Mouse Studies Achieve Dramatic Drop in Graft-Versus-Host Disease Following Bone Marrow Transplant

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Mouse studies achieve dramatic drop in graft-versus-host disease following bone marrow transplant

BOSTON ñ In experiments with mice, researchers at Dana-Farber Cancer Institute and Childrenís Hospital have used a naturally occurring protein to thwart one of the most common ñ and potentially lethal ñ complications associated with bone marrow transplants.

In a study published in the July 1 issue of the Journal of Clinical Investigation, the researchers report that mice given interleukin-11 (IL-11) after receiving an allogeneic, or non-self, bone marrow transplant were protected from the effects of graft-versus-host disease, an often debilitating condition that can follow marrow transplants. The protection enabled the mice to outlive other mice that had received bone marrow transplants but were not given IL-11.

ìThis research shows that it may be possible to significantly reduce the complications experienced by patients receiving bone marrow transplants,î says the studyís senior author, James Ferrara, M.D., of Dana-Farber and Childrenís Hospital. ìIL-11 may also hold promise for the treatment of other immune-related problems such as autoimmune diseases and organ transplant rejection.î

Graft-versus-host disease (GVHD), which results from an imperfect ìmatchî between donated bone marrow and recipientsí own tissue, affects more than half of all bone marrow transplant recipients. When T cells inside the donated marrow recognize the host tissue as foreign, they mount an immunological assault against it. The result of this ìTrojan horseî attack can be severe damage to organs such as the skin, liver and intestines. Ninety percent of severe GVHD cases are fatal.

Although drugs that suppress the immune system such as steroids and cyclosporin can alleviate the problem, GVHD remains the major cause of disease and death, either directly or indirectly, in patients receiving allogeneic bone marrow transplants.

In the current study, lead author Geoffrey Hill, M.D., and his colleagues administered IL-11 for a short period to mice that had received allogeneic bone marrow transplants. IL-11 was chosen because it suppresses proteins called cytokines that can cause tissue inflammation, and because it protects the gastrointestinal tract from damage by radiation that is used in preparation for the transplant.

The results of the study were striking: the long-term survival rate of the mice receiving IL-11 was 90 percent. For mice that had received bone marrow transplants but were not given IL-11, the rate was 10 percent. In addition, IL-11 provided long-term protection of the organs that usually are targeted by GVHD.

Researchers identified three ways that IL-11 acts to blunt the effects of GVHD: by reducing the production of inflammatory cytokines, by protecting the intestines and other organs, and by altering the responsiveness of T cells from the donated marrow.

Another encouraging sign was that IL-11 didnít seem to produce any adverse side effects in the mice, but, Ferrara cautioned, the study was not geared specifically to detect such side effects. He noted that IL-11 is currently given to cancer patients after chemotherapy to increase their number of blood platelets, and that it generally produces only minor side effects.

The success of the experiments in mice has prompted Ferrara and his colleagues to design a clinical trial to test IL-11 in patients receiving bone marrow transplants. He expects the trials to begin toward the end of this year.