Molecular persistence of chronic myeloid leukemia caused by donor T cells specific for lineage-restricted maturation antigens not recognizing immature progenitor-cells

Abstract

Although donor lymphocyte infusion (DLI) induces complete remissions in 70% of patients with relapsed chronic myeloid leukemia (CML) after allogeneic stem-cell transplantation (SCT), some patients are refractory to DLI by showing disease persistence. In a patient who received DLI for relapsed CML, we observed persisting molecular disease despite a hematological and cytogenetic remission in the absence of graft-versus-host disease (GVHD). To determine the nature of this immune response, we isolated leukemia-reactive donor T-cell clones from the bone marrow (BM) of the patient at the time of clinical response. Four different types of CD8+ HLA class I restricted T-cell clones were obtained that were cytotoxic against Ebstein-Barr virus-transformed B-cell lines (EBV-LCL) of the patient, but not the donor, indicating recognition of minor histocompatibility antigens (mHags). By using survival studies with CFSE labelled BM cells populations, a hematopoietic progenitor cell inhibition assay and direct morphological examination we showed that the T-cell clones recognized mature monocytic and myeloid cells, whereas immature BM progenitor cells were insufficiently lysed. This patient's refractoriness for DLI appears to be caused by inadequate lysis of progenitor cells by these cytotoxic T cells. These findings support the hypothesis that for eradication of CML a cytotoxic T-cell response against leukemic progenitor cells is essential.