Targeting innate immunity for induction of robust renal allograft tolerance

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SUMMARY Establishing a reliable method to achieve allograft tolerance remains an ultimate goal in organ transplantation. We previously reported long-term immunosuppression (I.S.)-free renal allograft survival in humans after induction of only transient hematopoietic chimerism through donor bone marrow transplantation. To expand the application of our approach, it is now imperative to 1) improve the consistency and robustness of hematopoietic chimerism and allograft tolerance; 2) refine the conditioning regimen by identifying novel agents that can induce mixed chimerism without genotoxic adverse effects; and 3) expand the understanding of mechanisms whereby I.S.-free renal allograft acceptance via induction of transient mixed chimerism is achieved. There is ample evidence that proinflammatory responses during the peri-transplant period adversely affects long- term outcome of the allograft and tolerance induction. Integrin CD11b/CD18 (CD11b) is highly expressed on the surface of innate immune cells and modulates several key proinflammatory functions in innate immune cells. Our previous studies showed that blocking CD11b with mAb107, a first-in-class pure antagonist of CD11b, markedly limits reperfusion injury after prolonged warm ischemia of native kidney or kidney allografts in nonhuman primates. These observations led to our preliminary studies for this application that revealed superior long-term outcome of renal allografts as well as improved hematopoietic chimerism in recipients of mAb107. Therefore, in Aim 1, we will test the hypothesis that blocking CD11b with mAb107 in our mixed chimerism protocol will induce a more robust allograft tolerance. To reduce comorbidity of our conditioning regimen for bone marrow transplantation, we recently showed that selective Bcl-2 inhibition with Venetoclax significantly promotes hematopoietic chimerism and allograft tolerance with minimal myelosuppressive complications. However, complete elimination of genotoxic treatments from the conditioning regimen was not achieved with Bcl-2 inhibition and a minimal non-toxic dose of total body irradiation (TBI) was still required. ImmTOR is synthetic biodegradable nanoparticles encapsulating rapamycin. It can be rapidly endocytosed by dendritic cells and other myeloid cells and induces antigen-specific non-responsiveness in NHPs and humans. We therefore hypothesize that potent immunomodulatory effects of ImmTOR may more effectively protect allogeneic HSCs from alloimmune responses, allowing engraftment of HSCs without any genotoxic treatments. Our preliminary studies with ImmTOR are encouraging with multilineage mixed chimerism being induced without irradiation and chemotherapy. Finally, we will elucidate the mechanistic pathways involved in successful I.S.-free renal allograft survival by transient hematopoietic chimerism induced by mAb107 and ImmTOR, utilizing extensive in vitro and in vivo experiments with novel immunological approaches. Our hypothesis is that the major tolerance mechanism will be defined as regulatory but deletional mechanisms are also involved.