Is there MHC class II restriction of the response to MHC class I in transplant patients?

Background. In this study, we evaluated distinct HLA-DRB1 alleles to determine class 11 restriction of the production of HLA-A2-specific antibodies in renal transplant patients. Methods. Data from 217 renal transplant patients who received an HLA-A2-mismatched renal graft were analyzed with regard to HLA-A2 humoral responsiveness. High-resolution DNA typing of class II HLA-DR alleles was performed by polymerase chain reaction-sequence-specific primer. Patients who had one of the following eight HLA-DRB1 alleles were included in the study: -*0101, -*0301, -*0401, -*0701, -*1101, -*1301, -*1401, and -*1501. Serum samples were screened post-transplantation with the standard complement-dependent cytotoxicity procedure. In addition, recombinant HLA-A2 monomers (the MonoLISA assay) were used as a target for the detection of HLA-A2 group-specific antibodies. The following HLA-A2 amino acid positions (termed epitopes) that are responsible for the induction of an antibody response were defined: 74H, 65-66GK, 62G, 114H, 142-145TTKH, and 107W-127H. The definition of the HIA-DR permittors of anti-HLA-A2 response was based on a class 11 restriction table designed for this purpose. Prediction of immunogenic and/or nonimmunogenic HILA-A,2 peptides was based on an MHC database. Results. The HLA-DRB1-*0101 and -*1401 alleles had a trend toward a positive correlation with the production of HILA class I-specific antibodies against the HLA-A2 shared (public) epitopes 65-66GK and -62G, respectively. Only the DRB1-*1501 allele had higher trend toward a positive correlation with the production of antibodies against the HLA-A2 private (74H) epitope. In 42 patients with the HLA-DRB1-*1501 allele, 11 (26%) patients produced HLA-specific antibodies against the HLA-A2 group of epitope(s). Moreover, in these patients, spreading of the alloreactivity against other HLA antigens was detected. Many of these other HLA antigens did not belong to HLA-A2 group but had newly defined shared epitopes with this group. Furthermore, the epitope prediction, based on an MHC database, revealed differences in the ligation strength (score) to the HILA allele (class I and II) for a specific HLA-A2 peptide in the 42 patients (responders and nonresponders). Conclusions. The data presented in this paper suggest that the HLA class II allele and the type of the bound allopeptide, may influence the humoral and cellular response. The immunogenicity of these allopeptides could be predicted with an MHC database (high-scored peptide = activating peptide and low-scored peptide = suppressor peptide). In the future, production of synthetic peptide analogues, on the basis of these predictions, could be used for induction of T-cell anergy and/or tolerance. In the short term, algorithms, on the basis of our approach, could be tested for influence on graft survival and allosensitization in current high-quality data sets.