This proposal will foster a career development program that will enable the clinical fellow (ZK) to gain experience in the basic science setting and make fundamental contributions in studies of type1diabetes (T1D). T1D is an organ-specific autoimmune disease that results from the loss of insulin-producing ?-cells in the pancreatic islets caused by pathologic loss of immune tolerance. Many aspects of the human disease are shared with the non-obese diabetic (NOD) mouse model of the disorder. Studies have shown that immune modulatory therapy eliminating B lymphocytes or T cells will delay disease, but are not sustainable therapies for diabetes prevention. Induction of immune tolerance using oral insulin has been successful in NOD mice and patients with high insulin autoantibody titers. Oral insulin results in alteration of T cell subsets. B lymphocytes play an important role as requisite antigen-presenting cells (APC) for auto reactive T cell activation, but their role in induction of oral tolerance is unknown. Ability to enhance the induction of oral tolerance offers promise to prevent T1D in the broader population. We hypothesize that treatment of T1D-prone NOD mice with oral insulin will induce tolerance through anti-insulin B lymphocyte-mediated alteration of effectors lymphocyte subpopulations and restore self-tolerance preventing overt autoimmune diabetes. This will be investigated by treatment of B lymphocyte receptor transgenic NOD mice with oral insulin. This mouse model is a near physiologic model of T1D with a traceable insulin reactive B lymphocyte population. This model will be used to define the contributions of auto antigen specific B lymphocytes to alterations of T regulatory (Treg) and T helper (Th) cell subsets and cytokine production in response to oral insulin therapy. Factors affecting auto antigen specific B lymphocyte trafficking will be evaluated using adoptive transferring of anti-insulin B lymphocytes. ???? is an integrand for gut-homing of both T and B lymphocytes. The homing of anti-insulin B lymphocytes with guts markers to PLNs and insulitis lesions after exposure to oral insulin would indicate an important local role for the anti-insulin B lymphocyte i oral tolerance. Additionally, experiments will be done using adoptive transfer of diabetogenic BDC2.5 T cells to determine if oral tolerance mediated by anti-insulin B lymphocytes provides broad immunoprotection from ?-cell destruction. Successful outcomes identifying alterations in immune function that accompany oral antigen in concert with antigen-specific B lymphocytes will suggest a new strategy that combines immunization with oral antigen for prevention of human T1D.

Public Health Relevance

Type 1 diabetes portends increased morbidity and mortality for patients. Oral tolerance is a promising intervention for the prevention of this disease. This proposal will test whether induction of oral tolerance to insulin is B lymphocyte-mediated and will evaluate the mechanistic contribution of antigen-specific B lymphocytes to immunoregulation that occurs upon induction of oral tolerance for insulin.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-R (M1))
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Castle, Arthur
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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