Background: Skin transplants are the most immunogenic of all transplants and donor DCs play a crucial role in activating effector alloreactive T cells and initiating rejection. Strategies to modulate donor cells prior to transplant may yield a new therapeutic approach in skin and VCA transplants.

Methods: Skins from WT, MARCH1, TLR2, IL-10 B6 (H-2^b) KO mice were transplanted into BALB/c hosts (H-2^d). Prior to transplant, skin grafts were immersed in a solution containing the mycobacterial protein DnaK. Alloreactive T cell responses and donor DCs activation status was analyzed in allografts' draining lymph nodes 24h or 96h after the transplant. For in vitro mechanistic analyses, we isolated DCs from skin draining lymph nodes or generated BMDCs, then treated them with DnaK and controls. Further analysis were performed by real time PCR, flow cytometry, immunofluorescence and immunoprecipitation analyzes.

Results: We found that the mycobacterial protein DnaK triggered the induction of the E3 ubiquitin ligase MARCH1 in murine DCs, leading to the downregulation of MHC II and CD80. MARCH1 induction in donor DCs limited the generation and proliferation of both CD4+ and CD8+ alloreactive T cells. In-situ treatment of donor skins prior to transplant with DnaK delayed rejection by modulating MHC II expression on donor DCs in a MARCH1-dependent manner. Also, the induction of MARCH1 and DnaK effects were dependent on TLR2/ERK/STAT3/IL-10 pathway.

Conclusions: MARCH1-dependent modulation of donor DCs limited the alloreactive T cell responses and delayed skin acute rejection, identifying a promising novel therapeutic target in VCA transplantation.

CITATION INFORMATION: Borges T, Machado F, Bonorino C, Riella L. An In-Situ Treatment of Donor Skin Induces MARCH1 and Decreases MHC II Expression on Donor Dendritic Cells, Promoting Skin Allograft Acceptance. Am J Transplant. 2016;16 (suppl 3).

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