The definitive cure for diabetes mellitus is beta cell replacement. Currently, available forms of replacement require generalized immunosuppressor, but promising alternatives to immunosuppression- dependent transplantation have recently been developed. These include donor-specific immune tolerance. An islet transplantation protocol based on a single donor-initially been targeted at non-autoimmune diabetes because animal data suggest the modification will be necessary in the cause of autoimmune juvenile-type diabetes. Additional new discoveries, however, discover that the generation of allogeneic hemopoietic chimerism based on sub-lethal conditioning in the presence of anti- CD154 antibody will permit islet transplantation for autoimmune diabetes to succeed. As human studies become imminent, concerns have been expressed about the potential of viral illness to compromise patient safety and islet graft durability. Host responses to infection that may occur during tolerance induction are not well characterized. In addition, virus infection poses a threat to both allotolerant and chimeric states because it can disrupt immunoregulation and induce allospecific T cells. This Program Project, based on a collaboration between basic virologists, immunologists, and clinicians proposes to document the mechanisms and safety of transplantation tolerance in the face of vital infection in mice. Project #1 will study the basic safety and durability of tolerance in mice given allografts and infected with various viral pathogens. It will study the effect of tolerance induction on the virus-specific immune response of the host, the host's ability to clear virus, and the mechanisms that underlie these responses. Project #2 will study the host immune response to allogeneic grafts in tolerant normal mice infected with viral pathogens, using allospecific T cell receptor transgenic model systems to identify the mechanisms by which virus infection alters the induction and durability of transplantation tolerance. Project #3 will study islet grafts in autoimmune, spontaneously diabetic NOD mice, treated by a new method to induce tolerance, in the presence and absence of viral infection. Two Core Facilities focused on Virology and Morphology will facilitate the work of these Projects. If the Project's goals are reached, we will gain a better understanding of the molecular, biochemical, and cellular mechanisms of tolerance induction. Equally important, we will evaluate the safety of this technology as it enters """"""""real world"""""""" implementation as a practical method of islet transplantation tolerance induction for the cure of diabetes without chronic immunosuppression.
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