Although total T cell numbers were significantly increased (p=0.0024,Fig. success and reduced AMR, associated with dampened post-transplant humoral responses, early monocyte and neutrophil activation, and T cell repopulation. After withdrawal of all immunosuppression, recipients that received kidneys from 3KO.7TG pigs rejected the xenografts via AMR. These data suggest that allosensitized recipients may be suitable candidates for xenografts from genetically modified porcine donors and could benefit from an optimized immunosuppression regimen designed to target the post-transplant humoral response, thereby avoiding AMR. == OVERLINE: KIDNEY TRANSPLANT == One sentence summary:Xenograft survival can be substantially extended in sensitized recipients by expressing seven human transgenes in triple knockout donor pigs. == Introduction == Xenotransplantation has long been proposed as a therapeutic strategy to address the global organ shortage (1,2). Recently, the field has undergone a renaissance, attracting both public and scientific interest. Improvements in graft and recipient survival have stemmed from two major advances: (i) utilization of immunosuppressive therapies targeting the CD40/CD154 co-stimulation pathway (35), and (ii) genetic engineering of porcine donors to reduce immunogenicity and inherent incompatibilities between the xenograft and the recipient (6,7). In the United States, Mohiuddinet al.reported a median survival of 300 days (with survival up to 900 days) in a INCB018424 (Ruxolitinib) heterotopic heart transplant baboon model using porcine donors genetically engineered to knock out the glycoprotein alpha-galactosyltransferase 1 (GGTA1) gene and to express theCD46and thrombomodulin (THBD) human transgenes (GTKO.hCD46.hTHBD), with administration of anti-CD40 monoclonal antibody (mAb)-based immunosuppression (3). Meanwhile, in Europe, Langinet al. reported survival of up to 200 days in a life-supporting orthotopic heart transplant baboon model using a porcine donor with the same genetic edits and anti-CD40 mAb-based immunosuppression (4). In kidney xenotransplantation, a similar approach usingGGTA1knockout and humanCD55transgene (GGTA1KO.CD55Tg) donor pigs with anti-CD154 mAbbased immunosuppression prolonged graft survival up to 400 days (5,8). Compared to earlier attempts (9), these studies exhibited that xenografts can survive many months when the CD40/CD154 pathway is usually blocked, and suggesting that this translation of xenotransplantation to the clinic may be within reach (10). Having exhibited convincing and repeatable outcomes of xenotransplantation in nonhuman primate (NHP) models, one key question regarding cross-species organ transplantation is usually, for whom does the potential benefit of xenotransplantation outweigh the risk? More than 100,000 patients await kidney transplantation in the US and only one in four are likely to receive transplants (11,12) in a given year. Despite changes to the deceased donor allocation system, highly sensitized patients, those who have developed anti-donor antibodies as a response to foreign human leukocyte antigen (HLA) exposure, remain challenging to transplant. Such patients experience increased wait times compared to non-sensitized counterparts (13,14), particularly the most highly sensitized who have antibodies against almost all HLA antigens [calculated Panel Reactive Antibody (cPRA) 100%], making them incompatible with virtrually all organ donors. Furthermore, should these patients receive a transplant, they have an increased risk of antibody mediated rejection (AMR) after transplantation (15,16). Although HLA sensitization is usually a barrier to successful allotransplantation, such patients have not been exposed to xenoantigens. Thus, theoretically, xenotransplantation might pose the same immunological risk to both sensitized and non-sensitized patients, but for sensitized patients who might otherwise remain untransplanted, xenotransplantation would potentially confer a greater relative benefit. On the INCB018424 (Ruxolitinib) other hand, if there is cross reactivity between allo- and xeno-antigens, allosensitization may INCB018424 (Ruxolitinib) primary the immune response to a xenotransplant. Here we used an immunosuppressive regimen that previously resulted in long-term graft survival in a nonsensitized NHP xenokidney transplantation model (5,8). We investigated whether HSPC150 comparable outcomes could be achieved in a well-established allosensitized NHP model. This study aimed to test the hypothesis that allosensitization does not incur additional immunological risks for xenotransplant recipients (17,18), and to compare the effects of two cohorts of genetically modified pigs. == Results == ==.