In the transplantation of a kidney from a sibling donor who is mismatched with the recipient for one HLA haplotype, graft survival is higher when the donor has maternal HLA antigens not inherited by the recipient than when the donor has paternal HLA antigens not inherited by the recipient.

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 immune responses to mismatched donor human leukocyte antigen (HLA) and major histocompatibility (MHC) class I related chain A (MICA) have been reported to contribute to immunopathogenesis of antibody mediated rejection (AMR) in early period (EP) and cardiac allograft vasculopathy (CAV) in late period (LP) following cardiac transplantation (HTx). The goal of this study is to define the roles of donor specific antibodies (DSA) and anti-MICA in AMR and CAV. 95 post-HTx recipients were enrolled; 43pts in EP (≤12months post-HTx) and 52pts in LP (>12months post-HTx). Development of DSA and anti-MICA were serially monitored using Luminex. Development of DSA (AMR+:n=6/8,75%, AMR−:n=4/35,11%, p=0.009) and anti-MICA (AMR+:n=5/8,63%, AMR−:n=4/35,11%, p=0.002) was significantly associated with AMR. AMR+DSA+ pts demonstrated increased anti-MICA levels compared to AMR+DSA− pts (p=0.01). Serial monitoring revealed DSA (2.7±1.4months) preceded development of anti-MICA (6.5±2.1months) in recipients diagnosed with AMR at 8.3±2.5months post-HTx. Development of DSA (CAV+:n=8/12,67%, CAV−: n=5/40,13%, p=0.004) and anti-MICA (CAV+:n=9/12,75%, CAV−:n=5/40,13%, p=0.001) was significantly associated with CAV. CAV+DSA+ pts demonstrated increased anti-MICA levels compared to CAV+DSA− pts (p=0.01). Abs to HLA are associated with and precede development of anti-MICA in AMR and CAV. Therefore, DSA and anti-MICA can be used as non-invasive markers for monitoring AMR and CAV.

No abstract

The development of antibodies (Abs) to major histocompatibility (MHC) class I related chain A (MICA) and human leukocyte antigen (HLA) and their role in the immunopathogenesis of chronic rejection (bronchiolitis obliterans syndrome (BOS)) following human lung transplantation (LTx) was analyzed. Sera from 80 LTx recipients were analyzed for anti-MICA and anti-HLA Abs using Luminex and flow PRA (panel reactive assay). Development of Abs either to MICA alone or MICA and HLA together significantly correlated (P<0.01) with development of BOS. Kinetic analysis in the post-LTx period revealed that development of anti-HLA Abs (7.6±4.7 months) preceded the development of anti-MICA Abs (10.0±3.5 months). Abs to MICA alleles (*001 and *009) developed approximately 6 months following LTx and peak titers were present at the time of clinical diagnosis of BOS (16.3±2.7 months). The development of Abs to both MICA and HLA was strongly associated with the development of BOS thereby suggesting a synergistic effect. Furthermore, immune response to mismatched HLA can lead to development of Abs to other MHC related antigens expressed on the airway epithelial cells. Cumulatively, these immune responses contribute to the pathogenesis of chronic rejection following human LTx.