A variety of DNA and RNA viruses cause autoimmune responses in humans and autoimmune disease in experimental models. This grant is concerned with dissecting and understanding the molecular mechanism(s) whereby multiple and sequential virus infections break immunologic unresponsiveness to """"""""self"""""""" antigens and cause autoimmune manifestations and disease. We developed two models where a viral protein (virus A) is expressed in beta cells of the islets of Langerhans or in oligodendrocytes using cell-specific promoters. In both, disease does not occur unless the host is challenged with virus A (disease incidence >90%, beta cell destruction by T cells resulting in hyperglycemia and hypoinsulinemia or T cell infiltration from the periphery into the CNS [white matter] and focal myelin loss). When a different virus B or C are used for the initial challenge disease does not occur but when viruses B or C are given four to six weeks after the initial inoculation with virus A, the kinetics and severity of disease is enhanced. The first business of this grant is to determine the mechanism by which multiple related or unrelated viral infections can enhance autoimmune disease. We will determine, by the use of the well established RIP-LCMV model of virus-induced autoimmune diabetes, whether the cross-reactive immune response is specific (shared peptide T cell epitopes) or due to bystander (cytokines, adhesion molecules) effects. Further, responses to self antigens (peptides) might contribute to activation and maintenance of autoreative T-lymphocytes. """"""""Self"""""""" antigens that contain the same MHC motif as the transgene's CTL epitope and bind at high affinity to the MHC allele have been uncovered. The ability of these """"""""self"""""""" peptides to be recognized by anti-viral T cells, maintain antiviral T cell memory and participate in autoimmune disease will be evaluated. Immunopathologic changes occur in normal islets transplanted under the renal capsule of transgenic mice developing IDDM. The second order of business is to determine the role of """"""""self"""""""" (islet-cell) antigens other than the initial triggering viral antigen in the pathogenetic process leading to and determine their role in IDDM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041439-02
Application #
2673015
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1997-08-01
Project End
2002-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Christen, Urs; Benke, Dirk; Wolfe, Tom et al. (2004) Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient. J Clin Invest 113:74-84
Stratmann, Thomas; Martin-Orozco, Natalia; Mallet-Designe, Valerie et al. (2003) Susceptible MHC alleles, not background genes, select an autoimmune T cell reactivity. J Clin Invest 112:902-14
Christen, Urs; McGavern, Dorian B; Luster, Andrew D et al. (2003) Among CXCR3 chemokines, IFN-gamma-inducible protein of 10 kDa (CXC chemokine ligand (CXCL) 10) but not monokine induced by IFN-gamma (CXCL9) imprints a pattern for the subsequent development of autoimmune disease. J Immunol 171:6838-45
Christen, Urs; von Herrath, Matthias G (2002) Transgenic animal models for type 1 diabetes: linking a tetracycline-inducible promoter with a virus-inducible mouse model. Transgenic Res 11:587-95
Holz, A; Brett, K; Oldstone, M B (2001) Constitutive beta cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes. J Clin Invest 108:1749-58
Hudrisier, D; Riond, J; Burlet-Schiltz, O et al. (2001) Structural and functional identification of major histocompatibility complex class I-restricted self-peptides as naturally occurring molecular mimics of viral antigens. Possible role in CD8+ T cell-mediated, virus-induced autoimmune disease. J Biol Chem 276:19396-403
Sevilla, N; Homann, D; von Herrath, M et al. (2000) Virus-induced diabetes in a transgenic model: role of cross-reacting viruses and quantitation of effector T cells needed to cause disease. J Virol 74:3284-92
Holz, A; Dyrberg, T; Hagopian, W et al. (2000) Neither B lymphocytes nor antibodies directed against self antigens of the islets of Langerhans are required for development of virus-induced autoimmune diabetes. J Immunol 165:5945-53