*Purpose: Xenotransplantation outcomes have been greatly improved due to the advent of genetically engineered pigs and agents targeting the CD40-CD40L signaling pathway. However, studies have reported heterogenous graft survival outcomes with higher incidence of early antibody-mediated rejection in a preclinical nonhuman primate model. In comparing lymphocyte repopulation and immune cell profiles from Rhesus Macaques following anti-CD4/CD8 depletion, we sought to elucidate differences in response to allo- versus xenotransplantation in highly sensitized recipients.

*Methods: 10 Rhesus Macaques were allosensitized with maximally MHC mismatched donor skin grafts. Five nonhuman primates received kidney transplants from their previous allo-donor and five were transplanted with porcine kidneys from genetically modified knockout a-1,3-galactosyltransferase (GGTA1KO) and human decay accelerating factor transgenic (CD55Tg) pigs. Both groups received anti-CD4/CD8 mAbs. The allotransplant group received carfilzomib and belatacept as desensitization therapy and tacrolimus, mycophenolate mofetil, and steroids as post-transplant immunosuppression. The xenotransplant group received anti-CD154, mycophenolate mofetil, and steroids as post-transplant immunosuppression without desensitization. Immune phenotypes were analyzed by flow cytometry of peripheral blood.

*Results: Following T cell depletion, xenotransplanted NHPs exhibited faster lymphocyte repopulation compared to allotransplanted NHPs (POD28: 2.36 vs. 0.47, p=0.01) (Figure A). However, there was no difference between absolute CD4 and CD8 T cell populations at all timepoints prior to and following transplantation (Figure B, C). Interestingly, the CD20 B cell population was significantly elevated in xenotransplanted NHPs compared to allotransplanted NHPs (POD28: 1.16 vs. 0.11, p=0.0008) (Figure D). In accordance with this, circulating isotype switched memory (IgD^‑CD27⁺CD20⁺; POD28: 0.29 vs. 0.03, p=0.01) B cell and follicular helper (ICOS⁺PD-1^hiCD4⁺; POD28: 0.20 vs. 0.03, p=0.04) T cell frequencies were significantly increased after xenotransplantation.

*Conclusions: Lymphocytic repopulation, driven specifically by B cell repopulation, was more robust in xenotransplanted NHPs compared to allotransplanted NHPs following CD4/CD8 induction therapy. This suggest that further therapies directed at suppressing post-transplant B cell and humoral responses may be required in xeno-kidney transplantation.

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