CD40/CD40 ligand interactions are critical for elicitation of autoimmune-mediated fibrosis in the lung.
Pulmonary interstitial fibrosis (PIF), associated with persistent inflammation and increased collagen deposition in the interstitium, is often considered an autoimmune disease. Hapten immune PIF (HIPIF), a model for PIF, is elicited in the lung by a single intratracheal (i.t.) challenge in mice sensitized with hapten (2,4,6-trinitrobenzene sulfonic acid, TNBS). In this study, we characterized the role of CD40/CD40 ligand (CD40L) interactions in the elicitation of secondary cell-mediated immune responses that lead to development of fibrosis in the lung using an adoptive transfer model of HIPIF. The expression of CD40 was detected on bronchoalveolar lavage (BAL) cells 1-3 days after i.t. challenge with hapten in the HIPIF lung, but not lungs from the control mice. The CD40(bright) BAL cells morphologically resembled infiltrating monocytes. Furthermore, blocking CD40/CD40L interactions with blocking Ab decreased BAL production of Th1-mediators (IL-12 and TNF-alpha). Moreover, either blocking CD40/CD40L interactions with the Ab or using IL-12 knockout recipient mice prevented the increased collagen deposition (accumulation of hydroxyproline) in the lungs during HIPIF induction. We conclude that second signals (CD40/CD40L interactions) are required for elicitation of secondary immune responses that lead to PIF in vivo. The results support the notion that CD40/CD40L interactions are involved in the pathogenesis of an ongoing autoimmune disease.
Zhang-Hoover
J
J
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
Sutton
A
A
Stein-Streilein
J
J
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology; D006909:Hydroxyproline / Q000378:metabolism; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007442:Intubation, Intratracheal; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D019138:Antibodies, Blocking; D019013:CD40 Antigens; D016207:Cytokines; D006241:Haptens; D023201:CD40 Ligand; D018664:Interleukin-12; D014302:Trinitrobenzenesulfonic Acid; D006909:Hydroxyproline