Monday, December 7, 2009

Massive doses of T regs, new hope for autoimmune?

Below is an article that lends hope to all of us with immune related problems who are hoping for a bone marrow transplant to replace our defective immune systems.

Teams in Italy and Israel have gotten remarkable success in preventing both the onset of infectious disease after bone marrow transplant and also graft versus host disease later. They were successful in 25 of 26 cases--96%! Remarkable. The success for the standard bone marrow transplant rate is far, far lower.*

How were our Italian and Israeli friends so successful?

By infusing massive doses from the donor of a special white blood cell called T regs three days before giving T cell depleted bone marrow to the recipient.

There are at least two kinds of T cells. The good ones for us are the T regs. They promote tolerance. The bad ones for us are the T effectors. They tend to attack our tissues when they are not fighting viruses and bacteria.

Donor T effectors also seem to be responsible for starting Graft versus Host Disease in recipients. GvHD is a very nasty, and often fatal, attack of the new bone marrow (containing the immune system cells) against the body of the recipient. Because of this bad tendency of T effector cells, the donor bone marrow is routinely depleted of all T cells both the 'good guy, T regs that promote tolerance and the "bad guy" T effectors. In the past no distinction was made between T regs and T effectors. It seems that was a mistake.

Getting rid of both the "good guys" and the "bad guys" T cells meant that when the donor T cell precursor cells were growing back, they might produce more T effector than T regs. The T effectors would see foreign tissue (the patient/recipient's body) and attack those 'foreign" cells. This could set up a feed back that turns into unstoppable GvHD.

However we do want T effectors or we would be susceptible to overwhelming infections. Depleting the transplanted immune cells of ALL T cells both T regs and T effectors also leaves the patient at risk for weeks or months while waiting for T cell precursor cells in the transplant to produce the full set of T cells. Months can pass before there are enough new T effectors, all the while an infection can quickly end the recipient's life. We just want T regs to be in place first to stop the T effectors from attacking the body of the patient recipient.

The Israeli and Italian doctors found that by giving the "good guy" T regs from the donor three days before the main infusion of bone marrow that the donor T regs somehow prepared the way for not only a VERY high rate of success in getting the transplants to grow but also to a much faster recovery of the immune system for the recipient without any Graft versus Host.

Of course no one knows for sure that this is going to be the magic bullet to improve bone marrow transplants until we have seen how the patients are doing at least five years down the line. If any where close to 96% are still alive in five years, then this is a miracle. Get the Nobel Prize for medicine ready for them. Fingers crossed.

For autoimmune folks the incredible initial success rate for this Italian/Israeli technique means that if we chose a bone marrow total or partial (chimeric) replacement as our way to the cure, than the odds of surviving have gone up dramatically. If the healthy donor's bone marrow successfully implants in a patient with autoimmune disease then the autoimmune disease ends. It is our 'sick" bone marrow cells that cause our autoimmune disease.

Right now the death rate for bone marrow transplants is somewhere in the 25% range for first five years. Deaths are caused initially by infections. Later by graft versus host disease. Some of the 75% that survive never regain a complete immune system leaving them vulnerable to infections and cancers. So this Israeli/Italian announcement seems to be a huge breakthrough.

*(Our bone marrow cells contain and make all of our immune system. An autoimmune disease can be cured by a bone marrow transplant from a healthy donor.)

Improving the Odds
A new method for bone marrow transplantation from mismatched donors restores the immune system faster

Although bone marrow transplants have long been standard for acute leukemia, current treatments still rely on exact matches between donor and patient. Now, scientists at the University of Perugia, Italy, and the Weizmann Institute of Science have improved on a method of transplanting bone marrow-based stem cells from a mismatched donor, making it safer for use when no exact match exists. They were invited to present their findings at the recent annual American Society of Hematology conference in New Orleans.

More than a decade ago, Prof. Yair Reisner of the Weizmann Institute’s Immunology Department pioneered a method for transplanting stem cells from family members who are a partial match. Based on these studies (in mice), he joined forces with Prof. Massimo F. Martelli, Head of the Hematology and Clinical Immunology Section at the University of Perugia, to demonstrate in more than 300 patients that the cure rate of these so-called ”mega dose” transplants is similar to that of transplants from matched, unrelated donors picked from international bone marrow donor registries.

To combat the body’s tendency to reject the foreign cells, these stem cells are stripped of immune cells called T cells and given in high doses that overwhelm the host’s own immune system. Although removing donor T cells from the bone marrow reduces the risk of graft-versus-host disease – caused when the T cells attack the recipient’s tissues – the immune system is slow to recover after the transplant, leaving the patient at risk of serious infection. Doctors are faced with a difficult choice: Either remove the T cells from the bone marrow, increasing the risk of infection, or leave the T cells in the graft, putting the patient at risk for lethal graft-versus-host disease.

Martelli, working with Reisner, has now found a way to facilitate the recovery of the immune responses in recipients of T cell-depleted bone marrow transplants. In a clinical trial, 25 of 26 leukemia and lymphoma patients who received mismatched mega dose T cell-depleted stem cell transplants from relatives showed prompt immune recovery, and their immune systems were functioning well several months later.

The scientists knew that certain regulatory T cells (T regs), rather than causing graft-versus-host disease, could actually help to prevent it in mice. T regs have also been shown to keep other immune responses in check, including preventing autoimmune attacks on the body’s own cells. In the present study, after purifying T regs from the donor’s blood, the cells were infused intravenously into the cancer patients, who had previously undergone standard radiation and chemotherapy treatments. Three days later, the patients received the donor stem cells, along with another kind of T cell – those that fight disease.

The patients who underwent this procedure showed quick, lasting improvements in immune activity; most experienced no symptoms even though they received large doses of the T cells that are generally associated with lethal graft-versus-host disease.

Further follow up on these patients and additional clinical trials will be needed before the procedure can be widely adopted. But these results strongly suggest that T regs used in mega-dose stem cells will further enhance the cure rate for bone marrow transplant patients without a matched donor in the family.

Prof. Yair Reisner’s research is supported by the M.D. Moross Institute for Cancer Research; the Kirk Center for Childhood Cancer and Immunological Disorders; the Mario Negri Institute for Pharmacological Research Weizmann Institute of Science Exchange Program; the Gabrielle Rich Center for Transplantation Biology Research; the Russell Berrie Foundation; and Mr. and Mrs. Seymour Spira, Palm Beach Gardens, FL.
Prof. Reisner is the incumbent of the Henry H. Drake Professorial Chair in Immunology.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.

Weizmann Institute news releases are posted on the World Wide Web at, and are also available at

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