CD40/CD40 ligand interactions are critical for elicitation of autoimmune-mediated fibrosis in the lung

Pulmonary interstitial fibrosis (PIF), associated with persistent inflammat ion and increased collagen deposition in the interstitium, is often conside red an autoimmune disease. Hapten immune PIF (HIPIF), a model for PIF, is e licited in the lung by a single intratracheal (i.t.) challenge in mice sens itized with hapten (2,4,6-trinitrobenzene sulfonic acid, TNBS), In this stu dy, we characterized the role of CD40/CD40 ligand (CD40L) interactions in t he elicitation of secondary cell-mediated immune responses that lead to dev elopment 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 I L-12 knockout recipient mice prevented the increased collagen deposition (a ccumulation of hydroxyproline) in the lungs during HIPIF induction. We conc lude that second signals (CD40/CD40L interactions) are required for elicita tion of secondary immune responses that lead to PIF in vivo, The results su pport the nation that CD40/CD40L interactions are involved in the pathogene sis of an ongoing autoimmune disease.