Development of antibodies to human leukocyte antigen precedes development of antibodies to major histocompatibility class I-related chain A and are significantly associated with development of chronic rejection after human lung transplantation

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]) after 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 after 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.

Figure 1

Comparison of Abs to various MICA alleles in BOS+ and BOS− patient sera. Luminex reactions were carried in duplicates using 1:3 diluted sera. Data are representative of mean ± SD of all the positive values obtained for each allele from various patients sera of both BOS+ and BOS− cohorts.

Figure 2

Development of anti-MICA, anti-HLA Abs and development of BOS after LTx. Anti-MICA and anti-HLA Abs were detected by LabScreen Luminex and flowPRA assay systems respectively. The MICA and HLA bars represent the time (mean ± SD) at which each Abs was first detected in serum samples of study patients. The remaining three bars represent the average time at which the patients developed BOS if they were HLA+, MICA+ or both MICA+ and HLA+.

Figure 3

Sequential measurements of anti-MICA and anti-HLA Abs in study patients. For specific MICA alleles (*001 and *019 in Panel A; * 027, *002 and *004 in Panel B), the figure represents the change in normalized MFI over time post-LTx. Panels A and B depicts BOS+ patients for alleles specified above while Panel C depicts BOS− patients for alleles *001 and *019. Panel D depicts the frequency of HLA positive recipients who were present in BOS + and BOS− cohorts over time post-LTx.