Pathological changes in the islet milieu precede infiltration of islets and destruction of beta-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM.
RIP-LCMV transgenic mice that express the viral glycoprotein (GP) or nucleoprotein (NP) from lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter (RIP) in pancreatic beta-cells develop autoimmune diabetes (IDDM) after infection with LCMV. Previous reports have described that the viral infection activates naive, potentially autoreactive CD8+ cytotoxic T-lymphocytes (CTL) that are present in the periphery of these mice, thus leading to the breaking of immunological unresponsiveness to the viral self-antigen expressed on beta-cells. However, we find that adoptive transfer of such CTL that were active in vitro and in vivo into uninfected RIP-LCMV recipients rarely resulted in hyperglycemia nor in insulitis, despite their ability to home to the islets and induce peri-insulitis. These observations indicated that, in addition to activated autoreactive lymphocytes, other factor(s) were required for beta-cell destruction. The present study shows that upregulation of MHC class II molecules associated with the attraction/activation of antigen presenting cells (APCs) to the islets occurs as soon as 2 days after LCMV inoculation of transgenic mice, clearly before CD4+ and CD8+ lymphocytes are found entering the islets (days 6 and 7 after LCMV inoculation). In contrast, although some MHC class II upregulation is also found in islets of non-transgenic mice 2-4 days after LCMV infection, no insulitis or IDDM develops and MHC is downregulated to normal (pre-infection) levels by day 7-10 in these mice. Associated with the activation of APCs and MHC upregulation observed in transgenic mice, viral (LCMV) infection of islets was detectable 2 days post-viral inoculation in some mice. Thus, beta-cell destruction by activated autoreactive lymphocytes is a multifactorial process that is likely to require changes within the islet milieu or dysfunction of islets.
von Herrath
M
M
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. matthias@scripps.edu
Holz
A
A
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000302:isolation & purification; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D051381:Rats; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015854:Up-Regulation / Q000276:immunology
D001324:Autoantigens; D000949:Histocompatibility Antigens Class II