Immune Response to Tissue-Restricted Self-Antigens Induces Airway Inflammation and Fibrosis Following Murine Lung Transplantation

Abstract

Immune responses against lung-associated self-antigens (self-Ags) are hypothesized to play a role in the development of chronic lung graft rejection. We determined whether immune responses to lung self-Ags, K-alpha-1-tubulin (Kα1T) and Collagen V (Col-V) in the absence of alloimmunity, could promote airway inflammation and fibrosis. Following syngeneic murine orthotopic lung transplantation (LTx) we administered antibodies (Abs) to either Kα1T or Col-V or in combination to both of these self-Ags. As compared to recipients of isotype control Abs Kα1T Abs and/or Col-V Abs-treated recipients had marked lung graft cellular infiltration and bronchiolar fibrosis, This inflammation was also associated the accumulation of Kα1T and Col-V specific IFN-γ+ and IL-17+ T cells. Notably, the administration of Abs to Kα1T led to cellular and humoral immune responses to Col-V prior to development of fibrosis, and vice versa, indicating that epitope spreading can occur rapidly in an alloantigen independent manner. Collectively, these data support a model of chronic lung transplant rejection where the progressive loss of self-tolerance through epitope spreading promotes airway fibrosis. Strategies that target autoreactive Abs may be useful to inhibit chronic rejection of lung grafts.

Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation

“…These findings demonstrate that the effects of the lung-restricted antibodies are not global, but, rather, specific to the transplanted lung alone. We recently demonstrated that de novo lung-restricted antibodies, administered after lung transplantation, can mediate rejection of syngeneic lung grafts and predispose to chronic rejection (17). In the present article, we establish that preexisting lungrestricted antibodies lead to PGD in a dose-dependent manner.…”

“…Th17 cells specific to sAgs play an important role in development of sAg-specific immune responses. Although we specifically did not block Th17, previous studies from our laboratory, and others, have shown that blocking of Th17 can prevent OAD (17,48). The phenomenon of tissue-restricted immunity leading to organ rejection has also been demonstrated in heart allograft, where antibodies against cardiac myosin have been shown to be pathogenic in chronic heart allograft rejection (49).…”

“…Antibodies to KAT and Col-V Rabbit polyclonal IgG antibodies to KAT and Col-V were produced against KAT and Col-V proteins as previously described (17). Specificity of the antibodies was determined by ELISA with plates coated with purified proteins (Col-V, Col-I, and Col-II; optical densities for: Col-V, 0.863 nm; Col-I, 0.124 nm; and Col-II, 0.109 nm).…”

“…sAgs, unlike HLA antigens, are nonpolymorphic, and do not differ between individuals within a species. Hence, preexisting antibodies can bind to the allograft when their target sAgs are revealed as a result of ischemia-reperfusion injury at the time of transplantation, leading to humoral rejection (16)(17)(18). Therefore, it is plausible that a subset of recipients affected by PGD represent a manifestation of humoral rejection caused by preexisting antibodies directed against sAgs.…”

Chronic lung allograft dysfunction phenotypes and treatment

“…Given the advantage of genetics knockouts in mice and possibility of invasive sampling, this model is an excellent set-up to study underlying mechanisms. For example, it was shown that progressive loss of self-tolerance through epitope spreading promotes airway fibrosis (22). In another experiment, it has been shown that the murine lung allograft fibrosis originates mostly from the donor (23).…”