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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2002-01-0024.
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Blood, 15 July 2002, Vol. 100, No. 2, pp. 547-552
IMMUNOBIOLOGY
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, and
Els Goulmy
From the Department of Immunohematology and Blood
Transfusion and the Department of Hematology, Leiden University Medical
Center, The Netherlands.
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 hematopoietic system-specific CTLs that are restricted 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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