Background: Development of donor specific antibodies has been shown to precede the development of chronic rejection, bronchiolitis obliterans syndroms (BOS) following human lung transplantation. Using a murine model of obliterative airway disease (OAD), we demonstrated that administration of antibodies to MHC endobronchially results in induction of autoimmune responses mediated by IL17 dependent induction of immune responses to two lung associated self-antigens (SAgs), KΑ1 Tubulin (KΑ1T) and Collagen V (ColV). BATF a member of the AP1 family expressed in immune cells plays a crucial role in the Th17 differentiation. The objective of this study is to determine the role of IL6 induced via BATF signaling in induction of immune responses against SAgs leading to OAD.
Methods: BATF-/- or wild type mice were administered monoclonal antibodies to MHC endobronchially. The lungs were analyzed for cellular infiltration, epithelial metaplasia and luminal occlusion on day 30 by H&E staining. Frequency of T cells secreting IL-17 specific for KΑ1T and ColV were enumerated by ELISPOT. Antibodies against KΑ1T and ColV were measured by ELISA. Expression of IL-6 in the lungs was determined by quantitative real time PCR.
Results: Endobronchial administration of anti-MHC in the BATF-/- mice did not result in OAD as evidenced by significant reduction in cellular infiltration (25 vs. 58%, p<0.05), epithelial metaplasia (14 vs. 63%, p<0.05) and collagen deposition (2 vs. 44%, p<0.05). BATF-/- mice also demonstrated significant reduction in the frequency of Th17 cells against KΑ1T (5 vs. 130, p<0.05) and ColV (4 vs. 140, p<0.05) and developed significant lower titers of antibodies to SAgs when compared to wild type controls. The expression of IL-6 in the lungs of BATF-/- mice was also significantly lower.
Conclusion: Deficiency in the BATF signaling results in decreased IL-6 induced Th17 differentiation, reduced SAg specific cellular infiltration and humoral responses to SAgs following administration of anti-MHC resulting in abrogation of OAD induced by anti-MHC. These results strongly suggest that blocking of IL6 and/or IL6R will be a novel therapeutic option to prevent the development of BOS following human lung transplantation.
To cite this abstract in AMA style:Ramachandran S, Subramanian V, Gelman A, Mohanakumar T. Inhibition of IL6 Mediated Th17 Differentiation Via BATF Signaling Prevents the Development of Obliterative Airway Disease Induced by Antibodies to MHC Molecules [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/inhibition-of-il6-mediated-th17-differentiation-via-batf-signaling-prevents-the-development-of-obliterative-airway-disease-induced-by-antibodies-to-mhc-molecules/. Accessed August 9, 2020.
« Back to 2013 American Transplant Congress