GSBS Dissertations and Theses

Date of Completion

March 2003

Document Type

Doctoral Dissertation

Department

Graduate School of Biomedical Sciences

Subjects

Islets of Langerhans Transplantation; Transplantation Tolerance; Immunosuppression; Autoimmunity; Graft Rejection; Antigens, CD40; Mice, Inbred NOD; Mice, Inbred C57BL; Academic Dissertations; Dissertations, UMMS

Abstract

The NOD mouse is a widely studied model of type 1 diabetes. The loss of self-tolerance leading to autoimmune diabetes in NOD mice involves at least 27 genetic loci. Curing type I diabetes in mice and humans by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. In addition to their genetic defects in self-tolerance, NOD mice resist peripheral transplantation tolerance induced by costimulation blockade using donor-specific transfusion and anti-CDl54 antibody. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Hypothesizing that these two abnormalities might be related, we investigated whether they had a common genetic basis. Diabetes-resistant NOD and C57BL/6 stocks congenic for various reciprocally introduced Idd loci were assessed for their ability to be tolerized. Surprisingly, in NOD congenic mice that are almost completely protected from diabetes, costimulation blockade failed to prolong skin allograft survival. In reciprocal C57BL/6 congenic mice with NOD-derived Idd loci, skin allograft survival was readily prolonged by costimulation blockade. Unexpectedly, we observed that (NOD x C57BL/6)F1 mice, which have no diabetes, nonetheless resist induction of tolerance to skin allografts. Further analyses revealed that the F1 mice shared the dendritic cell maturation defects and abnormal CD4+ T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. Finally, using a genome wide scan approach, we have identified four suggestive markers in the mouse genome that control the survival of skin allografts following DST and anti-CD154 mAb therapy. We suggest that mechanisms controlling autoimmunity and transplantation tolerance in NOD mice are not completely overlapping and are potentially distinct, or that the genetic threshold for normalizing the transplantation tolerance defect is higher than that for preventing autoimmune diabetes. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice are not under identical genetic control.

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