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 II 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 posttransplantation 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-127K. The definition of the "HLA-DR permittors" of anti-HLA-A2 response was based on a "class II restriction table" designed for this purpose. Prediction of immunogenic and/or nonimmunogenic HLA-A2 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 HLA 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 HLA 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.
Papassavas
Andreas C
AC
Transplantation Immunology, Oxford Transplant Centre, Churchill Hospital, Oxford Radcliffe Hospitals Trust, United Kingdom. acpapass@otenet.gr.
Barnardo
Martin C N M
MC
Bunce
Mike
M
Welsh
Kenneth I
KI
D000483:Alleles; D000595:Amino Acid Sequence; D000917:Antibody Formation; D000939:Epitopes / Q000032:analysis / Q000737:chemistry; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology; D006681:HLA-D Antigens / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007111:Immunity, Cellular; D007518:Isoantibodies / Q000097:blood; D008285:Major Histocompatibility Complex; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D014181:Transplantation Immunology
D000939:Epitopes; D015789:HLA-A2 Antigen; D006681:HLA-D Antigens; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies