HLAMatchmaker algorithm is not a suitable tool to predict the alloreactive cytotoxic T-lymphocyte response in vitro

Area of Science:

• Immunology
• Transplantation immunology
• Molecular immunology

Background:

• Donor-specific anti-human leukocyte antigen (HLA) antibodies and cytotoxic T lymphocytes (CTLs) are key factors in organ transplant rejection.
• The HLAMatchmaker algorithm identifies mismatched amino acid triplets on antibody-accessible HLA sites.
• Previous research linked triplet mismatches to HLA antibody production.

Purpose of the Study:

• To investigate if the number of HLA triplet mismatches, as determined by HLAMatchmaker, can predict cytotoxic T-lymphocyte precursor (CTLp) frequency in vitro.
• To assess the predictive value of HLAMatchmaker for T-cell mediated immune responses in transplantation.

Main Methods:

• Analysis of 108 HLA-DRB1 and DQB1 identical patient-donor pairs with a single HLA class I mismatch.
• Inclusion of healthy responder-stimulator combinations mismatched for at least one HLA class I antigen.
• Quantification of CTLp frequency in vitro.

Main Results:

• No strong correlation was found between the number of triplet mismatches and CTLp frequency.
• High CTLp frequencies were observed even with zero triplet mismatches.
• The HLAMatchmaker's focus on antibody-accessible sites may explain the lack of correlation with CTLp frequency.

Conclusions:

• The number of HLA triplet mismatches identified by HLAMatchmaker is not a reliable predictor of CTLp frequency.
• CTLs recognize HLA epitopes beyond antibody-accessible sites, including bound peptides, which HLAMatchmaker does not account for.
• Further research is needed to understand the complex epitope recognition involved in T-cell mediated graft rejection.