Focal expression of interleukin-2 does not break unresponsiveness to "self" (viral) antigen expressed in beta cells but enhances development of autoimmune disease (diabetes) after initiation of an anti-self immune response.
The participation of IL-2 in insulin-dependent (type 1) diabetes (IDDM) was analyzed in transgenic (tg) mice expressing the nucleoprotein (NP) of lymphocytic choriomeningitis virus and IL-2 under control of the rat insulin promoter focally in beta cells of the islets of Langerhans. Insertion and expression of the viral (self) gene or of the IL-2 gene alone did not lead to IDDM. Infiltration primarily of CD4 and B lymphocytes and increased expression of MHC class I and II molecules occurred in islets where IL-2 was expressed. By contrast, neither cellular infiltrates nor expression of MHC class I or II glycoproteins above base levels was noted in tgs expressing the viral protein alone. Double tg mice expressing both the viral protein and IL-2 in their islets displayed a modest increase in incidence of spontaneous diabetes compared with that of single transgenic mice expressing IL-2 alone. Breaking of immunological unresponsiveness or sensitization to self antigens did not occur. Neither cytotoxic T lymphocytes (CTL) nor antibodies directed against the viral tg (NP) were generated. However, after challenge with lymphocytic choriomeningitis virus, double tg mice developed anti-self (viral) CTL and IDDM (incidence > 95%) within 2 mo. The generation of virus ("self")-specific MHC-restricted CTL was dependent on CD4+ help. In contrast, viral inoculum to single tg mice expressing either the viral protein or IL-2 failed to enhance the incidence of IDDM over 30% for viral protein or 10% for IL-2 after an 8-mo observation period. Hence, in this autoimmune model in situ expression of IL-2 did not break unresponsiveness but markedly enhanced ongoing disease.
von Herrath
M G
MG
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037.
Allison
J
J
Miller
J F
JF
Oldstone
M B
MB
D000704:Analysis of Variance; D000818:Animals; D000956:Antigens, Viral / Q000096:biosynthesis*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D017931:DNA Primers; D004279:DNA, Viral / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression; D005814:Genes, Viral; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010179:Pancreas / Q000276:immunology; D016133:Polymerase Chain Reaction; D051381:Rats; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013997:Time Factors
D000956:Antigens, Viral; D015704:CD4 Antigens; D016827:CD8 Antigens; D017931:DNA Primers; D004279:DNA, Viral; D007376:Interleukin-2