Antibodies to K-α 1 Tubulin and Collagen V Are Associated With Chronic Rejection After Lung Transplantation

Abstract

Bronchiolitis obliterans syndrome (BOS), the clinical correlate of chronic rejection after lung transplantation, is the leading obstacle to better long-term outcomes. We previously instituted a clinical protocol to screen for donor-specific human leukocyte antigen (HLA) antibodies (DSA) and a preemptive antibody-directed therapy protocol consisting of rituximab and/or intravenous immune globulin. In this study, we retrospectively analyzed serum samples from lung transplant recipients (n = 108) for antibodies to self-antigens (K-α 1 tubulin and collagen V) before and after antibody-directed therapy and correlated the results with the subsequent development of BOS. Seventy-two of the 108 recipients developed antibodies to self-antigens. There was a correlation between the development of antibodies to self-antigens and DSA. Sixteen of the 54 patients who had antibodies to self-antigens and were treated with antibody-directed therapy cleared the antibodies, and they were significantly less likely to develop BOS than those who had persistent antibodies. Furthermore, those who cleared DSA after treatment but had persistent antibodies to self-antigens were significantly more likely to develop BOS than those who cleared these antibodies. We conclude that antibodies to self-antigens are an important risk factor for the development of BOS.

Humoral Immunity and the Development of Obliterative Bronchiolitis after Lung Transplantation

“…In the same study, the clearance of alloimmunity using the preemptive antibody-directed therapy of patients who developed alloimmunity was associated with an increased rate of clearance for antibodies to self-antigens. Interestingly, the clearance of antibodies to self-antigens was associated with a lower risk of OB/BOS, and this effect was independent of reduced antidonor antibodies (8). These data strongly suggest a putative role of humoral autoimmunity in the development of OB/BOS.…”

“…Although this evidence is compelling, studies continue to show that not all patients who develop autoimmunity demonstrate previous or coincident robust alloimmune processes. This suggests that although alloimmunity can result in autoimmunity after lung transplantation, it is not the only pathway for the development of autoimmunity (8,21).…”

“…Specifically, therapy that decreased anti-HLA antibodies was associated with a decreased risk for OB (8,20). However, anti-HLA immunity was not been detected in a proportion of lung-transplant recipients who developed OB (8,21). This observation led to identifying and further linking the presence of antibodies to self-antigens (autoimmunity) to the development of OB.…”

“…A significant body of evidence has associated the development of chronic allograft rejection with the presence of anti-HLA antibodies in the lung (8,(17)(18)(19). Specifically, therapy that decreased anti-HLA antibodies was associated with a decreased risk for OB (8,20).…”

“…Several risk factors have been associated with the development of OB, including acute rejection, human leukocyte antigen (HLA) mismatches, HLA antibodies, lymphocytic bronchiolitis, viral infection, gastroesophageal reflux, and primary graft dysfunction (PGD) (5). Although a clear role exists for immune responses in the form of anti-donor antigen (anti-HLA) antibody formation, referred to as alloimmunity, a role has also emerged for immune responses to self-antigens (autoimmunity) in the development of OB (6)(7)(8). We will review our current understanding and recent advances in the study of humoral immunity, along with the implications of humoral immunity in the development of OB in lung transplant recipients.…”