Insulin dependent diabetes mellitus (IDDM) also known as Type l diabetes is an autoimmune disease of unknown etiology is manifested as destruction of beta cells in the pancreatic islets of Langerhans. T cells are implicated in the pathogenesis of this multigenic inflammatory disease. From an immunological point of view, two hypotheses (at least) can be suggested for the development of human IDDM. The first states that beta cell destruction is an autoantigen targeted process; the second that beta cell destruction is the result of an inflammatory process that is not specifically directed to those cells but results in their destruction because of their susceptibility to cytokines produced by infiltrating cells. Transgenic mice will be used to evaluate these hypotheses and to study mechanisms of inflammation. The long term goal of this project is to evaluate the role of tumor necrosis factor-alpha (cachectin) and beta (lymphotoxin) in the pathogenesis of IDDM. Mice transgenic for the rat insulin promoter II (RIP) driving TNF-alpha or TNF-beta express the transgene in their islets. Both types of RIP-TNF mice exhibit periinsulitis and insulitis, but no beta cell destruction, insulin reduction, or diabetes. These animals appear to be locked in the first stages of IDDM.
The specific aims and methods to evaluate the cells and mechanisms of inflammation and pathogenesis in a transgenic model of IDDM are: A) To determine the requirements for progression from periinsulitis and insulitis to diabetes in TNF transgenic mice by testing whether TNF under the control of the glucagon promoter also induces inflammation and then analyze the response of RIP-TNF and GLU-TNF mice to activation signs (anti-CD3, anti-CD 28, superantigens) delivered in vivo or in vitro. TNF transgenic mice will be compared to NOD mice, a well established model of human IDDM and crossed to mice that possess the NOD but lack the background genes to determine if TNF expression in the islets can substitute for these genes; B)To determine the role of T cells specific or not for beta antigens in inflammation and beta cell destruction in TNF transgenic mice by analyzing T cells specific for GAD, BSA, and additional islet antigens or highly purified homogeneous populations of cells activated to cytochrome c or ovalbumin; C)To determine the mechanism of inflammation and beta cell destruction in TNF transgenic mice by analyzing the role of T and B cells, adhesion molecules, MHC antigens, cytokines, and chemokines. Transgenic mice that express TNF at inappropriate levels in islet tissue represent an interesting model system to test the mechanism of inflammation and beta cell destruction in IDDM and the role of particular immunologic cells in this process. They provide a unique opportunity to investigate the effect of targeted expression of a single cytokine gene on autoimmune disease pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI034404-01A1
Application #
2069516
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1994-05-01
Project End
1998-01-31
Budget Start
1994-05-01
Budget End
1995-01-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Yale University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Sacca, R; Cuff, C A; Lesslauer, W et al. (1998) Differential activities of secreted lymphotoxin-alpha3 and membrane lymphotoxin-alpha1beta2 in lymphotoxin-induced inflammation: critical role of TNF receptor 1 signaling. J Immunol 160:485-91
Cuff, C A; Schwartz, J; Bergman, C M et al. (1998) Lymphotoxin alpha3 induces chemokines and adhesion molecules: insight into the role of LT alpha in inflammation and lymphoid organ development. J Immunol 161:6853-60
Koni, P A; Sacca, R; Lawton, P et al. (1997) Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 6:491-500
Sacca, R; Cuff, C A; Ruddle, N H (1997) Mediators of inflammation. Curr Opin Immunol 9:851-7
Sacca, R; Turley, S; Soong, L et al. (1997) Transgenic expression of lymphotoxin restores lymph nodes to lymphotoxin-alpha-deficient mice. J Immunol 159:4252-60
Kratz, A; Campos-Neto, A; Hanson, M S et al. (1996) Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J Exp Med 183:1461-72
Sacca, R; Kratz, A; Campos-Neto, A et al. (1995) Lymphotoxin: from chronic inflammation to lymphoid organs. J Inflamm 47:81-4