Date of Award

12-2005

Level of Access

Campus-Only Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry

Advisor

David Serreze

Second Committee Member

Edward Leiter

Third Committee Member

Charles Moody

Abstract

Type 1 diabetes (TlD) in both humans and the non-obese diabetic (NOD) mouse model is caused by the destruction of insulin producing pancreatic β cells by autoreactive T cells. Though polygenically controlled, genes encoding this strain's major histocompatiblity complex (MHC), designated H2g7, play a major role in disease succeptibility. The MHC is indeed an essential component to T1D progression in the NOD mouse as the congenic expression of MHC haplotypes from T1D resistant strains results in strong protection from disease. Consistent with this data, studies have demonstrated that expression of T1D resistant MHC alleles on hematopoietically derived antigen presenting cells (APC) is sufficient to induce disease protection. While allogeneic bone marrow transplantation seems to be an attractive means to protect against T1D, its clinical application is tarnished by the necessity to pre-condition the host with what would be a lethal dose of irradiation in the event that the donor bone marrow failed to engraft. There have been numerous reports where non-lethal pre-conditioning protocols were used to engraft NOD mice with T1D protective allogeneic marrow. In these studies, nearly all the hematopoietic cells were converted to donor type in the NOD recipients. In this present study, we demonstrate that full allogeneic chimerism leads to an immune-compromised state. This is primarily due to the fact that the T cells present in the host are positively selected in the thymus on non-hematopoietically derived host MHC molecules; however, the only APC present in the periphery to activate T cell effector functions are those expressing donor MHC molecules. For these reasons, generation of mixed hematopoetic chimerism with non-lethal pre-conditioning protocols would provide a more effective means of preserving immune-competence as well as protecting the host from T1D. This study demonstrates the achievement of T1D protection with a state of stable mixed hematopoietic chimerism in the NOD mouse through a preconditioning regiment consisting of sub-lethal irradiation, transient CD8 T cell depletion, and CD40-CD40L co-stimulatory pathway blockade.

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