Identification of novel minor histocompatibility antigens responsible for graft-versus-leukemia (GVL) effect on chronic myeloid leukemia: Usefulness of determining the clonotype of T cells associated with GVL effect after donor leukocyte infusion

Abstract

In an attempt to identify novel mHas that induce GVL effect on chronic myeloid leukemia (CML), we analyzed peripheral blood T cells of 4 CML patients who relapsed after allogeneic stem cell transplantation and received donor leukocyte infusion (DLI), for the presence of antigen-specific T-cell proliferation. When peripheral blood lymphocyte collected from patients every 2–4 weeks after DLI were subjected to complementarity determining region (CDR) 3 size distribution analysis of T-cell receptor β chain, clonal proliferation of a limited number of CD4⁺ T cells was detected in all patients 2–4 months after DLI in association with the occurrence of GVL effect. To identify an epitope of the T-cell clone that probably mediates GVL effect, we determined nucleotide sequence of CDR3 of the T cells and screened the database for the presence of T cells with a CDR3 sequence similar to that of the GVL-mediating T cells. In one of 4 patients who showed clonal proliferation of a BV16⁺ T cell, a CDR3 motif QDR was shared by a T-cell clone that recognized an 85–99 peptide of myelin basic protein presented by HLA-DRB1^*1501. When the I domain of CD49b, a candidate peptides that could bind to this CDR3 motif in the context of DRB1^*1501, was studied, codon 256 in the I domain of the recipient was ATT (Ile) while that of the donor was GTT (Val). The BV16⁺ T cells showed proliferative response to DRB1^*1501 L-cell transfectant pulsed with the recipient type CD49b. Thus, identification of a clonotype of T cells that mediate GVL effect in patients receiving DLI and a search for T-cell clones with a similar clonotype to the GVL-mediating T cells followed by screening of polymorphic peptides that could stimulate the T cells appears to be useful in identifying novel mHas serving as target antigens of GVL effect. *** DIRECT SUPPORT *** A00RC002 00015