Cross-dressing of recipient cells with allogeneic MHC molecules carried by donor exosomes occurs regularly after transplantation. However, it is still unknown whether this phenomenon plays a significant role in the T cell alloresponse and allograft rejection.

In this study, we tested whether GW4869, a sphingomyelase 2 inhibitor known to inhibit cell release of exosomes, could prevent allo-MHC cross-dressing and thereby impair the alloresponse and rejection process in transplanted mice. To test this hypothesis, we administered GW4869 (60ug/mouse/dose) to B6 or BALB/c donors on days -5, -3, -1 pre-transplantation. We transplanted fully mismatched recipients with skin, heart, or islet allogeneic grafts and administered GW4869 on days 1, 3, and 5 post transplantation. Imaging flow cytometry of leukocytes from recipients' draining lymphoid organs showed greater than 33% reduction of the frequency of recipient cells cross-dressed with donor MHC in GW4869 treated mice compared to control recipients. In addition, GW4869 treatment markedly reduced the frequency of inflammatory T cells activated through direct allorecognition in the recipients' lymphoid organs. Finally, short-term treatment of recipient mice with GW4869 significantly prolonged heart allograft survival (> 80 days). These findings support the view that donor exosome release by the transplant and subsequent cross-dressing of recipient cells with donor MHC molecules is an essential element of T cell allorecognition and allograft rejection. This study also set the path for the design of new exosome-based strategies to alter the process of allorecognition and prevent allograft rejection.

CITATION INFORMATION: Marino J, Tector H, Gonzalez-Nolasco B, Lellouch A, Harney A, Cetrulo, Jr C, Markmann J, Benichou G. Reduction of Recipient Cell Cross-Dressing with Donor MHC Molecules Prolongs Allograft Survival in Mice. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress