Human leukocyte antigen class II antibodies and transplant outcome.

During recent years, increasing evidence has accumulated that preformed antidonor human leukocyte antigen (HLA) class II antibodies represent significant risk factors for transplant dysfunction and failure (1– 6). Also, the posttransplant development of anticlass II antibodies is associated with a higher incidence of acute and chronic rejection (7–14). In this issue, the report by Issa et al. (15) on “Transplant Glomerulopathy: Risk and Prognosis Relate to Anti-HLA Class II Antibody Levels” describes a pretransplant serum analysis of anticlass II antibodies with solid-phase assays using single HLA antigen-coated flow beads. Their patients had been previously transplanted solely on the basis of a negative T-cell antiglobulin-augmented, complementdependent cytotoxicity crossmatch, a standard approach during that era. This retrospective study showed that 28% of these patients had pretransplant anticlass II antibodies and approximately one-half of them were donor specific. This group had a higher incidence of transplant glomerulopathy and subsequent graft failure than patients without anticlass II antibodies pretransplant. Higher anticlass II antibody levels were also associated with the presence of CD4 in transplant biopsies. These findings provide further support of the concept that anticlass II antibodies have a detrimental effect on kidney transplant outcome. This analysis did not consider crossmatches with Bcells that express class II antigens presumably because they were not used for this cohort of transplant recipients. Although many reports show that positive B-cell crossmatches represent risk factors for early graft loss and lower graft survivals, there has been widespread debate about the value of the B-cell crossmatch (16, 17). The test seems technically difficult and false-positive result can often occur with nonHLA–specific antibodies. Therefore, it is difficult to say whether a positive B-cell crossmatch could have predicted a greater risk for transplant glomerulopathy, a long-term complication. In the study by Issa et al. (15), almost 50% of the patients with relatively strong anticlass II antibody reactivity and approximately 25% of these patients with weaker antibody reactivity developed transplant glomerulopathy during a 4-year follow-up period. One might raise the question whether any particular antibody specificity patterns could be implicated. Although Issa et al. indicated that their sensitized patients had similar incidence of anti-DR and anti-DQ antibodies, it seems worthwhile to differentiate between antibodies reacting with each class II gene product including DRB1, DRB3/4/5, DQB, DQA, and even DPB and DPA. Solid-phase assays with single DRB, DQ, and DP alleles together with high-resolution typing for class II loci of donor and recipient are now routinely performed in many tissue typing laboratories. Such detailed information about donor-specific class II antibody specificity may reveal why some patients develop transplant glomerulopathy and others do not. In addition, the determination of glomerular expression of different class II genes may provide a better understanding of the pathogenesis of class II antibody-associated transplant glomerulopathy. In the management of sensitized patients considered for transplantation, any HLA antibody specificity analysis should consider the fact that HLA antigens have multiple epitopes that now can be readily identified from molecular structural modeling and amino acid sequence differences between HLA antigens. Figure 1 shows the polymorphic amino acid residues on the surface of stereochemical models of crystallized DR and DQ molecules. The structural polymorphisms of DR are restricted to the chains. The DR chain is largely monomorphic. Many polymorphic DRB residues are on the top of the molecule adjacent to the bound peptide and are often in contiguous sequences. Polymorphic residues on the side of the molecule generally comprise distinct clusters in both 1 and 2 domains. Some polymorphic residues reside at the bottom part of the molecule that is nearby the cell membrane. Both and chains of the DQ-heterodimer have polymorphic positions. The structural polymorphism of HLA is obviously complex, and the determination of the epitope repertoires cannot be solely based on single polymorphic residues. Recent studies based on stereochemical modeling of crystallized complexes of antibodies with different protein Division of Transplantation Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA. Address correspondence to: Rene J. Duquesnoy, Ph.D., Division of Transplantation Pathology, University of Pittsburgh Medical Center, Thomas E. Starzl Biomedical Research Tower Room W1552, Pittsburgh, PA 15261. E-mail: [email protected] Received 29 April 2008. Accepted 8 May 2008. Copyright © 2008 by Lippincott Williams & Wilkins ISSN 0041-1337/08/8605-638 DOI: 10.1097/TP.0b013e318183749a