Delayed graft function (DGF) is a manifestation of ischemia-reperfusion injury (IRI) in the transplanted kidney allograft. DGF is an important risk factor in T-cell or antibody-mediated biopsy-proven acute rejection, and the strongest risk factor for chronic allograft dysfunction, exceeding even that of pre-transplant diabetes. IRI is an acute inflammatory response mediated by the recipient's activated innate immune cells that infiltrate the ischemic organ following reperfusion. Previous efforts to limit IRI, conducted primarily in rodents, have targeted individual proinflammatory mediators and showed promise in rodents, but this approach was less effective in large animals and failed in human trials. We have demonstrated that the archetypal innate immune receptor leukocyte integrin CD11b/CD18 mediates IRI in native nonhuman primate (NHP) kidneys, and that a first-in- class anti-CD11b monoclonal antibody (mAb107) protected IRI native kidneys from otherwise irreversible kidney failure. The main objective of this exploratory R21 is to evaluate the effect of limiting IRI with mAb107 on DGF in our well-studied NHP kidney transplant model. We have also shown that the recipient's innate alloreactive memory T cells present in primates but absent in laboratory mice, play a critical role in allograft rejection. Our preliminary data show that these cells express CD11b, and are inhibited by mAb107 in vitro. Therefore, a second objective of this study is to evaluate the effect of mAb107 on the proinflammatory functions of these alloreactive cells in NHP transplant recipients. These studies should help elucidate the mechanisms linking innate DGF, rejection and allograft outcome, and may help define an effective approach to limiting the progressive fibrosis currently observed clinically in 65% of renal allografts.
Delayed graft function (DGF) of kidney allografts, most often caused by injury of the transplant by the recipient's immune response upon reperfusion, continues to be a major clinical challenge with no effective treatment, and resulting in a 40% decrease in long-term graft survival. We have recently shown in a clinically relevant non-human primate (NHP) model that the first-in-class anti-CD11b mAb107 protected native kidneys from reperfusion injury long-term. This application will test the hypothesis that mAb107 will protect the transplanted kidneys from DGF and its pathologic sequelae in an established NHP allograft transplant model.
