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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Protective viral infection results in increased IP-10 expression in the ...
Protective viral infection results in increased IP-10 expression in the PDLN and a decrease of islet-infiltrating CD8 lymphocytes. Left: RIP-LCMV-NP mice were infected (inf.) i.p. with 105 PFUs of LCMV-Arm and received a secondary i.p. infection (2nd inf.) after 1 month with 105 PFUs of LCMV-Arm or LCMV-Past. Right: Nine-week-old NOD mice were infected i.p. with 105 PFUs of LCMV-Arm (Arm) or LCMV-Past (Past). (a) Some RIP-LCMV-NP and NOD mice were sacrificed at day 1 after secondary infection for assessment of the expression of IP-10 (CXCR3) in the pancreas and PDLN. The relative IP-10 mRNA expression was analyzed by RNase protection assay and normalized against L32 housekeeping RNA expression (n = 3–4). (b) At day 3 after secondary infection, pancreata and PDLNs were harvested, and 6-μm tissue sections were probed for cellular infiltration by CD4 and CD8 T cells. These representative tissue sections show an average degree of islet infiltration per group as found in the pancreas of individual mice (n = 3–4). (c) Insulitis score as obtained from sections of 3–4 mice per group. Scoring system: 0, no infiltration; 1, some peri-insular infiltration; 2, heavy peri-insular infiltration with some intra-insular infiltrates; 3, heavy intra-insular infiltration and/or islet scars. The mean score was obtained by division of the sum of all individual islet-infiltration scores by the total number of islets analyzed.