Contact Hypersensitivity Responses Following Ribavirin Treatment In Vivo Are Influenced by Type 1 Cytokine Polarization, Regulation of IL-10 Expression, and Costimulatory Signaling

• Published in: The Journal of immunology (1950) Vol. 163; no. 7; pp. 3709 - 3717
• Main Authors: Tam, Robert C, Lim, Charmaine, Bard, Josie, Pai, Bharati
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.10.1999
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - pharmacology; Administration, Cutaneous; AIDS/HIV; Allergens - administration & dosage; Allergens - immunology; Animals; Antigens, CD - biosynthesis; B7-1 Antigen - biosynthesis; B7-2 Antigen; Cytokines - biosynthesis; Cytokines - secretion; Dermatitis, Contact - immunology; Dermatitis, Contact - metabolism; Dinitrofluorobenzene - administration & dosage; Dinitrofluorobenzene - immunology; Female; Interferon-alpha - pharmacology; Interleukin-10 - biosynthesis; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymph Nodes - secretion; Membrane Glycoproteins - biosynthesis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Ribavirin - administration & dosage; Ribavirin - pharmacology; Signal Transduction - immunology; Species Specificity; Th1 Cells - drug effects; Th1 Cells - metabolism; Th1 Cells - secretion; Th2 Cells - drug effects; Th2 Cells - secretion
• DOI: 10.4049/jimmunol.163.7.3709
• ISSN: 0022-1767

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.