ALLOANTIBODIES TO MHC INDUCES AUTOIMMUNITY AND OBLITERATIVE AIRWAY DISEASE (OAD)

Washington University, Saint Louis MO

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Abstract

? DESCRIPTION (provided by applicant): Lung transplantation (LTx) is a viable treatment option for end-stage pulmonary diseases. Unfortunately long-term survival and function of lung allografts is limited by development of chronic rejection that is clinically diagnosed as bronchiolitis obliterans syndrome (BOS), an irreversible condition unresponsive to therapy and often fatal. Using newly developed models of obliterative airway disease (OAD), we demonstrated a seminal role for antibodies (Abs) to MHC and to lung self-antigens (Ags) (K?1 Tubulin (K?1T) and Collagen V (Col-V)) in inducing cellular and humoral immune responses to self-Ags and MHC leading to OAD. Passive administration of Abs resulted in induction of several important molecules involved in the activation of T helper cells (Zbtb7a), inflammatory cascade (Laptm5) and limiting regulatory T cell populations (Mt1). Our results using syngeneic and allogenic murine single LTx models have demonstrated that administration of Abs to lung Ags can lead to OAD. Further, we have evidence that Abs to MHC as well as Abs to K?1T or Col-V can break tolerance to lung allografts resulting in OAD in a MHC mismatch LTx model in which tolerance was established using co-stimulatory blockade. Administration of anti-K?1T resulted in not only cellular autoimmunity to K?1T but also cellular as well as humoral responses to Col-V and donor MHC indicating spreading of immune responses in lung allograft rejection. These results collectively demonstrate an important role for Abs to MHC and self-Ags in the pathogenesis of OAD. The goals of this project are to: 1) define the early events following administration of Abs that leads to activation of T helper cells, inflammatory cascade, and T regulatory cells using RNA interference based targeted gene knockdown, 2) to define the mechanisms by which anti-MHC and anti-lung self-Ags induce exosome formation and define the role of exosomes in the spreading of immune responses. We demonstrated that bronchoalveolar lavage (BAL) fluids from mice following administration of Abs as well as anti-MHC (DSA)+ human LTx recipients contain increased concentration of exosomes in the local milieu, which express lung self-Ags (K?1T, Col-V and Col-I). Our hypothesis is that these exosomes play an essential role in eliciting augmented immune responses leading to intermolecular spreading, breaking of tolerance and allograft rejection. Towards this we will isolate and characterize exosomes from BAL fluid and determine if immunization with exosomes regulates the polarization and switch in macrophage phenotypes that stimulates auto-immune and alloimmune responses, and 3) determine the role of neutrophils in the Ab induced exosome formation in murine LTx. The overall goal of this proposal is to employ unique preclinical murine models of OAD to delineate the molecular mechanisms leading to autoimmunity in the pathogenesis of BOS following human LTx and to develop new therapeutic strategies towards preventing and/or treating chronic lung allograft rejection.