More than 50 years ago, surgeons at Brigham and Women’s Hospital performed the first successful kidney transplant. Today, tens of thousands of people receive organ transplants each year in the United States, with impressive near-term survival rates. Yet despite modern immunosuppressive drugs, many organ transplants still fail in the long run.
New work from HMS researchers may help explain what causes this chronic organ rejection. A team at the Transplant Research Center of Brigham and Women’s and Children’s Hospital Boston has found in mice that certain immune cells, dubbed T17s, elude immunosuppressive drugs and cause transplants to fail. The investigators also identified ways to block the cellular pathways that activate these cells. Since other recent research suggests that these same cells play a role in chronic human organ rejection, this work may lead to novel posttransplant therapeutics.
The researchers used knockout mice that serve as a model of human transplant patients on immunosuppressive drugs such as cyclosporin or rapamycin. The mice have no T helper 1 cells, the pro-inflammatory immune cells that these drugs suppress to prevent transplant rejection. “Our hypothesis was that these mice would be protected from organ rejection,” said senior author Mohamed Sayegh, the Warren Grupe–John P. Merrill professor of transplantation medicine. “But their rejection was worse.”
Led by co–first authors Xueli Yuan, HMS instructor in medicine at BWH, and M. Javeed Ansari, a former research fellow and instructor in medicine at HMS, the team discovered that these knockout mice have excess interleukin-17 (IL-17), the hallmark immune signaling molecule, or cytokine, produced by T17 cells. With this information, they determined that the CD4 class of T17 cells, T helper 17 cells, plays a role in chronic rejection primarily by damaging the vasculature of a graft. This work is described in the December 2008 Journal of Experimental Medicine.
They later found that a different type of IL-17–producing T cell, CD8 T17s, eluded the blockade and caused the rejection. By closing a pathway called Tim-1, they prevented the formation of these cells and improved long-term survival of the mice. The researchers describe this work in the June 15 online Proceedings of the National Academy of Sciences.
“Our traditional thinking that it’s pro-inflammatory Th1 cells that do all the damage is not entirely correct,” said Sayegh. He and Yuan will continue to investigate the specific mechanisms behind the deleterious effects that T17 cells have on transplants. They are also working with Ansari, now at Northwestern University, on a clinical study to determine if T17 cells play a role in chronic rejection in humans. This work is particularly exciting now since it dovetails with investigations into therapeutics targeting T17 cells in autoimmune diseases.
Students may contact Mohamed Sayegh at msayegh@rics.bwh.harvard.edu for more information.
Conflict Disclosure: Co-author Laurie Glimcher is on the board of directors and holds equity in Bristol-Myers Squibb pharmaceutical company.
Funding Sources: This work was supported by the National Institutes of Health. Xueli Yuan received funding from an American Society of Transplantation Basic Science Faculty Development Grant, and M. Javeed Ansari received support from an American Society of Transplantation-Wyeth Basic Science Faculty Development Grant; the content of the work is the responsibility solely of the authors.
