*Purpose: Sensitization to human leukocyte antigens (HLA) due to prior exposure to foreign antigens through events such as blood transfusions, previous kidney transplant, or pregnancy is associated with worse post-transplant graft survival and increased risk of graft loss due to antibody-mediated rejection (AMR). We sought to explore xenotransplantation in the highly sensitized recipient to characterize how allosensitization impacts immunologic rejection after xeno-kidney transplant.

*Methods: Four nonhuman primates (NHP) were allosensitized with maximally HLA-mismatched rhesus donor skin grafts. Six to eight weeks after the second skin graft, porcine kidneys from genetically modified knockout a-1,3-galactosyltransferase (GGTA1KO) and human decay accelerating factor transgenic (CD55Tg) pigs were transplanted into the allosensitized NHPs. The immunosuppression regimen consisted of rhesus anti-CD4 and anti-CD8 induction, and anti-CD154 mAb (rh5C8), mycophenolate mofetil, and corticosteroids as maintenance therapy. Both xeno-reactive and allo-specific antibodies were evaluated with flow crossmatch.

*Results: All animals tolerated xeno-kidney transplantation well with no cases of hyperacute rejection. NHPs received pulsed corticosteroid per rejection protocol but no rejections reversed. All four animals rejected their grafts at POD 12, 15, 27, and 55 (MST = 27.25d). Xeno-graft survival was greatly prolonged compared to highly sensitized animals with allo-kidney transplants without desensitization (MST=7d). However, compared to previously reported non-sensitized recipients with xeno-kidney transplantation (MST=201.8d), graft survival was significantly reduced by allosensitization (Figure 1A and 1B). Interestingly, flow crossmatch revealed elevated xeno-DSA that coincided with rejection (Figure 1C), and allosensitization was not boosted by rejection of a xenograft.

*Conclusions: This is the first attempt, to our knowledge, to perform xenotransplantation in highly allosensitized NHP recipients. Allosensitization leads to overall decreased xeno-graft survival and increased risk of graft loss due to AMR compared to non-sensitized recipients. Further studies in optimizing desensitization and maintenance immunosuppression therapies are warranted to further characterize the clinical utility of xenotransplantation in the allosensitized recipient.

« Back to 2021 American Transplant Congress