Tuesday May 02, 2023 - 16:15 to 17:20
Yaxun Huang, United States has been granted the AST-COTS Scientific Congress Award
Donor hematopoietic cell expression of PD-L1 is required for prevention of split tolerance in MHC-mismatched mixed chimeras
Yaxun Huang1, Xiwei Wu2, Shanshan Tang1, Ubaydah Nasri1, Qi Qin1, Anita Chong3, Arthur D Riggs1, Defu Zeng1.
1Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, Virgin Islands (U.S.); 2Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, United States; 3Section of Transplantation, The University of Chicago, Chicago, United States
Introduction: Induction of HLA (MHC)-mismatched mixed chimerism (MC) is a promising approach for organ transplantation immune tolerance, but MC can develop split tolerance in which recipients accept donor hematopoietic cells but reject donor-type solid organ transplant. The mechanisms remain unclear and requires further study.
Methods: Induction of MHC-mismatched mixed chimerism (MC) in murine models was achieved using a published regimen consisting of conditioning with cyclophosphamide, pentostatin, and rabbit anti-murine thymocyte globulin and infusion of BM and CD4+ T-depleted spleen cells as well as transplanted with heart and/or skin graft from WT or PD-L1-/- BALB/c donors. The recipients were monitored for MC status as well as heart and skin graft survival, and further analyzed for mechanisms of tolerance.
Results: With clinically applicable murine models, we show that while MC with wild-type donor hematopoietic cells (WT MC) provides tolerance to donor-type heart and skin grafts, MC with PD-L1-/- hematopoietic cells (PD-L1-/- MC) showed split tolerance by rejecting the WT donor-type organ grafts while maintaining mixed chimerism. A split tolerance was also observed in WT MC transplanted with PD-L1-/- grafts. The PD-L1 deficiency in donor APCs were associated with expansion of host-type Tcon cells and reduction of host-type Helios-Nrp1+ pTreg cells. On the other hand, depletion of host-type Treg cells results in reduction of donor-type CD8+ DCs and down-regulating PD-L1 expression by the residual CD8+ DCs.
Conclusions: These results indicate that, in MHC-mismatched MC, PD-L1 expressed by donor-type tolerogenic DCs augments pTreg differentiation and expansion, thereby preventing split tolerance.
This work was supported by Riggs Institutional fund, the Legacy Heritage Fund Limited, and private donations from Arthur and Judith Lubin.