Improving Xenograft Outcomes: Exploring Novel Molecular Targets and Developing Translational Therapies
Synopsis: Kidney transplantation offers a life-saving and life-improving surgical therapy to patients with end-stage renal disease. Xenotransplantation, using genetically-modified porcine organs, has the potential to dramatically increase the organ supply to provide more patients with a new kidney. The proposed study seeks to explore two major barriers to applications of xenotransplantation: hyperacute rejection due to pre-formed antibodies against nonhuman donor cell markers, and acute rejection due to recipient lymphocytic cell-mediated response.
First, we will examine the effect of a genetically optimized porcine donor on rejection, by performing renal transplants using the newly-developed double-knockdown GAL -/-, β4GAL-NT2 -/-, hCD55 pig on as donors into rhesus macaques with the resulting elimination of targets for xeno-directed antibody. Next, using this optimized double-knockout pig, we can then examine impact of “next generation” costimulatory blockade gents (anti-CD28 dAb and anti-CD154 dAb) in a pig-to-NHP model using these genetically optimized donor pigs.
Second, we will explore the T-cell derived lymphocytic response to xenotransplanted donor organs through analysis of the CD4+/CD8+ cells that mediate rejection. Here, we will explore the impact of CD4+ and CD8+ T cell-directed depletion immunosuppressive regimens, as well the impact of swine leukocyte antigen (SLA) class I or II deletion on T-cell mediated cytotoxicity by generating porcine donors with SLA class I or class II deletions on the Gal-/-, β4GAL-NT2 -/-, hCD55 tg background pigs.
These novel and highly efficacious new strategies in to the field of xenotransplantation has the potential to bring direct clinical and therapeutic applications to the >100,000 patients on the waiting list for a new kidney.