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
- Author(s)
- VONHERRATH, MG; Allison, J; Miller, JFAP; OLDSTONE, MBA;
- Details
- Publication Year 1995-02,Volume 95,Issue #2,Page 477-485
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- Publication Type
- Journal Article
- Abstract
- The participation of IL-2 in insulin-dependent (type I)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 MNC 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 lO% 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.
- Publisher
- ROCKEFELLER UNIV PRESS
- Keywords
- LYMPHOCYTIC CHORIOMENINGITIS VIRUS; NEONATALLY THYMECTOMIZED MICE; CYTOTOXIC T-LYMPHOCYTES; INTERFERON-GAMMA; CLONAL ANERGY; CLASS-I; INDUCTION; IL-2; INFECTION; PROLIFERATION
- Publisher's Version
- https://doi.org/10.1172/JCI117688
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- Refer to copyright notice on published article.
Creation Date: 1995-02-01 12:00:00