My research interests are to understand the pathogenesis of insulin dependent diabetes mellitus (IDDM) so that effective forms of therapy for treatment and prevention may be devised. My previous training has been in clinical Endocrinology with further advanced training in basic immunology, with Dr. Frank Fitch, and the immunology of diabetes with Dr. Ake Lemmark. Much of this experience has included fundamental cellular and molecular techniques which are involved in this project. With this proposal, I plan to test the hypothesis that, in a murine model, diabetes is caused by the destruction of beta cells by T lymphocytes. I plan to identify these T cells and the antigens they recognize. IDDM is now believed to be the result of an autoimmune destruction of the islets of Langerhans. However, the antigens that are involved or the pathogenesis of the immune component of the disease are unknown. In previous studies, I have found that T lymphocytes are mediators of insulitis and diabetes induced in mice with multiple subdiabetic closes of streptozotocin (MDSDM). More recently, I have found that T cells that use the VB8 chain of the T cell receptor are involved. Two recent developments make it now possible to isolate T cells reactive with islet cells and identify the antigens they recognize. First, antigen reactive T cells that maintain their antigen reactivity may be grown in the absence of antigen with an anti-CD3 antibody. Second, tumor cell lines are now available that appear similar to islet cells in a number of ways and represent a plentiful source of antigen. I plan to derive T cell clones from the insulitis in animals with MDSDM that are reactive with an islet cell tumor line, BTC3. These clones will be extensively characterized and their ability to transfer diabetes will be studied. The use of subtypes of the BV8 T cell receptor among these clones will be analyzed, and in future studies, the effects of immunotherapies against the VB8 subtypes may be tested for their ability to prevent MDSDM. Finally, a cDNA library will be prepared from BTC3 cells and expressed with a eucaryotic expression vector system. Transfectants will be made from this library and screened for the production of antigen recognized by the T cell clones. Once the gene encoding recognized by the T cells is present in normal islets or is acquired, perhaps as a result of streptozotocin treatment, in future studies the structure and identity of this antigen will be determined. The academic environment at the University of Chicago is ideal for these studies. Dr. Frank W. Fitch is an outstanding immunologist and will serve as my sponsor. In addition to his expertise, other individuals in the Committee on Immunology and the scientific community at the University will provide support and resources that are necessary for these studies. These include molecular biologists such as Graeme Bell, immunologists such as Jeffery Bluestone, and diabetologists such as Arthur Rubenstein and Kenneth Polonsky.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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University of Chicago
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Herold, K C; Bloch, T N; Vezys, V et al. (1995) Diabetes induced with low doses of streptozotocin is mediated by V beta 8.2+ T-cells. Diabetes 44:354-9
Herold, K C; Vezys, V; Gage, A et al. (1994) Prevention of autoimmune diabetes by treatment with anti-LFA-1 and anti-ICAM-1 monoclonal antibodies. Cell Immunol 157:489-500
Herold, K C; Nagamatsu, S; Buse, J B et al. (1993) Inhibition of glucose-stimulated insulin release from beta TC3 cells and rodent islets by an analog of FK506. Transplantation 55:186-92
Herold, K C; Bluestone, J A; Montag, A G et al. (1992) Prevention of autoimmune diabetes with nonactivating anti-CD3 monoclonal antibody. Diabetes 41:385-91
Herold, K C; Montag, A G; Buckingham, F (1992) Induction of tolerance to autoimmune diabetes with islet antigens. J Exp Med 176:1107-14
Herold, K C; Rubenstein, A H (1992) New directions in the immunology of autoimmune diabetes. Ann Intern Med 117:436-8