Type 1 diabetes (T1D) is an autoimmune disorder that results in destruction of insulin-producing beta cells by autoreactive T cells. T1D autoimmunity arises from defective central and peripheral tolerance, which is associated with the MHC II molecule I-Ag7 in mice and HLA-DQ in humans. Central tolerance defects are associated with defective thymic deletion of autoreactive T cells, which is mediated by thymic medullary dendritic cells (DCs). Peripheral tolerance defects are associated with quantitative and qualitative defects in regulatory T (Treg) cells such as Foxp3 + Treg cells and expansion of autoreactive B cells. Therapies that modulate peripheral tolerance, such as anti-CD3 treatment that depletes pathogenic T cells and expands Treg cells, or anti-CD20 treatment that depletes pathogenic B cells, have failed to yield lasting therapeutic effects. Therefore, a regimen that can simultaneously correct multiple defects may be needed to reverse autoimmunity in T1D patients.
Since T1D autoimmunity arises from abnormalities in the hematopoietic system, and T1D can be transferred into non-T1D patients by hematopoietic cell transplantation (HCT) from potential T1D donors, or vice versa, it has been proposed that HCT could be a curative therapy for T1D autoimmunity. Unfortunately, classical HCT procedures are not acceptable for T1D patients because of toxicity of the total body irradiation procedure and the risk for a severe side effect, graft versus host disease (GVHD). As an alternative to total body irradiation, the Zeng laboratory developed a radiation-free anti-CD3/CD8-conditioning regimen that induces mixed chimerism without causing any signs of GVHD in pre-diabetic and overtly diabetic NOD mice. Mixed chimerism is a state in which donor- and host-type hematopoietic system co-exist. Induction of mixed chimerism reverses autoimmunity, eliminates insulitis and allows the host beta-cells to regenerate, resulting in a cure of overt T1D. However, the mechanisms underlying this reversal of autoimmunity remain unknown. This thesis project has aimed to dissect mechanisms by which mixed chimerism reverses autoimmunity in a T1D animal model, the autoimmune NOD mouse. These mechanisms include: elimination of insulitis and thymic deletion of autoreactive T cells with MHC-mismatched but not MHC-matched mixed chimerism; deletion of autoreactive T cells with promiscuous T cell receptors that cross-react with mismatched MHC molecules; maintenance of tolerance with MHC-mismatched transplantation for clones without cross-reactivity; donor-type DC and Tregs interacting for maintenance of tolerance of residual cross-reactive T cells; and deletion of autoreactive B cells.
Together, these studies demonstrate that induction of mixed chimerism can simultaneously re-establish both central and peripheral tolerance, repairing multiple steps in the pathogenicity of type 1 diabetes.
|Commitee:||Ku, Hsun Teresa, Serreze, David, Shively, John, Sun, Zuoming|
|School:||City of Hope's Irell & Manella Graduate School of Biomedical Sciences|
|Department:||Graduate School of Biological Sciences|
|School Location:||United States -- California|
|Source:||DAI-B 74/10(E), Dissertation Abstracts International|
|Keywords:||Autoimmunity, Bone marrow transplantation, Chimerism, Hematopoietic stem cell transplantation, Tolerance, Type 1 diabetes|
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