Friday, December 26, 2008

Fix our B cells, Cure Autoimmune Disease

More evidence that a small subset of our B cells are responsible for keeping the autoimmune process going. B cells are the cells that produce antibodies that give us immunity to childhood diseases. Those are among the 80% of our B cells that are the "good guys". We cannot live without B cells manufacturing very specific antibodies for the various pathogens "germs" we encounter throughout our lives. Yet there are some B cells that if not suppressed produce antibodies that attack our own tissues and give rise to the 80 or so named autoimmune diseases examples of which are Rheumatoid Arthritis, psoriasis, Psoriatic Arthritis, Lupus (SLE), Multiple Sclerosis, Scleroderma, etc.

Good News is that there is an FDA approved drug, Rituxan, that can get rid of all the mature B cells. Unfortunately both "good" (protective) and "bad" (autoimmune causing) are eliminated. Losing all the "bad" B cells can turn off our autoimmune disease for weeks to years.

More good news is that the "baby" B cells (immature) are unaffected by Rituxan and they rapidly mature into fully competent "adult" B cells that will protect us against infections.

Bad news is that during the interim between the Rituxan caused death of all the mature B cells and the development of the unaffected "baby" B cells into fully competent "adult" B cells, there is a window of vulnerability to disease and infections for the patient.

Worse news most of us are carrying dormant viruses can become reactivated if the immune system is disabled even temporarily.

The very worst news some of those viruses can kill us if our immune system lacks mature B cells to keep them in check.

The most feared and the most deadly of these dormant horrors is a brain virus with the innocuous initials of PML. Sadly the P stands for Progressive which basically means unstoppable. The M stands for multifocal which means lots of location all over the brain. Worst of all the L stands for Leucoencephalopathy--white patches of dead brain tissue. PML is VERY deadly. I believe the survival rate even with the best possible current medical care is less than 10%. The hidden and undetectable presence of this virus makes any B cell depletion therapy a little scary.

Too bad Rituxan targets all our mature B cells both the kind that protect us from infection and dormant viruses as well as the "bad guy" B cells that cause autoimmune.

Wouldn't it be nice if only the bad guy B cells could be targeted?

What we need is a way to kill only the autoimmune B cells and not the good guy B cells. So far no one has done that even in the research lab.

Or find a way to 'tame' the bad autoimmune B cells, so they no longer act like bad guys. Taming them is very possible and has been done repeatedly in the research lab--both with various kinds of vaccines and with manipulations of immune system to produce more cells that calm down the immune system. The cells that calm down the bad guy B cells are called T regs. T-regs? Yes T regs. No it is not that scary dinosaur with big sharp teeth. The name just sounds a bit like T rex, but T regs are very different. They have the ability to turn off autoimmune disease. Apparently a signal called Interleukin 10 (IL-10) controls their numbers and effectiveness.

Lots of really nifty ways to increase IL-10 from a little bit gross--genetically engineered gut bacteria to pretty darn gross--good old fashioned parasites (hook worms, whip worms) to over the top gross out--fecal seeding of our colon with bacteria from a healthy donor. Fecal seeding means just exactly what it sounds like! The intestinal worms and the fecal bacteria from a healthy donor both seem to produce IL-10 or a biologically similar substance that our bodies use as though it were IL-10. IL-10 in small amounts in the right places increases our T regs and helps them to be better at controlling bad guy B cells.

Another way to deal with the overactive autoimmune B cells is to find a way to decrease their activity. The following article describes an FDA approved drug, bortezomib, for cancer that seems to interfere with B cells that are over active and stop them If you have an active case of autoimmune disease, then the B cells that are most active are likely to be the bad guy auto-antibody producing ones. Turn them down and the autoimmune disease should get better. Unless of course you are fighting an infection then turning off the active B cells would turn off the good guys that are most active in the infection fight. Not good. You must not be sick if you take this medication and you probably should stay away from sick people while you are taking it.

Here is the article from
(1. Plasma cells are B cells. 2. Because autoimmune disease is basically us rejecting parts of our own body, any drug that stops organ(kidney, heart) transplant rejection) will also stop autoimmune disease.)

Cancer drug effectively treats transplant rejections

CINCINNATI—University of Cincinnati (UC) researchers have discovered a new therapy for transplant patients, targeting the antibody-producing plasma cells that can cause organ rejection.

Results of the study are published in the Dec. 27, 2008, edition of the journal Transplantation.
Steve Woodle, MD, and colleagues found that a cancer drug—bortezomib—used to treat multiple myeloma, or cancer of the plasma cells, is effective in treating rejection episodes caused by antibodies that target transplanted kidneys and reversing rejection episodes that did not respond to standard therapies.

B-lymphocytes, or B cells, play a large role in the humoral immune response by making immune proteins ( these are antibodies) that attack transplanted organs.

"We found a body of literature demonstrating that bortezomib works well in suppressing transplant rejection in the laboratory," says Woodle, lead author of the study and chief of transplant surgery at UC. "Moreover, it worked well in models of autoimmune diseases."
T-lymphocytes, or T cells, are white blood cells that were commonly thought to cause the rejection of transplanted organs.

Woodle and his team began searching for agents that targeted plasma cells in 2005.
"It has become clear that plasma cells and the antibodies they produce play a bigger role in rejection than previously thought, and the development of therapies targeting these cells has lagged," he says. "We realized that current therapies don't target the plasma cells which may produce the antibody, in general."

Researchers administered this drug to six kidney transplant recipients with treatment-resistant organ rejection, evaluating and recording their responses to the treatment.

In each case, treatment with the drug provided prompt rejection reversal, prolonged reductions in antibody levels and improved organ function with suppression of recurrent rejection for at least five months.

Jason Everly, a board-certified oncology pharmacist in the division of transplant surgery at UC and co-author of the study, says the toxicities associated with this drug were predictable and manageable and were much less than those associated with other anti-cancer agents.
"We are pleased to see its toxicities are similar in transplant recipients suffering from treatment-resistant mixed organ rejection," he adds. "We hope it will be a viable therapeutic treatment option in this patient group."

Woodle says although this data is promising, it is difficult to overestimate the implications of this drug.

"We have an immunosuppressive agent that for the first time can target antibody-producing plasma cells with an efficacy similar to drugs that target T cells," he says. "This has significant implications for transplantation and auto immune disease."

UC researchers are currently conducting four industry-supported clinical trials to expand these findings.

This research was investigator-initiated. In addition to grants,
researchers have received honoraria from the manufacturer of bortezomib.

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