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 language | English |
|---|---|
| Pages (from-to) | 547-552 |
| Number of pages | 6 |
| Journal | Blood |
| Volume | 100 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 15 Jul 2002 |
| Externally published | Yes |
Cite this
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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 journal › Article › Academic › peer-review
TY - JOUR
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
PY - 2002/7/15
Y1 - 2002/7/15
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=0037100320&partnerID=8YFLogxK
U2 - 10.1182/blood-2002-01-0024
DO - 10.1182/blood-2002-01-0024
M3 - Article
VL - 100
SP - 547
EP - 552
JO - Blood
JF - Blood
SN - 0006-4971
IS - 2
ER -