Antibodies to MHC Class I Induce Autoimmunity: Role in the Pathogenesis of Chronic Rejection

Abstract

Alloimmunity to mismatched donor HLA-Ags and autoimmunity to self-Ags have been hypothesized to play an important role in immunopathogenesis of chronic rejection of transplanted organs. However, it is not known what role, if any, alloimmune response plays in inducing autoimmunity. To test whether Ab-developed posttransplantation to mismatched donor MHC induces autoimmunity and chronic rejection, we developed a murine model wherein anti-MHC class I Abs or control (C1.18.4/anti-keratin) were administered intrabronchially into native lungs. Animals receiving anti-MHC class I, but not control Abs, developed marked cellular infiltration around vessels and bronchiole of lung by day 15, followed by epithelial hyperplasia, fibrosis, and occlusion of the distal airways similar to chronic rejection following human lung transplantation. Lungs of mice receiving anti-MHC class I showed increased expression of chemokines, their receptors, and growth factors, and induced IL-17 as well as de novo Abs to self-Ags, K-α1 tubulin, and collagen V. IL-17 neutralization by anti-IL-17 resulted in reduction of autoantibody and lesions induced by anti-MHC class I Abs. Thus, our results indicate that Abs to donor MHC can induce autoimmunity, mediated by IL-17, which plays a pivotal role in chronic rejection postlung transplantation. Therefore, approaches to prevent autoimmunity should be considered for the treatment of chronic rejection postlung transplantation.

Oral immunotherapy with type V collagen in idiopathic pulmonary fibrosis

“…VITTAL et al [10] reported that col(V) was highly overexpressed in the IPF lung. In addition, pre-clinical studies have confirmed that anti-col(V) autoimmunity can result in fibrotic changes in the lung [11,14].…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…While the mechanisms of AMR are not firmly established, de novo donor-specific antibodies against HLA have been shown to predispose to the development of immune responses to lung self-antigens and BOS (69)(70)(71). To define mechanisms leading to anti-MHC-mediated development of rejection, a preclinical murine model was developed in which exogenous anti-MHC was administered into the native lungs and elicited production of antibodies and T cell responses specific for lung-associated self-antigens, type V collagen [col(V)], and K-α 1 tubulin, culminating in fibrotic pathology (72,73). Human lung transplant recipients develop antibodies against col(V), a protein mainly located in the lung interstitium and not ordinarily exposed to the immune system.…”

Association Between Panel Reactive Antibody and Antiendothelial Cell Antibody Positivity in Kidney Transplant Patients

“…It is accepted that blood group antigens and HLA class I and II are not targets for AECA-associated autoimmune disease. 15 The AECAs may be joined to destructive potential of PRA on graft endothelial cells.…”