Research provides new insight into transplant rejection
Thursday, September 27, 2018
Surgeons now perform more than 30,000 organ transplants a year, according to the U.S. Department of Health and Human Services, and each of the recipients of those organs face the possibility of organ rejection.
Not all organ transplant rejection is the same. Recipients of liver transplants rarely experience organ rejection, for example, while skin graft rejection rates are high. Researchers are still working to understand why skin grafts have such a high rejection rate.
In a new study, published in Nature Communications, researchers from Brigham and Women’s Hospital reveal insights that may help explain the mechanisms behind skin graft failure. The results of the study may also help make organ transplantation more successful in the future.
"Mice were selected since they are the best studied model of transplantation that allows manipulation both with drug therapies as well as genetic approaches to investigate and validate our scientific hypothesis," said co-senior author Dr. Leonardo V. Riella, medical director of the Vascularized Composite Tissue Transplant Program at Brigham and Women's Hospital in a press release.
The scientists identified a new subset of cells in the donor-transplanted organs that triggered rejections. When the researchers removed these cells, known as CD103 dendritic cells, the transplanted skin survived longer.
The researchers also found a way to prevent rejection prior to transplantation. Incubating the grafts with an anti-inflammatory mycobacterial protein before transplantation boosted survival rates. The investigators also treated the transplant site with the enzyme March-2, which inhibits CD103+ dendritic cell growth.
The results of the study show that the treatment protocol was effective in both mouse models and in human skin grafts. The protocol may be a new strategy in preventing rejection of transplanted organs.
"Skin transplantation in the form of face or extremity transplant is a clinical reality despite the high rate of rejection. Our discoveries shed light into the reason these transplants are associated with significant rejection compared to other transplants such as kidney or liver," concluded the lead author.
"We plan to further investigate our findings in other transplant models such as heart and kidney in addition to validating our findings in larger animals such as primates. We are also in parallel optimizing our drug targeting with more powerful agents that manipulate the same MARCH1 pathway that was found to be effective when treating the donor organ."
Donor dendritic cells (do-DCs) trigger the alloimmune reaction in one of two ways: by direct interaction with host T cells or through the transfer of intact donor major histocompatibility complex (MHC) to host dendritic cells. Researchers are still working out methods of targeting do-DCs to improve allograft survival.
In this study, the researcher shows CD103+ DCs are the primary do-DC subset associated with skin transplant rejection. Absence of CD103+ do-DCs results in less donor MHC moving to the host lymph nodes, the priming of fewer allogenic T cells, and prolonged allograft survival.
Incubating skin grafts with DnaK reduces donor MHC-II to prolong graft survival. IL-10-induced March1 mediates the effect to ubiquitinate and decrease MCH-II levels. In vitro pre-treatment with DnaK reduces the ability of human DCs to prime alloreactive T cells.
The team’s findings could represent a new therapeutic approach to reduce rejection rates by targeting donor MHC-II on CD103+DCs.
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