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.
View: Text | PDF
Article Aging

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

×

Figure 6

Options: View larger image (or click on image) Download as PowerPoint
Blockade of IFN-γ or TNF-α prevents abrogation of diabetes by secondary ...
Blockade of IFN-γ or TNF-α prevents abrogation of diabetes by secondary viral infection. (a) Cumulative incidence of diabetes in RIP-LCMV-NP mice infected i.p. with 105 PFUs of LCMV-Arm on day 0 and 105 PFUs of LCMV-Past 1 month after LCMV-Arm infection. Blood glucose was measured in weekly intervals, and values greater than 300 mg/dl were considered diabetic. The number of diabetic mice and the total number of animals used per group are indicated in brackets. Human TNFR55-IgG1 fusion protein (38, 39) or neutralizing rat anti–mouse IFN-γ antibody (Pharmingen, San Diego, California, USA) were given at 100 μg (i.v.) or 50 μg (i.v.), respectively, at days 1, 3, 6, and 9 after secondary (Past) infection. (b) In vitro hyperstimulation with Db(NP396)-tetramers (16 hours at 37°C) of lymphocytes isolated from spleen and PDLN of C57BL/6 mice at 1 week after LCMV-Arm infection. Apoptosis of Db(NP396)-specific CD8 T cells was determined by staining with annexin V–phycoerythrin conjugate in parallel to staining with Db(NP396)-tetramers. Cells were incubated in medium alone (control) or in the presence of human TNFR55-IgG1 fusion protein (100 μg/well) or neutralizing rat anti–mouse IFN-γ antibody (100 μg/well). *Among splenocytes, significant differences in the number of Db(NP396)-specific CD8 T cells that undergo apoptosis (annexin Vhi cells) were observed after blockade of TNF-α compared with the control stimulation, but not after IFN-γ blockade (Student’s t test, P < 0.05). **PDLNs were collected from three mice, and cells were pooled in order to increase the number of Db(NP396)-specific CD8 T cells within the experimental setup.