Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient.
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-alpha or IFN-gamma 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.
Christen
Urs
U
Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Benke
Dirk
D
Wolfe
Tom
T
Rodrigo
Evelyn
E
Rhode
Antje
A
Hughes
Anna C
AC
Oldstone
Michael B A
MB
von Herrath
Matthias G
MG
D000375:Aging; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control* / Q000821:virology; D008216:Lymphocytic Choriomeningitis / Q000473:pathology / Q000503:physiopathology*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011236:Prediabetic State / Q000517:prevention & control* / Q000821:virology; D013997:Time Factors