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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2002-01-0024.
Submitted January 3, 2002
Accepted March 5, 2002
Generation of minor Histocompatibility antigen HA-1 specific cytotoxic T cells restricted by non-self HLA molecules: a potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation
Tuna Mutis*, Els Blokland, Michel Kester, Ellen Schrama, and Els Goulmy
Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
Dept. of Hematology, Leiden University Medical Center, Leiden, The Netherlands
* Corresponding author; email: t.mutis{at}lumc.nl.
Successful stem cell transplantation (SCT) across HLA barriers can be performed with cord blood, megadoses of stem cells or with nonmyeloablative conditioning strategies. Since 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 SC donor. Adoptive transfer of these hematopoietic system specific CTLs that are restricted by non-self 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 (mHag) HA-1 that is known to induce HLA-A2-restricted CTLs. HLA-A2- PBMC were stimulated with HLA-A2+ T2 cells pulsed with synthetic HA-1 peptide or with dendritic cells (DCs) 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 three rounds of antigen specific stimulations and up to 87% by FACS sorting of tetramer+ T cells. The HA-1-specific CTLs showed specific lysis of the relevant target cells, including leukemic cells. As the polyclonal CTL cultures also contained NK-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 non-self HLA-A2 molecules can be generated in an HLA-A2 mismatched setting.
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