Abstract and Introduction
Abstract
Despite progress in the field of organ transplantation for improvement in graft survival and function, long-term graft function is still limited by the development of chronic allograft rejection. Various immune-mediated and nonimmune-mediated processes have been postulated in the pathogenesis of chronic rejection. In this review, the authors discuss the important role of alloimmune responses to donor-specific antigens and autoimmune responses to tissue restricted self-antigens in the immunopathogenesis of chronic rejection following solid organ transplantation. In particular, the authors discuss the role of induction of Th17-type autoimmune responses and the crosstalk between autoimmune and alloimmune responses. These self-perpetuate each other leading to activation of profibrotic and proinflammatory cascades that ultimately result in the development of chronic rejection.
Introduction
The first reported organ transplantation was that of a kidney transplant carried out between identical twins in 1955.[1] Since then, organ transplantation has become a well-accepted life saving therapeutic strategy in end stage diseases of several organs including the heart, lung, liver, kidney, pancreas, small bowel and so on. Most of this success can be attributed to significant advances in surgical technique, organ preservation, patient management and immunosuppression.
Early studies in transplantation were primarily aimed at improving outcomes and preventing acute rejection of the transplanted organ.[2–6] These strategies, including histocompatibility and blood group matching as well as newer and better immunosuppressive protocols, contributed to a significant improvement in early allograft function and survival.[7–12] This is primarily due to prevention of acute rejection resulting in improved graft survival during the early period following transplantation. Unfortunately, studies in the last decade have shown that despite this improvement and prevention of acute rejection, long-term survival of allografts has remained relatively unchanged, mostly due to late graft loss resulting from chronic allograft rejection.[13,14] The development of chronic rejection in allografts remains the most important limitation toward long-term organ graft survival of most of the solid organ transplants performed to date.
Chronic rejection is clinically diagnosed as cardiac allograft vasculopathy (CAV) following heart transplantation,[15,16] bronchiolitis obliterans syndrome (BOS) following lung transplantation[17] and pathologically diagnosed as obliterative bronchiolitis (OB) and chronic allograft nephropathy (CAN) following kidney transplantation. The current understanding of the process of chronic allograft rejection points to it being an immune-mediated tissue inflammatory process that leads to tissue-remodeling resulting in replacement of organ parenchyma with fibrous tissue. This inflammatory process is more prominent around vascular and other tubular structures in organs (bronchioles in lung, tubules and glomeruli in kidneys), which results in their occlusion and eventual graft dysfunction.
Unlike acute rejection, which is mainly mediated by 'alloimmune' responses against donor MHC antigens as well as minor histocompatibility antigens, chronic rejection is hypothesized to be multifactorial in etiology.
Expert Rev Clin Immunol. 2012;8(7):663-672. © 2012 Expert Reviews Ltd.
