Contact hypersensitivity responses following ribavirin treatment in vivo are influenced by type 1 cytokine polarization, regulation of IL-10 expression, and costimulatory signaling.
We previously described the promotion of type 1 cytokine responses by the nucleoside analogue, ribavirin, in human T cells in vitro. In this study, we examined whether type 1 cytokine polarization by ribavirin in vivo could promote contact hypersensitivity (CHS) responses to dinitrofluorobenzene, a type 1 cytokine-mediated immune response. Unexpectedly, although type 1 cytokine responses were enhanced following ribavirin treatment in vitro and in vivo, the magnitude of CHS responses in BALB/c and C57BL/6 mice was influenced more by a second ribavirin-regulated pathway. The key regulatory molecule in this pathway was IL-10. Ribavirin-mediated suppression of IL-10 in BALB/c mice was associated with increased B7-2 expression and enhanced CHS responses, whereas enhanced IL-10 levels, following ribavirin administration, led to increased B7-1 expression and impaired CHS responses in C57BL/6 mice. The effect of ribavirin on the expression of B7 molecules and on CHS responses was neutralized by IL-10 administration in BALB/c and by anti-IL-10 Ab in C57BL/6. Thus, ribavirin controlled CHS responses directly through the modulation of IL-10 expression, and in vivo outcome was dictated by the preferential expression of either B7-1, an inappropriate costimulatory molecule in CHS, or B7-2, the predominant costimulatory molecule in CHS. Replacing dinitrofluorobenzene priming with IFN-alpha stimulation, we showed that the ribavirin-regulated pathway could function independent of Ag priming. Altogether, these data showed that, although ribavirin treatment induced a type 1 cytokine bias in contact allergen-primed BALB/c and C57BL/6 mice, in vivo CHS responses were dependent on ribavirin-mediated regulation of both IL-10 and preferential costimulatory signaling.
Tam
R C
RC
Immunology Laboratory, ICN Research Center, Costa Mesa, CA 92626, USA. rctam@icmpharm.com
Lim
C
C
Bard
J
J
Pai
B
B
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000279:Administration, Cutaneous; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D003877:Dermatitis, Contact / Q000276:immunology* / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D016898:Interferon-alpha / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012254:Ribavirin / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology*; D013045:Species Specificity; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000485:Allergens; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D016207:Cytokines; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D016753:Interleukin-10; D012254:Ribavirin; D004139:Dinitrofluorobenzene