilogram in non-human primates. If the same dosing were translated to humans, a potential therapy would only require an injection of less than 1 milliliter to specifically inhibit a gene, compared with previous formulations that would have required hundreds of milliliters, says Anderson.

Other authors from MIT include Kevin T. Love, Kerry P. Mahon, Christopher G. Levins, Kathryn A. Whitehead and Institute Professor Robert Langer.

Next steps: The MIT/Alnylam team hopes to start clinical trials within the next couple of years, after figuring out optimal doses and scaling up the manufacturing capability so they can produce large amounts of the siRNA-lipidoid complex.
More information: "Lipid-Like Materials for Low Dose, in vivo Gene Silencing," Kevin T. Love, Kerry P. Mahon et al. Proceedings of the National Academy of Sciences, week of Dec. 28, 2009.
Provided by Massachusetts Institute of Technology

Wednesday, December 23, 2009

Jonsson Comprehensive Cancer Center discovery: Lower dCK levels, turn off autoimmune, GvHD, and hypersensitivity?

New immune enzyme discovered at Jonsson Comprehensive Cancer Center that has great potential in a number of terrible diseases including autoimmune disease, Graft versus Host Disease, and perhaps hypersensitivity reactions to foods and drugs.

The discovery indicates very good work being done at UCLA.

Let's hope the research teams work quickly to develop drugs that can turn down this dCK signal and thereby modulate our out of control immune systems. We desperately need new approaches to our diseases and new drugs. This discovery might give us both.

Enzyme Necessary For Development Of Healthy Immune System

Mice without the deoxycytidine kinase (dCK) enzyme have defects in their adaptive immune system, producing very low levels of both T and B lymphocytes, the major players involved in immune response, according to a study by researchers with
UCLA's Jonsson Comprehensive Cancer Center.

The finding could have ramifications in treating auto-immune disorders, in which the body attacks itself, and possibly certain cancers of the immune system. A drug could be developed to create lower levels of dCK in the body, thereby tamping down immune response. Such a drug might also be effective in transplant patients to decrease risk for rejection, said Dr. Caius Radu, an assistant professor of Molecular and Medical Pharmacology, a Jonsson Cancer Center researcher and senior author of the study.

The study, part of a long-term research project that has resulted in the development of a new probe for Positron Emission Tomography (PET) scanning and the creation of a non-invasive approach to observe chemotherapy at work in the body, appears this week in the early online edition of the Proceedings of the National Academy of Sciences.

"It would be desirable to have drugs that can inhibit immune response when that response is detrimental and increase response when needed," said Radu, who also is a scientist with the Broad Stem Cell Research Center. "We are now trying to identify drugs that inhibit or activate dCK in the hopes of testing them on certain diseases."

The dCK enzyme helps recycle the products of DNA degradation, allowing cells to efficiently replicate their DNA during cell division. Until now, the enzyme was thought to play a relatively minor role in providing cells the material for DNA replication. However, this finding challenges that view and indicates the enzyme plays a profound role in normal lymphocyte development.

Wayne Austin, a graduate study in Molecular and Medical Pharmacology and first author of the study, said the research team expected to find widespread defects in development when they knocked out the dCK enzyme in the mice.

"Surprisingly, we found that the gene had a highly specific role in the development of organs crucial to a normally-functioning immune system," Austin said. "Mice lacking the dCK enzyme have thymuses that are reduced in size by 90-fold. That defect in thymus size resulted in mice having 5 to 13-times fewer lymphocytes circulating throughout the body."

This finding is part of research that was launched several years ago and represents the third significant discovery. The first was the development of a new probe for PET scanning created by modifying a common chemotherapy drug, an advance that allowed UCLA researchers to model and measure the immune system in action and monitor response to new therapies.

Researchers created the molecule, called FAC, by slightly altering the molecular structure of gemcitabine, a chemotherapy drug that is activated by dCK activity. They added a radiolabel so the cells that take in the probe can be seen during PET scanning.

The probe was based on a fundamental cell biochemical pathway called the DNA Salvage Pathway, which includes dCK. All cells use this biochemical pathway to different degrees. But in lymphocytes, which are the active players in the adaptive immune system, the pathway is activated at very high levels. Because of that, the probe accumulates at high levels in those cells, said Dr. Owen Witte, director of the Broad Stem Cell Research Center and a Howard Hughes Medical Institute investigator.

That work was published June 8, 2008 in the journal Nature Medicine.

The second significant finding was the development of a non-invasive approach that may allow doctors to evaluate a tumor's response to a drug before prescribing the treatment, enabling physicians to personalize therapy to the patient's unique biochemistry.

In this study, the UCLA team injected the FAC probe into mice that had developed leukemias that either had or did not have active dCK enzyme. After an hour, the researchers imaged the animals' bodies with a PET scan, which operates like a molecular camera, enabling the researchers to watch biological processes inside animals and people.

The PET scan offered a preview for how the tumor will react to a specific therapy because tumor cells that retained the probe also will be sensitive to chemotherapy drugs that also are activated by dCK. If the cells didn't absorb the probe, the tumor might respond more favorably to the drugs that don't need interaction with dCK to be effective.

That work appeared Feb. 2, 2009 in the Proceedings of the National Academy of Sciences.

The next step, outlined in this study, was to determine what would happen without any dCK in the body at all, and what ramifications that might have on certain diseases and their treatment.

The study was funded by grants from the National Cancer Institute/National Institutes of Health, the U.S. Department of Energy, California Institute for Regenerative Medicine and the Dana Foundation.

Source: Kim Irwin
University of California - Los Angeles

Stop Th17 cells, stop inflammation and autoimmune, more evidence from study of T.B.

For us Th17 immune cells seem to be the ones that produce the out of control inflammation and the "cytokine storms" that can be so damaging.

Cytokine storms happen when our immune cells release too many and too much of several kinds of inflammatory cytokines (immune signals) which drive our defensive cells into a frenzy of destruction. This frenzy can cause these normally helpful cells to damage or kill the person they are supposed to defend.

Apparently having too many TH17 cells is a primary cause of at least some of these inflammatory cytokine storms. The importance of blocking IL-17 the seemingly 'master' inflammatory cytokine that drives inflammation as been know since at least 2003.

Currently creating a monoclonal to use therapeutically in autoimmune arthritis is a goal of the research community, and big pharma.

If you are interested in Eli Lily's Rheumatoid Arthritis phase II study of its anti IL-17 compound read here:

The study is currently enrolling patients as of December 2009. Study locations are here:

Here basic research on TB leads to answers in autoimmune disease. Let's keep funding basic research at high levels. Information gleaned leads to quicker cures for all of us.

NYU Langone Medical Center / New York University School of Medicine
New pathway discovered that may prevent tissue damage resulting from inflammation
Study could pave the way for new treatments for immune diseases

(New York, New York – December 22, 2009): Interferon gamma is a protein secreted by lymphocytes that is used to fight the bacteria in white blood cells that cause tuberculosis. In a study published this week in Immunity, scientists at NYU Langone Medical Center have discovered that in addition to white blood cells, other cells such as epithelial and endothelial cells, also respond to interferon gamma and also protect mice from uncontrolled tuberculosis infection. This new pathway could lead to the developments of treatments that could limit or prevent tissue damage resulting from inflammation.

"Through research on tuberculosis, we discovered a new way that the immune system response is controlled," said lead author Joel Ernst, MD, director of the Division of Infectious Diseases and the Jeffrey Bergstein Professor of Medicine at NYU Langone Medical Center. "Further study may reveal treatments that could be useful in control of inflammation and tissue damage in certain infections and autoimmune diseases."

In this study, researchers looked at interferon gamma responses in epithelial and endothelial cells to control tuberculosis in mice. Cells such as epithelial and endothelial cells were found to respond to interferon gamma by producing an enzyme, indolelamine-2-3-dioxygenase (IDO), that converts the amino acid tryptophan to products called kynurenines. These kynurenines inhibit the production of Th17 cells, the lymphocytes that contribute to tissue-damaging inflammation.


The study's co-author is Ludovic Desvignes, PhD of the Department of Microbiology at NYU Langone Medical Center. The research was funded by grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health in Bethesda, Maryland.

About NYU Langone Medical Center

NYU Langone Medical Center is one of the nation's premier centers of excellence in healthcare, biomedical research, and medical education. For over 168 years, NYU physicians and researchers have made countless contributions to the practice and science of health care. Today the Medical Center consists of NYU School of Medicine, including the Smilow Research Center, the Skirball Institute of Biomolecular Medicine, and the Sackler Institute of Graduate Biomedical Sciences; the three hospitals of NYU Hospitals Center, Tisch Hospital, a 705-bed acute-care general hospital, Rusk Institute of Rehabilitation Medicine, the first and largest facility of its kind, and NYU Hospital for Joint Diseases, a leader in musculoskeletal care; and such major programs as the NYU Cancer Institute, the NYU Child Study Center, and the Hassenfeld Children's Center for Cancer and Blood Disorders.

Tuesday, December 22, 2009

CAPTURED! When a non-profit accepts corporate sponsors, agendas change

Too many of our non-profits accept money from Big Pharma and Big Health Insurance corporations to 'sponsor' an activity or a website. It is hard to resist the money for the financially struggling non-profit.

Having once been a trustee of non profit Trust (SCEET) that was supposed to provide low cost health related insurance to local school districts in southern California, I have some insight into what happens to the non-profit as its being captured.

The good intentioned directors of the non profit see that with a bit more financial support they can do so much more to help victims of disease or disability that their organization was formed to help. Besides the company representative offering financial support assures the director that there are no strings attached to the financial offer. the offer is pure charity to help the organization. The rep for the big corporation is such a nice guy. Why he invited me to a sky box in XYZ stadium to watch our local professional sports team. The rep said the sky box was already paid for by his company, why don't I come along to the game? I really like this guy and with no strings attached, how could accepting the money being offered hurt anyone?

The problem is in a short time the extra income becomes crucial to running the non-profit. The directors do not see how they can do all they want to do without this money. When an issue comes up that might make that "nice rep" unhappy or perhaps result in less or no 'sponsorship' the following budget year, it becomes so easy to just go along with what that nice rep wants the board of directors to do. The rep is a lot more real and present than the victims of disease or disability that the board of directors is supposed to represent. It is such an easy slide from accepting a sponsorship to making the easier decision that helps the company to complete capitulation to the wishes of the sponsors.

I wrote about this problem before regarding the Lupus Foundation of America. Read here:

Here is an editorial in the Anderson Indiana, Herald Bulletin by someone who agrees with me on this issue. He is specifically speaking about the seemingly unwholesome relationship between the AARP and one of its main corporate sponsors, United Health Care.

Published December 19, 2009 11:00 pm - The Beatles might have been right, money might not buy you love. But the insurance companies seem to know something else, money buys you the AARP’s betrayal of seniors.

Viewpoint: AARP gets money top promote insurance company

The Beatles might have been right, money might not buy you love. But the insurance companies seem to know something else, money buys you the AARP’s betrayal of seniors.
A few days ago June Lyle, state director for the AARP, commented at a local Triad meeting that AARP was supporting legislation on the health care reform bill that would “allow” seniors under 65 to seek health insurance through the private sector. Those over 65 could keep their Medicare and Medicaid coverage.

In other words, seniors under 65 will be at the mercy of the insurance companies until they reach an age when they can no longer be profitable for the companies.
Am I the only one that sees a problem here? AARP endorses United Health Care for a fee. That’s right. The AARP receives money to endorse an insurance company. The AARP presents itself as an advocate for seniors. Seniors rely on the AARP for information the way some consumers rely on Consumer Reports magazine. The difference, Consumer Reports does not accept money from the companies it reports on, the AARP is receiving money from an insurance company to endorse it.

Making matters worse, their ads would lead you to believe AARP was the insurance company. If AARP is to remain a nonprofit organization it would be to their best interest not to blatantly become involved in this type of conflict of interest. Until then, the AARP is no more credible than any other paid celebrity endorsement.
What insurance company would not like to take the money paid on insurance premiums until you become a major health risk, like someone over 65, and say let Medicare take of them from here on out? How long do you think the Medicare fund would last until it was totally depleted?

The answer seems to lie in not trusting either the government, AARP, or the insurance industry.

If you remember, Medicaid Part D was draining the seniors of their money with exorbitant pricing of medicine. It was not until several large discount stores, grocery stores, and drug stores started selling generic medicine for $4 a prescription that the cost came down. All along, we had been price gouged by the drug companies and the government was totally complacent.

It appears the government decided not to compete with the unregulated health care program (similar to not competing with communication companies, oil companies and food industries). We can only hope the same companies that saved us from outlandish costs of medicine will step forward and do the same for health care.

Public option appears to be dead, and with the health care and HMO industries spending 52.8 million and employing approximately three lobbyists per law maker, it is doubtful they won’t get their money’s worth. With the AARP in the insurance industry’s pocket, they obvious can’t be counted on to defend us.

In the end, maybe only the discount stores will be able to save us.
How does WAL-CARE sound to you?

Darrell E. Baylor, president of United Senior Action, Anderson Chapter, is an Anderson resident

Monday, December 21, 2009

Closing in on environmental causes for autoimmune diseases

Below is an identical twins study of identical twins with identical DNA and indentical genes however ONLY ONE has autoimmune disease.

The problem is as we age and are exposed to environmental insults, chemicals, disease etc, these insults change the way are genes work. This change in function is called an epigenetic change. The genes remain the same but something affects their ability to function.

In this study one twin had genes whose functions were changed to cause autoimmune disease and the other twin did not.

These Cold Springs Harbor researchers were able to determine the difference in gene function that lead to autoimmune disease in this case lupus.

The next step is to find out what causes the changes--those pesky environmental insults-- and then how to reverse those changes to get normal HEALTHY gene function back again.

We know that autoimmune disease turns on suddenly. It likely can be turned off just as quickly when we find the right switches which our friends at Cold Harbor have done. Next let's get those switches back on and all of us back to good health.

There are already a class of drugs that can reverse changes to genes that go by the acronym HDAC. We need a lot more work done on these drugs so they can target specific parts of our genes that need turning back on.

Finding the gene that have been affected to cause autoimmune disease is a big step forward.

Come on researchers let's get to the cures sooner than later. Get those genes turned on again.

Good job Cold Harbor Laboratory on this first big step.

Cold Spring Harbor Laboratory
Genomes of identical twins reveal epigenetic changes that may play role in lupus
Identical twins look the same and are nearly genetically identical, but environmental factors and the resulting cellular changes could cause disease in one sibling and not the other. In a study published online in Genome Research (, scientists have studied twins discordant for the autoimmune disease lupus, mapping DNA modifications across the genome and shedding light on epigenetic changes that may play a role in the disease.

Because the genetic makeup of monozygotic twins (commonly known as identical twins) is nearly identical, phenotypic traits and heritable diseases are often concordant, manifesting in both siblings. However, some phenotypes and diseases such as autoimmune disease can arise in only one sibling, suggesting other factors such as environment likely play a role in determining phenotypic differences.

Epigenetic modifications, cellular changes that can influence expression of genes, are now widely recognized to influence phenotype and frequently occur in disease. Furthermore, environmental factors such as diet and chemical exposure can change the epigenetic status of genes. Recent research has identified epigenetic modifications at several aberrantly regulated genes in autoimmune diseases such as systemic lupus erythematosus (SLE), and other studies have suggested that epigenetic differences are associated with phenotypic discordance between identical twins.

In this work, researchers from Spain and the United States performed the first genome-wide high-throughput analysis of a specific epigenetic modification, DNA methylation, in the context of autoimmune disease. Taking advantage of the identical genetic background in monozygotic twins, the group directly compared DNA methylation in healthy twins and twins discordant for autoimmune diseases, including SLE, looking for changes that could be related to pathogenesis in one sibling and not the other.

In the case of SLE, the group found widespread changes in DNA methylation status at a significant number of genes. Dr. Esteban Ballestar, senior author of the study, noted that this is the largest number of genes exhibiting DNA methylation changes observed in an autoimmune disease to date, and includes genes previously implicated in SLE pathogenesis. Importantly, Ballestar's team found that a significant number of the novel differentially methylated genes are related to multiple immune system functions and are potentially linked to SLE.

"Our study suggests that the effect of the environment or differences in lifestyle may leave a molecular mark in key genes for immune function that contributes to the differential onset of the disease in twins," Ballestar said. Most studies of DNA methylation and human disease have been in the context of cancer research, Ballestar noted, and he hopes that this work will attract more researchers to also investigate DNA methylation alterations in autoimmune disease and other disorders for the development of therapies.
Scientists from Bellvitge Biomedical Research Institute (Barcelona, Spain), Christian-Albrechts-University Kiel (Kiel, Germany), Centro de Investigacion Principe Felipe (Valencia, Spain), the Broad Institute of MIT and Harvard (Cambridge, MA), Brigham and Women's Hospital (Brookline, MA), the National Institute of Environmental Health Sciences (Bethesda, MD), Gregorio Marañon Hospital (Madrid, Spain), ISCIII Center for Biomedical Research on Rare Diseases (Valencia, Spain), Institut de Medicina Predictiva i Personalitzada del Càncer (Badalona, Spain), and the University of Oklahoma Health Sciences Center (Oklahoma City, OK) contributed to this study.
This work was supported by the Spanish Ministry of Science and Innovation, the National Institute of Environmental Health Sciences, the National Institutes of Health, the Alliance for Lupus Research, the US Department of Veterans Affairs, and a BEFI Predoctoral Fellowship from the Carlos III Health Institute, Spain.
Media contacts:
Esteban Ballestar, Ph.D. (Bellvitge Biomedical Research Institute;, +34 932607133) and Diomaris Gonzalez (Alliance for Lupus Research; have agreed to be contacted for more information.
Interested reporters may obtain copies of the manuscript from the Genome Research Editorial Office (; +1-516-422-4012).
About the article:
The manuscript will be published online ahead of print on December 22, 2009. Its full citation is as follows: Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O'Hanlon TP, Rider LG, Jacinto FV, Lopez-Longo FJ, Dopazo J, Forn M, Peinado MA, Carreño L, Sawalha AH, Harley JB, Siebert R, Esteller M, Miller FW, Ballestar E. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res doi:10.1101/gr.100289.109.
About Genome Research:
Launched in 1995, Genome Research ( is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.

About Cold Spring Harbor Laboratory Press:
Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory's five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.
Genome Research issues press releases to highlight significant research studies that are published in the journal.

Sunday, December 20, 2009

Dose of sibling stem cells, can cure sickle cell, autoimmune disease next?

Our tax dollars are at work and paying off in chances for new cures for a host of genetic diseases by using new less toxic and less fatal techniques to fix our immune systems.

Where is it happening? At a division of the National Institute of Health called the National Institute of Diabetes, Digestive and Kidney Disease

What is happening? The researchers at this institute and the Institutional Review Board had the courage to try a new kind of stem cell transplant that can cure without the patient's immune system being destroyed in its entirety. The patient/recipient's bone marrow is only partially destroyed to give room for HEALTHY donor cells to grow. The two bone marrows grow together as one in a process called mixed chimerism. The healthy part of the new bone marrow/immune and blood system cures the defective part of the patient's immune system.

The procedure written about below is being used in this case for a blood disorder, sickle cell anemia, but it could just as well be used for an autoimmune disease.

For most of us only need a few healthy immune cells to stop our disease.

In traditional therapies the bone marrow, the seat of the blood and immune system in a patient/recipient's body, is TOTALLY destroyed by radiation and/or drugs before donor blood and immune system cells are given to the patient/recipient. The donor cells can then have room in the now empty patient/recipient's bone marrow to reproduce and fully replace the destroyed immune system in the patient. Most of the time that happens, but not always.

Sometimes there is only
(1) partial replacement and the patient/recipient is left with a less than fully functioning immune system for the rest of their lives.
(2)Sometimes an infection appears in the patient/recipient before the immune system has time to fully regrow. The infection then often kills the patient/recipient.
(3)Sometimes GvHD starts a few years later after an apparently completely successful transplant. For unknown reasons the new immune system of the donor starts attacking the patient recipient's body. This horrible process is called Graft Versus host Disease or GvHD. The skin and mucous membranes of the patient/recipient are dissolved away by the donor's immune system. Overwhelming infection results, the patient often dies.

The lifetime success rate for full replacement of bone marrow and immune system is about 75% at best which is far better than zero chance for a cure. This full replacement procedure does work and is a life saver.

A teacher friend of mine contracted leukemia in the early 1990's and was given a full bone marrow/immune system replacement using her siblings bone marrow cells. That teacher is alive and well today. She would have died of the leukemia, more than 15 years ago without the full replacement of her bone marrow. In cancer full replacement is necessary to make sure all the cancer cells are gone.

In autoimmune diseases and blood disorders without cancer, only a relatively small number of healthy cells are needed.

While full replacement can work, researchers continue to look for better methods with higher life time success rates. This mini transplant protocol at NIDDK looks like a good one.

The idea of not completely destroying the patient's immune system has been used before with different drugs and amounts of radiation. Read about recent try with this technique at Johns Hopkins here:

If a best practices procedure can be found and codified, then many other hospital bone marrow centers might FINALLY have the courage to give it a try. I am hoping for someone at the UCLA or UCSD bone marrow transplant centers here in Southern California to have this kind of courage soon. I would like to see my youngest son walk and run again.

I especially hope they take note of the remarkable success of the Italian and Israeli teams of researchers in using massive infusions of donor T regs days before the donor's immune cells are given to the patient. Read more here:

Here is the article from NIDDK a division of our NIH paid for by our federal income tax dollars. Hooray for the federal government!

N Engl J Med. 2009 Dec 10;361(24):2309-17.

Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.
Hsieh MM, Kang EM, Fitzhugh CD, Link MB, Bolan CD, Kurlander R, Childs RW, Rodgers GP, Powell JD, Tisdale JF.

Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.

BACKGROUND: Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease.

METHODS: Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward.

RESULTS: All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean (+/-SE) donor-recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3+/-8.6% and 83.3+/-10.3%, respectively, in the nine patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0+/-0.3 and 12.6+/-0.5 g per deciliter, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient.

CONCLUSIONS: A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor-recipient chimerism and reverse the sickle cell phenotype. ( number, NCT00061568.) 2009 Massachusetts Medical Society

Tuesday, December 15, 2009

Finally! New kind of asthma treatment--blocking mast cell activation

For that last twenty years all we have gotten from Big Pharma and drug researchers for new treatments of asthma is the same old steroids and antihistamines just slightly reformulated, so they can be patented over and over again. Nevertheless these "new", "reformulated" same old, same old medications do exactly the same job and help in the exactly the same way. Those that have symptoms not helped by these medications (like me) are given nothing new. Just big hype as a 'brand new' antihistamine is released.

However, now finally someone out there is running clinical trials for what could be a revolution for allergies, asthma, and those like me with hypersensitivities to many foods and meds apparently due to dysregulated mast cells. (Mast cells are a kind of stationary white blood cell. Millions and millions line the surfaces of all wet and dry epithelial tissue--skin and mucous membranes).

Improperly functioning mast cells are not just a problem for allergy and asthma. There has also been evidence that when mast cell activation (degranulation) is not well controlled in folks with autoimmune disease that their disease progression is faster and more severe. So this new med has the potential to alleviate some autoimmune symptoms as well. Fingers crossed. My typing to G-d's ear.

I hope this new med is a home run and not another Osiris Prochymal disappointment (scam?). I dare not hope too much. I was crushed by the failure of Prochymal after my hopes were raised so high. If only there really was a way to get healthy immune cells to live inside of us who have immune related disorders. Imagine if healthy immune cells could get inside and regulate our malfunctioning immune cells. Cure! Freedom! Life again!

I hate being stuck with the crummy immune system I was born with. Far worse is the immune system that gave my youngest son, Paul, psoriasis, psoriatic arthritis, and ankylosing spondylitis. If only my wife could give a few of her immune cells to Paul. There is supposed to be mother/son privilege for cell swaps. Come on someone give it a try with Paul and my wife. Or if my mother (or brother or sister) were healthy enough to give me some of their nicely functioning immune cells. I want a big batch of IL-10 producing T regs first.

Not that everyone in my birth and married families is not willing to donate and receive. But try to find a researcher/doctor who will try such things. No luck. None zero. All a bunch of cowards out to protect their "career investment" instead of finding cures as fast as possible. That is why Prochymal's promise of not needing to match HLA types when infusing someone else's immune cells seemed so wonderful. Too good to be true always is. I hope the folks who hyped the lie at Osiris are happy with their piles of stock money that they undoubtedly made by hyping the "lie".

Anyway here is the article about blocking mast cells to stop allergies. Please immune god(s), please let this one work. Aren't you tired of torturing us?
Still seem to have nasal infection. Seems no worse. Saw another doctor today. A really nice one. He is trying a different formulation of the same topical ointment I am using it to stop the infection so that I do not have to apply ointment with a super long "Q tip" which may be irritating the tissue.

Oxagen Announces Completion Of Recruitment In Phase IIb Dose Range-Finding Clinical Trial In New Oral Treatment For Asthma
Main Category: Respiratory / Asthma
Also Included In: Clinical Trials / Drug Trials
Article Date: 10 Dec 2009

Oxagen Limited, a drug discovery and development company specializing in inflammation, announced that the recruitment for its double blind, randomised, placebo controlled Phase IIb clinical trial in asthma with OC000459, its lead oral CRTH2 (DP2) antagonist, has now been completed.

The study, which was initiated in mid May 2009, is expected to complete by the end of Q2 2010. It involves 440 asthmatic patients with moderate persistent asthma who will be randomised to one of three possible dose levels of OC000459 or placebo by oral tablet for a 12 week dosing period, with lung function (improvement in clinic FEV1) being the primary end point.

The purpose of the study is to determine the magnitude of further improvement in lung function and asthma symptoms on longer term therapy and to define the optimal once daily oral dose of OC000459.

Mark Payton PhD, Oxagen's Chief Executive Officer said "This represents an exciting time for Oxagen and a key phase in the clinical development of this compound following our recent successful proof-of - concept studies in both asthma and allergic rhinitis. We believe oral CRTH2 antagonists offer a valuable contribution to respiratory medicine and this study maintains Oxagen's position as one of the leading players in this field."

The Phase IIb trial follows the successful completion of a Phase IIa programme in which four Phase IIa trials were completed with efficacy demonstrated in asthma and allergic rhinoconjunctivitis. Over 600 subjects have been treated with OC000459 to date and results so far indicate the drug to be well tolerated.

Oxagen recently completed a £16 Million ($26.7 Million) Series C financing led by Novartis Venture Funds. The proceeds of the funding are being used primarily to advance the Company's CRTH2 antagonist programme in inflammatory and respiratory diseases, including the completion of this Phase IIb clinical study of OC000459 in moderate persistent asthma.

About Oxagen

Oxagen is a biopharmaceutical company building a novel drug pipeline with a focus on inflammatory and respiratory diseases. Oxagen's pipeline of novel small molecule drugs is based on targets validated in man.

Oxagen was established in April 1997. The Company is based in Milton Park, south of Oxford. For more information on Oxagen, please visit

About CRTH2 and OC000459

The G-protein coupled receptor, CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells also known as DP2) mediates allergic responses by interaction with the mast cell product prostaglandin D2. There is now overwhelming evidence that CRTH2 plays a central role in the recruitment of leukocytes and their activation to elaborate Th2 cytokines in allergic disease, findings which highlight the potential therapeutic utility of CRTH2 antagonists.

OC000459 is a potent, selective and orally active CRTH2 antagonist, effective in reducing the recruitment and activation of Th2 lymphocytes, eosinophils and other cell types to sites of allergic inflammation.

Monday, December 14, 2009

Tuberculosis research discovery lends hope for autoimmune diseases

Researchers at the University of Washington discovered that a protein secreted by skin and mucous membranes (wet and dry epidermis) called MMP9 causes infections to be more severe. Blocking it in mice leads to less inflammation and less disease.

Perhaps it will become a target for autoimmune diseases as well. I cannot help wondering if my susceptibility to infections and my son's terrible set of autoimmune diseases might be tied to a biochemical pathway that has this or a similar protein in it.
I go to another ENT tomorrow. I still have an active infection in my nose that is 'controlled' by the topical I put way up inside but not killed. It is painfully bloody high up inside. The topical in now being noticed by my insane immune system and I am beginning to itch intently, but have no choice but to use it. I will try to get Zyvox, a new pill antibiotic, but its use is restricted. I went to the ER today to talk to the doctor I saw a week ago that gave me the sulfa drugs that caused my immune system to itch so violently, but after parking in the lot and getting out of the truck, I just could not get up the courage to go in. There were so many sick people and I just could not get over an illness. Stupid in the 21st century to force immune compromised folks to go to the most infectious dangerous places to get care. Why not use the computer. i have a camera built in to this one. Most do now a days. Doctors sure do not like to change practices.

Instead of the ER I drove to a nearby salt water lagoon near the corner of Highway 78 and Interstate 5 I had not been to since I memorized all the names and photos of California birds a couple of years ago. I have been housebound for eight years. I used to get bored sometimes and it was fun memorizing the pictures and names in a couple of bird books. At the lagoon, I saw a Belding or Savannah sparrow at the edge of the road, western Grebe in the middle of the lagoon, and I am pretty sure I saw a Sora come out of the reeds for a second and go back in. Great birding as they say.

Here is the article: The URL is at the end of the article.

Finding How To Block The Infection Pathway May Lead To New Therapies For TB And Other Disorders
12 Dec 2009

Scientists have discovered a signaling pathway that tuberculosis bacteria use to coerce disease-fighting cells to switch allegiance and work on their behalf. Epithelial cells line the airways and other surfaces to protect and defend the body. Tuberculosis bacteria co-opt these epithelial cells into helping create tubercles: the small, rounded masses characteristic of TB. The tubercles enable the bacteria to expand their numbers and spread to other locations.

By inciting parts of the immune system to go into overdrive, this same molecular signaling pathway may play other roles in inflammatory conditions such as arthritis and some forms of heart disease and cancer

"If we could keep this pathway from inciting the host immune system, we may be well on the way to finding innovative new therapies against TB, as well as other serious disorders," said the senior researcher on the study, Dr. Lalita Ramakrishnan, University of Washington (UW) associate professor of microbiology, medicine, and immunology. The results appear in the Dec. 10, 2009 express edition of Science.

Global health researchers are eager for new treatments for TB because many strains worldwide have become resistant to standard antimicrobials. Blocking a host pathway that the bacteria use would be an entirely different approach, Ramakrishnan explained, because it would keep the body from allowing the infection to take hold and be sustained, rather than a treatment aimed at killing the bacteria themselves. A host pathway blocker, if one becomes available, might also be quicker than current therapies, which take a long time to subdue the TB infection.

"Most diseases, such as high blood pressure and depression, are already being treated by blockers and inhibitors of host enzymes and pathways," Ramakrishnan noted, "Many of these turn down certain cell signals as part of their therapeutic action. We and some other researchers are now exploring the possibility of blocking or inhibiting molecular mechanisms in the body to prevent or treat infectious diseases as well. "

Earlier studies in the zebrafish by the Ramakrishnan lab demonstrated that TB tubercles were not, as previously thought, the way that the body walls off the bacteria to protect itself. Instead, these nodules (also called granulomas) are hubs for bacteria production and distribution. Uninfected macrophages - the body's frontline soldiers that can eat and destroy many bacteria - are recruited to the nodules, where they become TB-infected. However, the TB bacteria are able to grow in the macrophages, rather than being killed, likely by dampening the macrophages' defenses.

So by wooing more macrophages into the granuloma, the bacteria can use them to expand further. Some germ-laded macrophages then move to a new location, where they again attract more macrophages. New tubercles form and the scene is repeated.

Ramakrishnan and her research team have identified a molecular mechanism by which the mycobacteria that cause TB induce the body to form these production and distribution nodules. Researchers have long known that TB virulence is associated with a small protein the bacteria secrete, called ESAT-6.

Ramakrishan's group now has found that this secreted bacterial protein induces epithelial cells - the cells that make up membranous tissue covers inside the body - to produce an enzyme called MMP9. This enzyme has many functions including breaking down gelatin - a connective tissue protein - into its components. In people, the presence of MMP9 is associated with increased susceptibility to infection and worse outcomes. The findings of this new study explain why this might be the case. MMP9 is also implicated in the development of several non-infectious inflammatory conditions, like arthritis, as well as heart disease and cancer.

Epithelial cells were once thought to be bystanders as tuberculosis took hold, according to the research group. However, their latest findings suggest that secretion of MMP9 by epithelial cells is amplified in the vicinity of a single TB infected macrophage. The activity of this enzyme draws in uninfected macrophages to join the infected macrophage to form and expand the granuloma.

"TB bacteria may have a two-prong strategy," said the first author of the Dec. 10 Science Express report, Dr. Hannah E. Volkman, who recently received her Ph.D. from the UW Molecular and Cellular Biology Program, "whereby the bacteria simultaneously suppress the macrophages inflammatory programs in order to create a hospitable niche inside them, while prodding epithelial cells to signal more macrophages to arrive and be unwitting participants in their home expansion project."

The researchers genetically "knocked out" MMP9 production in zebrafish embryos to see if that made them more resistant to TB. After TB infection, these embryos indeed had greater survival rates, fewer bacteria, and fewer granulomas than their normal, MMP9-producing siblings. This finding suggested that intercepting the production of MMP9 in epithelial cells should be further studied as a possible TB therapy.

"These novel findings," said Dr. William Parks, a UW professor of medicine and director of the UW Center for Lung Biology who was not part of this study, "point to new ways in which the body's resident cells can effect an inflammatory response and may have relevance beyond TB infection. The pathogen-to-epithelium-to-macrophage pathway they uncovered should provide several new avenues that could be targeted for intervention."

Co-authors of the article, "Tuberculous Granuloma Induction via Interaction of a Bacterial Secreted Protein with Host Epithelium," in addition to Volkman and Ramakrishnan, are Tamara C. Pozos, a former UW infectious disease fellow who is now on the faculty of Children's Hospital and Clinics of Minnesota; John Zheng, a UW medical student; J. Muse Davis, an M.D./Ph.D. student at Emory University; and John F. Rawls, assistant professor of cell and molecular physiology, University of North Carolina, Chapel Hill.

The study was funded by the Burroughs Wellcome Fund, Pew Scholars Program, National Institutes of Health, American Heart Association, Pediatrics Infectious Disease Society, Children's Health Research Center, and a National Defense Science and Engineering fellowship

Source: Leila Gray
University of Washington

Article URL:

Main News Category: Tuberculosis

Friday, December 11, 2009

New B cell hope, a humanized Rituxan from Genetech

A humanized B cell depletion therapy is successful in phase III clinical trials. This means that the FDA approval can likely be no more than two or three slow agonizing years away.

The only sad thing about this news is that this new B cell depletion therapy, monoclonal antibody is only "humanized". It is not a fully human monoclonal. Humanized means it is about 90% human. There will still be a chance for adverse reactions to the 10% of it that is mouse protein.

But since a portion of our B cells drive our autoimmune process with autoantibodies that they produce any new B cell depletion therapeutic product is a welcome addition to our arsenal against autoimmune.

Currently Rituxan is the only B cell depletion therapy on the market and it is about half mouse protein. No drug can be in the US market without FDA approval and Rituxan has that approval exclusively among drugs that could deplete B cells.

We know from many many trials with various autoimmune diseases that B cell depletion can turn off almost any autoimmune disease for months or even years. On the downside of B cell depletion it that dormant viruses, particularly the deadly PML virus, can be awaken when B cells are depleted. These virus without B cell to keep them in check can be fatal. Luckily reawakening of potentially deadly viruses is rare.

Here is the story:

Business News - Local News
Friday, December 11, 2009, 11:04am PST
Genentech, Biogen: RA drug study positive
San Francisco Business Times - by Ron Leuty

A late-stage rheumatoid arthritis drug under development by Genentech Inc. and Biogen Idec Inc. showed that it improved the signs and symptoms of the disease.

South San Francisco-based Genentech, a subsidiary of the Roche Group, and Cambridge, Mass.-based Biogen Idec (NASDAQ: BIIB) said they will submit the data from the Phase III trial for presentation at an upcoming medical meeting.

The study is the first of four needed to win approval of the humanized monoclonal antibody ocrelizumab, which is similar to Genentech and Biogen Idec’s Rituxan, from the Food and Drug Administration.

The study combined ocrelizumab with methotrexate —the gold standard for treating rheumatoid arthritis — in patients with active RA but who had an inadequate response to prior treatment with methotrexate. It consisted of 1,015 patients and recorded their responses at 24 weeks and 48 weeks.

"These results are significant because they are the first data from a large Phase III trial to show that a humanized antibody targeted at B-cells improves the signs and symptoms of rheumatoid arthritis," said Dr. Hal Barron, Genentech's chief medical officer.

Deeper data about the study wasn’t released, but the companies said a higher percentage of serious infections occurred in those receiving ocrelizumab versus those receiving a placebo. Overall adverse events were comparable between the two groups, the companies said.

Results of the three other required Phase III studies of ocrelizumab are expected in the first half of 2010, the companies said.

Roche and Biogen split Rituxan profits, with 60 percent of the U.S. profit going to Roche, according to the Reuters news agency. Biogen would receive 30 percent of the profit from both Rituxan and ocrelizumab if the new product is approved, Reuters said.

A radiographic study of ocrelizumab in patients who hadn’t previously been exposed to methotrexate was placed on clinical hold and dosing was stopped.

Email Ron Leuty at / (415) 288-4939.

Mast Cells and hypersensitivity a connection

Another article that seems to confirm my suspicions that my hypersensitivity reactions to foods, drugs especially antibiotics and insect stings are all caused by defective mast cells. In addition my son's autoimmune disease severity could also be as a result of mast cell malfunction. I mentioned that to a rheumatologist who was treating Paul three years ago. She called it nonsense. Of course she also was the rheumy who did not know the names of all six biologicals approved at that time.

Notice in the article below that our old friend, IL-10 is mentioned. What ever happened to the genetically engineered gut microbs that produce high levels of IL-10? There was a guy in England that created them several years ago. He thought they could help in asthma and allergy. He was going to give them to patients. There was a small problem with them being GMOs but I thought he could have gotten past that problem. Sadly I have not heard anything since the initial article.

Read more here:
and here:

Last night I took a few grains of crushed up Xanax which was enough to calm me and allow sleep. I was able to get nine hours, best night in a week.

I woke up in the middle of the night with breathing difficulties, centering on my lower right lung. It would not clear with my usual steaming and asthma breathing exercises. I woke up my wife and she brought me tea which helped. This morning I am feeling pain inside that lung in the same place as the congestion last night. Hope it is not the bacteria in my lungs now. I think it might be from hunching over the computer and typing. I am not in my usual computer typing place as I am restricted to master bedroom and bath to protect our son Paul from catching what I have.

Have not gone to ER. I hate the place. Sick people are one thing but the disrespect the medical community shows to those of us with hypersensitivity reactions is really insulting. Infection control procedures seemed good at the ER unlike the EMT's office where they seemed to be practicing in a 19th century pre microbe theory of disease mode.

I have found a code under Zyvox restrictions that would allow me to get it due to failure of first line antibiotics. The last time I had it I had a syncope episode after sixth pill, may not have been related to the medication but I stopped anyway as the infection had ended. If I have another episode this time I figure it is better to faint away than to have my skin itch so bad I could hardly keep from tearing off. What torture hypersensitivity reactions are. Too bad our doctor friends do not seem to be able to emphasize with people who get these kinds of reactions.

Am waiting to feel worse before I go to hospital ER. The ER folks like you to be really well advanced with an infection before they take you seriously.

Here is the article about mast cells with its link:

World Allergy Organization Journal:
October 2009 - Volume 2 - Issue 10 - pp 224-232
doi: 10.1097/WOX.0b013e3181c2a95e
Review Article

Mast Cell Regulation of the Immune Response
Ryan, John J. MD; Morales, Johanna K. MD; Falanga, Yves T. MD; Fernando, Josephine F. A. MD; Macey, Matthew R.


Mast cells are well known as principle effector cells of type I hypersensitivity responses. Beyond this role in allergic disease, these cells are now appreciated as playing an important role in many inflammatory conditions.

This review summarizes the support for mast cell involvement in resisting bacterial infection, exacerbating autoimmunity and atherosclerosis, and promoting cancer progression.

A commonality in these conditions is the ability of mast cells to elicit migration of many cell types, often through the production of inflammatory cytokines such as tumor necrosis factor.

However, recent data also demonstrates that mast cells can suppress the immune response through interleukin-10 production.

The data encourage those working in this field to expand their view of how mast cells contribute to immune homeostasis.

Thursday, December 10, 2009

Last post

I made it though the night with a dose of sulfa in the morning, I still itched terribly but my nose was better.

I went to my doctor today and told him about the problem. He said I should stop taking the oral antibiotics and concentrate on the topical.

I did that today. Sadly it did not work. The infection is back with a vengeance. My the inside of nose really hurts again for the first time since I started the oral antibiotics. It is very bloody with bright red blood again. This morning it was all dead with only brown blood coming out. Had I been able to tolerate the sulfa drug antibiotic a few more days, I would have been cured.

I expect to go to the hospital in next day or two. I expect to die there. The infection is growing so fast that they will give me intravenous antibiotics. I cannot live. My immune system is too reactive. I will go into anaphylaxis or have my airways swollen shut.

Sure wish I could go back in time and know how I got this bacteria and make sure I did not get it. Too bad.

Life has been great except for my allergies.

I made it to 56 years way past my expiration date. Most folks with my allergies die much younger. I was hoping for a cure. It did not happen.

My only chance would be Tblisi, Georgia half a world away. I would be dead before I got my passport and transportation there. This is a VERY aggressive bacterial strain. It must have multiple ways to disarm the human immune system.

Actually I just thought of one more hope, the antibiotic Zyvox. It is supposed to kill staph but it is also supposed to be restricted to hospital acquired multi drug resistant strains of enterococcus according to my primary care doctor. Perhaps I can get an exemption. Perhaps it will work.

Wednesday, December 9, 2009

IL-22 too much or too little implicated in psoriasis, colitis, and pneumonia

Below is a series of articles showing the critical importance of controlling IL-22. We need ways to boost it for some diseases and ways to turn it down for others. When will drugs be developed for IL 22?
Update on my progress with the sulfa reaction I have been mentioning in last few blogs.
I itch so bad now. Really terrible. Yep the sulfa drug was a mistake. Stuck between a rock and a hard place. I had to try. If I do not, then the infection wins. Worse I continue to expose my son to this horrible resistant and 'rare' bacteria. His immune suppresants would allow the bacteria to grow even faster than it has in me. And it has been pretty agressive in me. Just does not want to die. Started Thanksgiving day after a series of dry Santa Anas. My right nasal passages cracked a little. The the infection came. Was the bacteria in the cat dander I breathed as I brushed the cat? Was it on my skin and in my nasal passages already from some silent colonization of my body that I was not aware of util the bacteria found a way through my skin? just waiting for a chance to grow? Was it my neighbor who sneezed a giant uncovered juioy sneeze ten yards up wind from me--a stong wind. I always move away from neighbors and others outside but I did not see him or hear him until he sneezed. Does it matter how I got the infection or just whether it dies or I do. Itch Itch Itch

Children's Hospital of Pittsburgh
Children's Hospital scientists identify possible target for prevention and treatment of pneumonia

Results of first-of-its-kind research published in the Feb. 10 online edition of Nature Medicine

Researchers at Children’s Hospital of Pittsburgh of UPMC have identified a key protein target that may be a crucial factor in the development of a vaccine to prevent and new therapies to treat pneumonia, the leading killer of children worldwide.

Research led by Jay K. Kolls, MD, chief of the Division of Pediatric Pulmonary Medicine, Allergy and Immunology at Children’s, identified for the first time the importance of a protein known as interleukin 22 (IL-22) in the immune response to a strain of bacterial pneumonia. In the laboratory, the researchers were able to effectively treat mice with pneumonia by using purified IL-22.

Results of the study are published in the February online issue of Nature Medicine.
“Currently there is no vaccine that covers all kinds of pneumonia and antibiotic treatment is sometimes limited by antibiotic resistance. As acute respiratory infections are the no. 1 killer of children in the world, progress in the development of novel vaccines or new, more effective treatments is critical,” said Dr. Kolls, the Neils K. Jerne Professor of Pediatrics and Immunology at the University of Pittsburgh School of Medicine. “Our results raise the possibility of developing new protein-based therapies using IL-22 to limit or prevent pneumonia.”

Pneumonia causes almost one in five deaths in children under age 5 worldwide – more than 2 million children each year, according to the World Health Organization. It kills more children than any other disease – more than AIDS and malaria combined.

IL-22 and interleukin 17A (IL-17A) are produced by a recently discovered lineage of cells known as T Helper Type 17 (Th17). Children’s researchers found evidence that the Th17 cell lineage and its cytokines IL-22 and IL-17A have evolved to promote host defense against certain infections in the lung caused by extracellular pathogens.

This is an important discovery because the Children’s research team proposes that by stimulating the Th17 arm of the immune system, they can more efficiently treat bacterial pneumonia. Furthermore, the researchers propose that Th17 is a less critical pathway for intracellular bacteria such as those that cause listeria and tuberculosis – thus raising the potential to target this pathway in diseases of chronic inflammation such as rheumatoid arthritis or inflammatory bowel disease without increasing susceptibility to these intracellular pathogens.
--Scientists discover cells that control inflammation in chronic disease
Imperial College London ontact: Lucy Goodchild
A new type of immune cell that can be out of control in certain chronic inflammatory diseases, worsening the symptoms of conditions like psoriasis and asthma, is described for the first time this week in the Journal of Clinical Investigation.
The authors of the study, from Imperial College London, the Istituto Dermopatico dell'Immacolata in Rome and the Center of Allergy and Environment (ZAUM) in Munich, hope their discovery could lead to new treatments for these diseases that would bring the cells under control.

The new cell described in the study, called a Th22 cell, is a kind of T-helper cell. These cells are white blood cells that help to activate other immune cells when the body is infected by a pathogen, such as a virus or bacterium. They also control inflammation in the body to help fight off infection.

According to the new study, Th22 cells play a special role in overseeing and coordinating immune cells that cause inflammation. In chronic and allergic inflammatory diseases like psoriasis and allergic eczema, Th22 cells appear to be malfunctioning, leading to excessive inflammation, which can worsen symptoms.
The researchers hope that it may ultimately be possible to treat chronic skin and possibly also airway diseases by targeting Th22 cells with new drugs.

Dr Carsten Schmidt-Weber, one of the lead authors of the study from the National Heart and Lung Institute at Imperial College London, said: "We are seeing an increase in chronic diseases like skin and airway disease because of changes in people's lifestyles. These diseases can have a big impact on people's lives and patients can face a constant battle to keep their symptoms at bay. We are very excited about discovering this new subset of T-helper cells, as we believe it could provide a new target for the treatment of chronic inflammatory diseases in the future."

The researchers discovered Th22 cells by looking at skin samples from people with psoriasis, atopic eczema and allergic contact dermatitis. They analysed the samples and found a completely new type of cell. The researchers examined the molecules the cells made and found that one of them was a signalling molecule called interleukin-22 (IL-22). This signalling molecule warns tissues that inflammation or infection is going to occur, so the tissues can get ready to recognise and attack pathogens or protect themselves against inflammation. The effect of this can be either protective or detrimental - for example, IL-22 molecules and Th22 cells can cause skin cells to grow too quickly, resulting in painful, flaking skin.

The authors of the new study hope that their new discovery will provide scientists developing treatments for inflammatory disorders with a new cellular drug target. The researchers are now investigating the role of these cells in greater detail and exploring their role in disease progression. In addition, Dr Schmidt-Weber and his colleagues want to know how the cells are generated in the body and whether there is any way to control these cells before they cause unwanted damage.

Gut Instincts: What Harms Some Cells May Protect Against Inflammatory Bowel Disease
19 Dec 2008

In a finding that could lead to improved treatment of chronic inflammatory bowel disease (IBD), Yale University researchers have uncovered a key mechanism in the immune system that appears to offer protection from the disorder. Their work appears in the December 19 issue of Immunity.

IBD is caused by an immune response gone awry. Detecting an inflammatory threat, T helper cells, which boost the body's defense system, overreact. They secrete harmful proteins (cytokines) that destroy the lining of the gastrointestinal tract, causing further inflammation. The Yale team, led by Richard A. Flavell, chair of the Department of Immunobiology, found that the cytokine interleukin-22 (IL-22), which can damage tissue in diseases such as psoriasis, actually seems to play a protective role in the case of inflammatory bowel disease.

"It seems likely that this relates to the type of cell that responds to the IL-22 signal," Flavell said. "Skin cells respond in an inflammatory manner and increase in number - that's psoriasis. In the gut, however, the response to the IL-22 signal is to preserve the life of cells that would otherwise die. IL-22 switches on genes that keep cells alive. We don't yet know why the reaction in the gut is different from that in the skin."

Flavell's team induced colitis in mice and found those that were deficient in interleukin-22 had more severe forms of the disease and higher mortality. In the mice that were protected by IL-22, researchers were surprised to find certain types of white blood cells of the immune system, commonly known as "natural killer cells," acting in ways they had not been known to act.

"Natural killers cells were previously thought to play a role in fighting infection and tumors," Flavell said. "Now, we can see that they also play a role in protecting host tissue from damage caused by an overreacting immune system."

More than half a million Americans suffer from inflammatory bowel disease each year. The most common forms of IBD are Crohn's disease and ulcerative colitis. Treatment most often consists of powerful anti-inflammatory drugs such as prednisone, which can weaken the body's immune response. Severe cases may require bowel resection or permanent colostomy.

Yale scientist Lauren A. Zenewicz, first author of the paper, said the discovery of interleukin-22's protective qualities could lead to treatment for IBD that avoids the side effects of current drug therapies, which can lead to increased susceptibility to disease.

According to Zenewicz, IL-22 only impacts tissues and has no direct effect on the immune response. "This specific targeting will allow us to modulate tissue responses to alleviate tissue destruction during inflammation, while having limited effects on the immune response itself."

Before a new drug treatment based on IL-22 can become reality, however, Zenewicz cautions that more study is needed on its dual nature, to learn why it reacts differently in the context of different diseases. In addition, she said, researchers need to study the impact of a continuous course of IL-22 stimulation. "Gaining a better understanding of both the short-term and long-term effects of IL-22 on different tissues is needed to be able to develop IL-22-related therapeutics," she said.

In addition to Zenewicz, Flavell's team included George D. Yancopolous, David M. Valenzuela, Andrew J. Murphy and Sean Stevens, all of Regeneron Pharmaceuticals, Tarrytown, New York.

Citation: Immunity; Volume: 29; Issue: 6

Helen Dodson
Contact: Vijay Reddy, MD, PhD
Cell Transplantation Center of Excellence for Aging and Brain Repair
Predicting acute GVHD by gene expression could improve liver stem cell transplant outcomes
Tampa, Fla. (July 21, 2008) – Many cell transplants involve the use of stem cells from another human being (known as an allograft), which raises the major concern of the potential for acute graft-versus-host disease (GVHD). GVHD occurs when an immune response is elicited by the grafted cells against the recipient, resulting in tissue damage for the treated individual.
Presently, there are no definitive markers for predicting the development of acute graft-versus-host disease (GVHD) or its progression following the transplant of allogenic stem cells as therapy for liver cancer.
However, in a study published in the current issue CELL TRANSPLANTATON (17:5), researchers at the University of Florida offer a preliminary "molecular signature" based on gene expression for the development of acute GVHD following allogenic hematopoietic stem cell transplants (HSCT).
Despite immunosuppressive drugs, acute GVHD can develop within 100 days post-transplant. Where tissue damage in the skin, liver and gastrointestinal tract is extensive, prognosis can be poor. Although clinicians can identify a well-defined pathophysiological mechanism for acute graft-versus-host disease (GVHD), being able to uncover molecular markers for a patient's potential to develop GVHD would be a significant breakthrough.
"Our study enrolled four acute GVHD patients and four acute GVHD-free patients and noted significant differences in the expression of 1,658 genes between the control and acute GVHD patients," explained Vijay Reddy, MD, PhD, the study's lead author.
Of the 1,658 genes observed, immune-related genes showed the greatest amount of change.
"We observed a predominately pro-inflammatory gene expression profile in acute GVHD patients, consistent with our knowledge of how GVHD develops," concluded Reddy. "Perhaps the most valuable finding was having discovered the possible role for IL-27, IL-22 and Th17 cellular inflammatory responses in the development of acute GVHD."
Future research, said Reddy and colleagues, may want to address gene expression profiling of acute GVHD immediately after noting clinical symptoms, yet before immunosuppressive drugs are administered.
"Nevertheless, this is an important study to help develop biomarkers for determining who is at risk for GVHD following current and future stem cell treatments," said Dr. Paul Sanberg, Distinguished Professor at University of South Florida Health and coeditor-in-chief of Cell Transplantation.
The editorial offices for CELL TRANSPLANTATION are at the Center of Excellence for Aging and Brain Repair, College of Medicine, the University of South Florida and the Diabetes Research Institute, University of Miami Miller School of Medicine. Contact, Dr. Paul Sanberg at or Dr. Camillo Ricordi at