Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection

Abstract

Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.

Keywords: AEC; AGTR1; AMR; APC; Ab; Ag; BOS; CAN; CAV; CMV; CR; ColV; DC; DSA; HCV; HIF-1α; HLA; IRI; Kα1 tubulin; Kα1T; MHC; MHC class I related chain A; MICA; NHBE; OAD; OLT; PGD; TG; TRALI; Tx; airway epithelial cells; angiotensin II type 1 receptor; antibody; antibody mediated rejection; antigen; antigen presenting cell; bronchiolitis obliterans syndrome; cardiac allograft vasculopathy; chronic allograft nephropathy; chronic rejection; collagen V; cytomegalovirus; dendritic cells; donor specific antibodies; hepatitis C virus; human bronchial epithelial; human leukocyte antigen; hypoxia inducible factor; iNKT; invariant natural killer T cells; mTOR; major histocompatibility complex; mammalian target of rapamycin; obliterative airway disease; orthotopic liver transplantation; primary graft dysfunction; schemia/reperfusion injury; transfusion-related lung injury; transplant glomerulopathy; transplantation.

Figure 1

Temporal depiction of the sequence of events leading to allograft failure. The temporal sequence of initial inflammatory events following solid organ transplantation such as surgical stress, viral infections, GERD, mismatched HLA, etc leads to inflammatory injury to the allograft. These risk factors potentially play an important role in the acute rejection episode. Further, presence of pre-transplant Abs to self-antigens could also lead to higher incidence of alloimmunity and allograft rejection. This initial inflammatory injury could potentiate tissue remodeling and exposure of cryptic self-antigens and leading to autoimmunity and potential development of CR. Potential therapeutic options have been listed in the last panel. Green, indicates functioning allograft; and red, indicates non-functional allograft (color code given only for representation and not intended to indicate exact allograft survival temporal percentage).

Figure 2

An overview of the potential mechanism for the exposure of cryptic antigenic determinants leading to development of Abs to self-Ags in CR following solid organ Tx. Various risk factors such as surgical stress, viral and bacterial infections, mismatched HLA following solid organ transplantation induces tissue remodeling and exposure of cryptic self-antigenic determinants. This leads to cellular and humoral responses and upregulated expression of fibrotic signaling molecules and growth factors such as HIF1α, VEGF, FGF, etc. All these culminate to fibrosis and loss of function manifesting as CR of the allograft.