Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient
Urs Christen, … , Michael B.A. Oldstone, Matthias G. von Herrath
Urs Christen, … , Michael B.A. Oldstone, Matthias G. von Herrath
Published January 1, 2004
Citation Information: J Clin Invest. 2004;113(1):74-84. https://doi.org/10.1172/JCI17005.
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Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient

Abstract

Viruses can cause but can also prevent autoimmune disease. This dualism has certainly hampered attempts to establish a causal relationship between viral infections and type 1 diabetes (T1D). To develop a better mechanistic understanding of how viruses can influence the development of autoimmune disease, we exposed prediabetic mice to various viral infections. We used the well-established NOD and transgenic RIP-LCMV models of autoimmune diabetes. In both cases, infection with the lymphocytic choriomeningitis virus (LCMV) completely abrogated the diabetic process. Interestingly, such therapeutic viral infections resulted in a rapid recruitment of T lymphocytes from the islet infiltrate to the pancreatic draining lymph node, where increased apoptosis was occurring. In both models this was associated with a selective and extensive expression of the chemokine IP-10 (CXCL10), which predominantly attracts activated T lymphocytes, in the pancreatic draining lymph node, and in RIP-LCMV mice it depended on the viral antigenic load. In RIP-LCMV mice, blockade of TNF-α or IFN-γ in vivo abolished the prevention of T1D. Thus, virally induced proinflammatory cytokines and chemokines can influence the ongoing autoaggressive process beneficially at the preclinical stage, if produced at the correct location, time, and levels.

Authors

Urs Christen, Dirk Benke, Tom Wolfe, Evelyn Rodrigo, Antje Rhode, Anna C. Hughes, Michael B.A. Oldstone, Matthias G. von Herrath

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Abrogative infection of RIP-LCMV mice with LCMV-Past results in decrease...
Abrogative infection of RIP-LCMV mice with LCMV-Past results in decreased pCTL frequencies and higher viral titers in the PDLN. Viral titers were determined in the pancreas, the spleen, and the PDLN of RIP-LCMV-NP mice at day 3 after primary i.p. infection with 105 PFUs of LCMV-Arm or LCMV-Past or, alternatively, at day 3 after secondary infection (administered 4 weeks after initial LCMV-Arm infection) with 105 PFUs of LCMV-Arm (nonabrogative) or LCMV-Past (abrogates diabetes). Data are shown as mean PFUs/10 mg tissue (± SD) as obtained from plaque assays (n = 4).