Reducing xenoantigens in donor pigs and chemical immunosuppression can be used to achieve prolonged renal xenograft survival in a preclinical model, suggesting that if a negative cross-match can be obtained for humans then prolonged survival could be achieved.

The shortage of available organs remains the greatest barrier to expanding access to transplant. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney xenotransplant has generally been limited to <100 days. We found that pretransplant selection of recipients with low titers of anti-pig antibodies significantly improved survival in a pig-to-rhesus macaque kidney transplant model (6 days vs median survival time 235 days). Immunosuppression included transient pan-T cell depletion and an anti-CD154-based maintenance regimen. Selective depletion of CD4 + T cells but not CD8 + T cells resulted in long-term survival (median survival time >400 days vs 6 days). These studies suggested that CD4 + T cells may have a more prominent role in xenograft rejection compared with CD8 + T cells. Although animals that received selective depletion of CD8 + T cells showed signs of early cellular rejection (marked CD4 + infiltrates), animals receiving selective CD4 + depletion exhibited normal biopsy results until late, when signs of chronic antibody rejection were present. In vitro study results suggested that rhesus CD4 + T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pretransplant anti-pig antibody and CD4 depletion resulted in consistent, long-term xenograft survival. K E Y W O R D Sanimal models: nonhuman primate, basic (laboratory) research/science, costimulation, immunosuppressant -fusion proteins and monoclonal antibodies: costimulation molecule specific, immunosuppression/immune modulation, kidney transplantation/nephrology, translational research/science, xenoantibody, xenoantigen, xenotransplantation

[structure: see text] Liphagal (1), a selective inhibitor of PI3K alpha, has been isolated from the marine sponge Aka coralliphaga collected in Dominica. The "liphagane" meroterpenoid carbon skeleton of liphagal (1) is new. A biomimetic total synthesis has been used to confirm the constitution of liphagal (1) and support a proposed biogenesis.

The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked Fc binding activity and resultant platelet activation. In a non-human primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (MST 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (MST 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+CD25+Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a non-human primate preclinical model.