Type: Oral
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Finding the Ideal Donor and Graft: Going Beyond HLA
Hematology Disease Topics & Pathways:
Research, Clinical Research, Health outcomes research
Recently, we discovered a large repertoire of new MiHAs in common HLA class I alleles by genome-wide association screening.1,2 T-cell clones were isolated from 39 patients who responded to donor lymphocyte infusion after T cell-depleted HLA-matched allogeneic stem cell transplantation. T-cell clones recognizing unknown MiHAs were tested for reactivity against 191 EBV-B cell lines of the 1000 Genomes Project to identify the target antigens. By discovering 89 new MiHAs, the repertoire of HLA class I-restricted MiHAs was expanded to 159 total antigens. The data showed that, despite many genetic differences between patients and donors, often the same MiHAs are targeted in multiple patients, demonstrating that the dominant repertoire of MiHAs in common HLA class I alleles has been largely discovered and available to screen patient cohorts to investigate the kinetics of MiHA-specific T-cell responses after allogeneic stem cell transplantation.
Here, the expanded repertoire of MiHAs was used to screen patients for specific T cells with barcoded peptide-MHC multimers. Barcoded peptide-MHC multimers were produced for 255 MiHA peptides and 103 viral peptides. The 255 MiHA peptides included 126 autosomal MiHAs and 5 H-Y antigens, as well as various length variants for MiHAs and peptides for allelic variants. All peptides were validated to form stable peptide-MHC complexes and tested for potential background staining on peripheral blood samples from healthy individuals. In total, 227 MiHA peptides and 93 viral peptides passed the quality controls and were selected for T-cell monitoring. In 16 patients who responded to donor lymphocyte infusion after T cell-depleted HLA-matched allogeneic stem cell transplantation, variable T-cell frequencies up to 30.5% of CD8+ T cells were measured against 49 MiHAs. High T-cell frequencies above 1% were measured in 12 patients against 15 mismatched MiHAs with peak responses detected 6-8 weeks after donor lymphocyte infusion and at onset of GvHD. The 12 patients included nine of ten patients with severe GvHD, two of three patients with limited GvHD, and one of three patients without GvHD. The data demonstrated that T-cell frequencies were particularly high in patients with GvHD, and that T-cell responses were directed against MiHAs with variable tissue distribution in all patient groups.
In conclusion, we explored whether barcoded peptide-MHC multimers are a feasible method to detect and follow MiHA-specific T-cell responses after allogeneic stem cell transplantation. We demonstrated that the technique can be used to measure and monitor patients for MiHA-specific T-cell frequencies during treatment to investigate the kinetics of immune responses and their impact on development of GvL and GvHD after allogeneic stem cell transplantation.
1. Fuchs KJ, Honders MW, van der Meijden ED, et al. Optimized Whole Genome Association Scanning for Discovery of HLA Class I-Restricted Minor Histocompatibility Antigens. Front Immunol. 2020;11:659.
2. Fuchs KJ, van de Meent M, Honders MW, et al. Expanding the repertoire reveals recurrent, cryptic, and hematopoietic HLA class I minor histocompatibility antigens. Blood 2024; 143(18):1856-1872.
Disclosures: No relevant conflicts of interest to declare.
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