Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: A potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation

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Abstract

Successful stem cell transplantation (SCT) across HLA barriers can be performed with cord blood, megadoses of stem cells, or with nonmyeloablative conditioning strategies. Because the HLA-mismatched transplants are often T-cell depleted, leukemia relapse rates are high. Treatment of relapsed leukemia after HLA- mismatched SCT is difficult. A novel potential strategy to treat relapsed leukemia after HLA-mismatched SCT is the use of patients' mismatched HLA molecules as antigen-presenting molecules to generate hematopoietic system-specific cytotoxic T cells (CTLs) from the stem cell donor. Adoptive transfer of these hematopoletic system-specific CTLs that are re-stricted by nonself HLA molecules may eliminate leukemia without affecting the patient's nonhematopoietic cells or donor hematopoietic cells. We investigated the feasibility of this strategy using the hematopoietic system-specific minor histocompatibility antigen HA-1, which is known to induce HLA-A2-restricted CTLs. HLA-A2- peripheral blood mononuclear cells were stimulated with HLA-A2+ T2 cells pulsed with synthetic HA-1 peptide or with dendritic cells transduced with the HA-1 cDNA. Tetrameric HLA-A2/HA-1 peptide complexes were used to monitor and enrich HA-1-specific CTLs. In the alloreactive cultures, HA-1-specific CTLs were enriched up to 7% by 3 rounds of antigen-specific stimulations and up to 87% by fluorescence-activated cell sorting of tetramer-positive T cells. The HA-1-specific CTLs showed specific lysis of the relevant target cells, including leukemic cells. Because the polyclonal CTL cultures also contained natural killer cells and allo-HLA-A2-specific CTLs, CTL clones were generated that showed the expected HA-1 specificity only. Thus, HA-1-specific CTLs restricted by nonself HLA-A2 molecules can be generated in an HLA-A2-mismatched setting. © 2002 by The American Society of Hematology.

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APA

Mutis, T., Blokland, E., Kester, M., Schrama, E., & Goulmy, E. (2002). Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: A potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation. Blood, 100(2), 547–552. https://doi.org/10.1182/blood-2002-01-0024

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