Induction of diabetes is influenced by the infectious virus and local expression of MHC class I and tumor necrosis factor-alpha.
To study self reactivity, a transgenic mouse model has been established in which the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) is expressed in the beta-islet cells of the pancreas (rat insulin promoter (RIP)-gp). These mice (H-2b) do not spontaneously develop diabetes; however, infection with the LCMV strain WE rapidly induces hyperglycemia. In this study, comparative analysis of H-2k RIP-gp-transgenic animals demonstrated that the haplotype influences the incidence and kinetics of diabetes and alters the requirement for the CD4+ T cell subset. This study also showed that the properties of the virus expressing the self target Ag determined whether hyperglycemia occurred in RIP-gp-transgenic mice. Various LCMV strains were able to induce diabetes in RIP-gp-transgenic animals, whereas infection with a recombinant vaccinia virus expressing LCMV-gp (vacc-gp) did not induce diabetes. However, vacc-gp could induce diabetes in double (RIP-gp/TCR)-transgenic mice, where the majority of CD8+ T cells expressed a receptor specific for LCMV-gp, suggesting that a critical number of self-reactive T cells must be activated to induce disease. Notably, histologic analysis of pancreata taken various days after LCMV or vacc-gp infections indicated that induction of diabetes coincided with an increase in MHC class I expression on the islets of Langerhans. Additional studies with vacc-gp were done to determine other factors that possibly enhance autoimmune attack. Transgenic mice expressing both LCMV-gp and TNF-alpha under the control of the RIP were infected with vacc-gp, and 50% of RIP-gp/TNF-alpha-transgenic animals became hyperglycemic. These data suggest that the increased local lymphocyte traffic as a result of TNF-alpha expression attracts activated gp-specific T cells, enhancing the possibility of hyperglycemia. Collectively, these results demonstrate that the induction of diabetes in this model is influenced by the MHC haplotype, the infectious agent, TNF-alpha expression, the level of MHC class I expression, and the induction of a threshold number of self-reactive CTL.
Department of Pathology, University of Zurich, Switzerland.
P S
PS
Ohashi
S
S
Oehen
P
P
Aichele
H
H
Pircher
B
B
Odermatt
P
P
Herrera
Y
Y
Higuchi
K
K
Buerki
H
H
Hengartner
R M
RM
Zinkernagel
D000818:Animals; D000956:Antigens, Viral / Q000032:analysis; D001483:Base Sequence; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D004198:Disease Susceptibility; D006023:Glycoproteins / Q000235:genetics; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000502:physiology*; D008216:Lymphocytic Choriomeningitis / Q000150:complications / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051381:Rats; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000502:physiology*; D014616:Vaccinia virus / Q000276:immunology
D000956:Antigens, Viral; D006023:Glycoproteins; D015395:Histocompatibility Antigens Class I; D014409:Tumor Necrosis Factor-alpha