Protecting Allogeneic Pancreatic Islet Grafts by Engineered Veto

Abstract

In todays clinical practice, general immune suppression regimens are used to prevent transplant rejection. Though highly effective, they impair a patients protection against infectious challenges. Strategies are being sought that prevent graft rejection without inhibiting beneficial immune functions. One such approach is based on the classical veto effect that employs donor-derived CD8+ T cells to inhibit cellular immune responses. Yet, allogeneic grafts may only be partially protected by classical veto as CD8+ T cells may fail to remove organ-specific alloreactive T cells. To induce transplant specific immune unresponsiveness, if not tolerance, it may be necessary to endow grafted tissues with veto. Adenoviral vectors were designed that expressed the CD8 -chain as transgene and thus conferred the immune inhibitory veto function to cells of grafted tissues. In the present model, adenoviral vector vectors protected transduced allogeneic pancreatic islets from rejection in fully immune competent recipients. These studies demonstrated that a tissue-engineering approached could be used to create universally acceptable transplants.