New Clues Could Point to Better Treatments for Chronic Graft-Versus-Host Disease (GVHD)

November 9, 2017 | by By Katie Neith

Defu Zeng City of Hope Ruishu Deng, M.D., Ph.D. (left), the paper’s first author and a former postdoctoral fellow at City of Hope and Defu Zeng, City of Hope professor of diabetes immunology and hematopoietic cell transplantation
One of the most serious complications that affects cancer patients undergoing a bone marrow or stem cell transplantation is chronic graft-versus-host-disease (GVHD). This occurs when immune system cells from a donor cause inflammation in the patient receiving them. The donor’s cells react to the patient as they would a foreign invader and attack the body’s cells.

GVHD is common among people who receive a bone marrow transplant to help treat leukemia, lymphoma and other blood disorders, and is therefore a major barrier for the success of this type of treatment.

Now, City of Hope’s Defu Zeng, professor of diabetes immunology and hematopoietic cell transplantation and colleagues have uncovered important information about the chronic form of the disease.

“Our new paper provides a novel concept about the pathogenesis, or development, of chronic GVHD which we believe will lead to better approaches for both preventing and treating chronic GVHD,” said Zeng, who led the study with a team of researchers including Ruishu Deng, M.D., Ph.D., the paper’s first author and a former postdoctoral fellow at City of Hope, as well as others from Fred Hutchinson Cancer Research Center, Fujian Medical University Union Hospital in Fuzhou, China, University of California San Francisco and University of Pennsylvania.

Their results were outlined in a paper, "Extra-follicular CD4+ T-B Interactions are sufficient for inducing Autoimmune-like Chronic Graft-Versus-Host Disease," that was published in the Nature Communications journal.

Of course, the best way to avoid chronic GVHD is to never get acute GVHD in the first place, and Zeng’s ongoing work, such as research reported earlier this year in the Journal of Clinical Investigation, is making strides in fighting the onset of the disease. But for those already suffering from GVHD, the new discovery could help prevent the acute disease from becoming chronic, or help ameliorate ongoing chronic GVHD, symptoms of which can include mouth ulcers, dry eyes, gastrointestinal distress and rashes.  

Chronic GVHD is an autoimmune-like syndrome caused by the interactions of cells from the donor called CD4+ T and B cells. Studies by Zeng and others have indicated that CD4+ T and B cells work together to bring about chronic GVHD tissue damage, but did not elucidate the mechanism involved. However, other research had reported that, in animal model studies, chronic GVHD onset is associated with enlarged "germinal centers," which are structures in the lymphoid tissues where CD4+ T and B cell interact to produce autoantibodies.

So, Zeng and colleagues used the same animal models to show that chronic GVHD onset is, in fact, associated with the destruction of lymphoid tissues and loss of germinal center structure, indicating that CD4+ T and B cell interaction in the GVHD target tissues (but not in the lymphoid tissues) may help perpetuate chronic GVHD.

Furthermore, they found that a combination approach of depleting one type of CD4+ T cells that the team found to play a critical role in perpetuating chronic GVHD tissue damage (PSGL-1lo) and expanding other regulatory CD4+ T cells (Foxp3+) could be an effective approach for prevention and treatment of chronic GVHD, said Zeng. Plus, he said that by removing a specific protein called STAT3 in the CD4+ T cells can do both of those things.

“For patients who have chronic GVHD onset already, using small molecules to target STAT3 in T cells could have some effect,” said Zeng. “In addition, we found that the thymus — which is an organ important for producing Foxp3+ regulatory T cells and other protective immune cells — is effectively destroyed by acute GVHD. So, in order to cure chronic GVHD, we also need to re-establish the thymus as a functioning organ.”

Next, he and his team will collaborate with Arthur D. Riggs, Ph.D., the Samuel Rahbar Chair in Diabetes & Drug Discovery, and Stephen J. Forman, M.D., the Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, to develop techniques that specifically target STAT3 in CD4+ T cells. They will also work with Riggs to produce thymic progenitors using a specific type of stem cells in order to reestablish thymus activity in chronic GVHD patients.

“Our work has provided the stem cell transplant community with an important shift in how we approach chronic GVHD development,” said Zeng. “I am confident that our work will lead to innovative advances in the prevention and treatment of chronic GVHD.”

The research work was supported by National Institutes of Health grants (R01-AI066008 and R56-AI066008) and a National Cancer Institute award (P30CA033572).
 
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