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

Tuna Mutis, Els Blokland, Michel Kester, Ellen Schrama, Els Goulmy

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)547-552
Number of pages6
JournalBlood
Volume100
Issue number2
DOIs
Publication statusPublished - 15 Jul 2002
Externally publishedYes

Cite this

@article{6e789fd9460c481f8a0bf80bb348ccc0,
title = "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",
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.",
author = "Tuna Mutis and Els Blokland and Michel Kester and Ellen Schrama and Els Goulmy",
year = "2002",
month = "7",
day = "15",
doi = "10.1182/blood-2002-01-0024",
language = "English",
volume = "100",
pages = "547--552",
journal = "Blood",
issn = "0006-4971",
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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. / Mutis, Tuna; Blokland, Els; Kester, Michel; Schrama, Ellen; Goulmy, Els.

In: Blood, Vol. 100, No. 2, 15.07.2002, p. 547-552.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules

T2 - A potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation

AU - Mutis, Tuna

AU - Blokland, Els

AU - Kester, Michel

AU - Schrama, Ellen

AU - Goulmy, Els

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AB - 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.

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