UNC Study Hints At New Approaches To Prevent Transplant Rejection

Main Category: Transplants / Organ Donations
Also Included In: Immune System / Vaccines
Article Date: 08 Feb 2009 - 0:00 PDT

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To prevent the rejection of newly transplanted cells, patients must take medicines that weaken their entire immune systems. Such potentially life-saving treatments can, paradoxically, leave those receiving them susceptible to life-threatening infections.

Now researchers at the UNC School of Medicine have discovered what seems to trigger the immune system to attack transplanted cells in the first place, charting a course to completely new therapies that may prevent graft-versus-host disease and its sometimes fatal complications.

Without a clear understanding of what has long been known to be the main cause of transplant failure, clinicians have had little choice but to treat transplant patients with toxic regimens of steroids and immunosuppressive drugs. But smarter, tailored treatments may be possible now that a UNC study has identified a subset of cells -- named TH17 cells -- that can bring about the condition.

"Our hope is that uncovering the mechanisms that cause graft-versus-host-disease will allow for treatments that specifically target its causes and do not have the harmful side effects of traditional immunosuppressive therapy," said lead study author Jonathan S. Serody, M.D., a member of the UNC Lineberger Comprehensive Cancer Center and the Elizabeth Thomas professor of medicine, microbiology and immunology at UNC.

The results of the study will appear in the February 5 issue of Blood, the journal of the American Society of Hematology.

Graft-versus-host-disease (GVHD) is a serious complication of transplants that occurs when the donor marrow (graft) produces immune cells that attack multiple organs of the recipient (host), typically the skin, gastrointestinal tract and liver. Scientists believe that most of the problems of GVHD come from the production of specific cytokines such as interferons, a class of proteins that arise in response to foreign agents like viruses and parasites.

This theory led several researchers to test whether or not blocking the action of these proteins would diminish GVHD. They found that getting rid of interferons made the disease worse. When Serody and his colleagues tried this experiment themselves, they found that blocking the action of interferons resulted in a huge increase in the number of a specific group of white blood cells or T lymphocytes called TH17 cells.

To determine if this specific subset of cells was actually aggravating the disease, the UNC researchers first cultured, expanded and purified cells of the TH17 lineage. In a technique pioneered by Michael J. Carlson, Ph.D., a postdoctoral fellow in Serody's laboratory, immature lymphocytes were incubated in petri dishes with a cocktail of proteins that "programmed" virtually all of them to become TH17 cells.

When the researchers transplanted the purified cells into mice, they found that the cells did in fact cause GVHD, with the most severe damage to the lung and skin. Not only did these findings implicate TH17 cells in the disease, but they also generated one of the first mouse models to display acute GVHD skin changes -- consistent with the most common manifestations of the disease in humans.

Having identified the role of TH17 cells in GVHD, Serody and his colleagues then wanted to know what substances the cells were producing to cause the disease. They knew that TH17 cells produce a number of specialized proteins -- called inflammatory cytokines -- that are involved in communication between cells during the immune response. So they methodically blocked the action of each of these cytokines to determine which ones were actually causing the damage to various organs of the transplanted mice they were studying.

They found that the skin damage appeared to stem from the production of IL17 and its sister cytokines, while destruction in other tissues came from a protein called TNF-alpha. Interestingly, these findings lend support to the strategy employed by some clinicians to treat the manifestations of GVHD with drugs that block TNF-alpha.

"For our findings to ever make an impact clinically we would have to confirm that there are two main branches leading to the disease," said Serody. "Then we would need to take an approach that neutralizes both - simultaneously blocking the original suspect, interferon gamma, and our newest culprit, cytokines made by TH17 cells, to treat GVHD."

Research on that TH17 branch has already sparked the interest of some pharmaceutical companies such as Wyeth, and Serody predicts that there will be a number of drugs coming out in the next five years to treat immune-based skin diseases.

The research was supported by the National Institutes of Health. Study co-authors from UNC include Lineberger center research analyst, Michelle L. West, and clinical fellow, James M. Coghill, M.D.; and Angela Panoskaltsis-Mortari Ph.D. and Bruce Blazar M.D. at the University of Minnesota Cancer Center.

UNC School of Medicine

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