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Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2197-2207
By
From the Fred Hutchinson Cancer Research Center, Seattle, WA; and the
University of Washington, Seattle, WA.
Cytotoxic T lymphocytes (CTL) specific for human minor
histocompatibility (H) antigens can be isolated from the blood of major histocompatibility complex (MHC)-matched allogeneic bone marrow transplant (BMT) recipients and may play a prominent role in the graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactions (Tsoi
et al, J Immunol 125:2258, 1980; Tsoi et al, Transplant Proc 15:1484, 1983; Goulmy et al, Nature 302:159, 1983;
Irle et al, Transplantation 40:329, 1985; and Niederwieser et
al, Blood 81:2200, 1993). The identification of
minor H antigens that are expressed in hematopoietic cells, including
leukemic cells, but not in fibroblasts and other tissue types has
suggested that such tissue-restricted antigens could potentially serve
as targets for T-cell immunotherapy to enhance GVL activity without
inducing GVH disease (de Bueger et al, J Immunol 149:1788,
1992; van der Harst et al, Blood 83:1060, 1994; and Dolstra et
al, J Immunol 158:560, 1997). To explore the feasibility of
this strategy, donor CD3+CD8+ CTL clones
specific for recipient minor H antigens were isolated and characterized
from allogeneic BMT recipients. CTL clones were obtained from the
majority of donor/recipient pairs. Seventeen distinct minor H antigens
distinguishable by their MHC-restricting allele, population frequency,
and/or distribution of tissue expression were defined by 56 CD3+CD8+ CTL clones isolated from these
patients. The MHC-restricting alleles for these CTL clones included
HLA-A2 and HLA-B7, which had previously been shown to present minor H
antigens to CTL, as well as HLA-A3, -A11, -B8, -B53, and -Cw7, which
had not previously been described to present minor H antigens to CTL.
Estimated phenotype frequencies for these 17 distinct minor H antigens
range from 0.17 to 0.92. In vitro cytotoxicity assays using
hematopoietic cells and fibroblasts as target cells showed that 5 of
the 17 minor H antigens were expressed in both hematopoietic cells and fibroblasts. However, 12 were presented for CTL recognition only by
hematopoietic cells and not by dermal fibroblasts derived from the same
donors. These results significantly extend the spectrum of CTL-defined
human minor H antigens that could potentially serve as target antigens
for cellular immunotherapy to promote GVL activity after allogeneic
BMT.
THE USE OF T-CELL-depleted bone marrow
(BM) for major histocompatibility complex (MHC)-matched allogeneic BM
transplantation (BMT) confers a reduced incidence of graft-versus-host
disease (GVHD) but a higher probability of leukemic relapse compared
with the use of unmodified BM.1-7 This observation and the
results of experimental studies in animal models have established a
critical role for donor T lymphocytes specific for recipient minor
histocompatibility (H) antigens in mediating the GVH and
graft-versus-leukemia (GVL) reactions that occur after allogeneic BMT
and have suggested that infusions of donor T cells may be useful
therapeutically in individuals at high risk of developing leukemic
relapse after BMT.8 The adoptive transfer of donor
peripheral blood mononuclear cells (PBMC) containing large numbers of
CD3+ T cells to patients with documented leukemic relapse
after allogeneic BMT has induced complete remissions in most patients
with relapse of chronic myelogenous leukemia (CML) and
some patients with relapse of acute myelogenous leukemia
(AML).9-22 Unfortunately, the administration of unselected polyclonal donor lymphocytes has also resulted in acute
and/or chronic GVHD in the majority of patients leading to
significant morbidity and mortality.9-22
A potential strategy to treat leukemic relapse without inducing GVHD
would be to isolate donor T-cell clones specific for recipient minor H
antigens and to administer to the recipient only those clones that
recognize hematopoietic cells, including leukemic blasts, but not
nonhematopoietic tissues. The feasibility of using T-cell clones has
been suggested by studies demonstrating that cytomegalovirus
(CMV)-specific T-cell immunity can be successfully reconstituted in allogeneic BMT recipients without causing GVHD by the
adoptive transfer of donor T-cell clones selected for reactivity with
CMV-infected but not uninfected recipient cells.23,24 However, CMV seropositive donors maintain a high frequency of CMV-reactive T cells in the PB, and T-cell clones specific for CMV
antigens can be readily isolated and expanded ex vivo.24 In
contrast, T cells reactive with minor H antigens are present in low
frequency in the blood of unprimed donors and the isolation of minor H
antigen-specific T-cell clones from donor PBMC samples is
difficult.25,26 Goulmy et al27-29 overcame this
obstacle and generated polyclonal T-cell lines and several T-cell
clones that recognized recipient minor H antigens by obtaining PBMC
from the recipient after BMT, and stimulating these cells in vitro with
These prior studies suggest the potential for adoptive T-cell
immunotherapy with minor H antigen-specific T-cell clones to augment
GVL reactivity after allogeneic BMT without causing GVHD. However, only
four CD8+ cytotoxic T lymphocyte (CTL)-defined minor H
antigens that appear to be selectively expressed by hematopoietic cells
have been described: HA-1, HA-2, and HA-5, which are all presented for
T-cell recognition by HLA-A2, and HB-1, which is presented by
HLA-B44.28,30 Because 50% of BMT donor/recipient pairs do
not express HLA-A2 and 80% do not express HLA-B44, most recipients
would not be eligible for therapy targeting any of these four minor H
antigens.31 Moreover, even for donor/recipient pairs
expressing HLA-A2, the clinical use of HA-2 and HA-5 as targets for GVL
therapy is limited because HA-2 and HA-5 are expressed in an estimated
95% and 7% of the population, respectively.29 Thus, less
than 10% of HLA-A2+ donor/recipient pairs would be
appropriately discordant for the expression of either of these
antigens. HA-1 and HB-1 are expressed in 69% and 28% of the
population, respectively, and recipients who express one of these
antigens and who have a donor that is discordant should be identified
more frequently.29,30 CTL clones specific for HA-1 appear
to recognize leukemias of both myeloid and lymphoid
lineages.30a However, HB-1-specific CTL recognize only
transformed B-lymphoid cells and show no cytolytic activity against
either monocytes or phytohemagglutinin (PHA)-stimulated T cells,
suggesting that expression of HB-1 is restricted to the B-cell
lineage.30 Thus, adoptive immunotherapy with
CD8+ CTL specific for minor H antigens as a general
strategy to induce GVL activity after allogeneic BMT will require the
identification of additional CD8+ CTL-defined antigens that
(1) exhibit restricted or preferential expression in hematopoietic
cells including myeloid and lymphoid leukemias and (2) are presented by
class I MHC molecules other than HLA-A2 and -B44.
To identify novel human minor H antigens that might be potential
targets for GVL therapy, we generated minor H antigen-specific T cells
from 10 allogeneic BMT donor/recipient pairs. T-cell lines with
recipient-specific reactivity were obtained from 8 of the 10 cultures,
and a panel of 56 CD3+ CD8+ CTL clones were
isolated from 6 of these 8 T-cell lines. Seventeen distinct minor H
antigen specificities restricted by 7 different class I MHC alleles
were identified using this panel of CD8+ CTL clones.
CD8+ CTL specific for 12 of these minor H antigens lysed
hematopoietic cells but not fibroblasts derived from the same donors,
and CTL specific for 6 of these tissue-restricted antigens lysed
leukemic blasts. These results show that T cells potentially capable of mediating GVL activity without causing GVHD can be isolated for use in
adoptive immunotherapy from a significant proportion of allogeneic BMT
recipients.
Donor/recipient pairs.
Ten patients with hematologic malignancies undergoing allogeneic BMT
and their HLA-matched related donors were enrolled on this study.
Characteristics of the 10 donor/recipient pairs, including sex, HLA
type, recipient's diagnosis, source of hematopoietic stem cells, GVHD
prophylaxis, and GVHD status, are shown in
Table 1. Nine of the 10 donor/recipient
pairs were full siblings. Eight of these nine sibling pairs (nos. 2, 3, 4, 5, 6, 8, 9, and 10 in Table 1) were HLA-A-, -B-, -Cw-, -DR-, and
-DQ-genotypically identical as demonstrated by serologic and DRB1 DNA
sequence-based typing of the siblings, the parents, and/or
other siblings in each family. One pair (no. 7 in Table 1) was HLA-A-,
-B-, -Cw-, and -DQ-identical by serology but mismatched for one DRB1
allele (1501 v 1601). The remaining donor/recipient pair (no. 1 in Table 1) was a mother/son combination who were HLA-A- and
-B-identical by serology but matched for only one DR allele (DR 7, 6 v DR 7, 8).
Generation of Epstein-Barr virus (EBV)-transformed B-cell lines, PHA
blasts, and primary fibroblast lines.
PB was obtained pretransplant from each donor and recipient to generate
EBV-transformed B-cell lines, and aliquots of PBMC were cryopreserved
for later preparation of PHA blasts. EBV-transformed B-cell lines
(EBV-LCL) were generated and cultured as described.32 Our
laboratory has compiled a cell bank containing a large number of
EBV-LCL lines generated from individuals of known HLA type, and these
were used in experiments to define the MHC-restricting allele and the
population frequency for each of the minor H antigens. PHA blasts were
generated by culturing PBMC for 72 hours in CTL media containing 3 µg/mL PHA (Sigma, St Louis, MO), washed and resuspended
in CTL medium supplemented with 25 U/mL recombinant human IL-2 (Chiron,
Emeryville, CA), and used as target cells in cytotoxicity assays within
7 days. Primary fibroblast lines were grown from explants of skin
biopsy specimens as described.33
Generation and characterization of minor histocompatibility
antigen-specific T-cell lines.
T-cell lines and clones were cultured in RPMI-HEPES supplemented with
10% pooled, heat-inactivated human serum, 2 mmol/L L-glutamine, and
1% penicillin/streptomycin (termed CTL medium). Donor T cells with
reactivity for recipient minor H antigens were generated in 24-well
plates by stimulating in each well 1 to 4 × 106
responder PBMC obtained from the recipient posttransplant with 1 to 4 × 106 Cytotoxicity assays and blocking studies.
Aliquots of 1 to 2 × 106 target cells were labeled
with 50 µCi of 51Cr overnight, washed twice, dispensed at
5 × 103 cells/well into triplicate cultures in
96-well round-bottom plates, and incubated for 4 hours with effector
cells at various effector to target ratios in a total volume of 200 µL. Some assays were performed by preincubating the target cells for
30 minutes at room temperature in the presence and absence of 25 µg/mL of the anti-pan class I MHC monoclonal antibody W6/32 (a
generous gift of Dr Daniel Geraghty, Fred Hutchinson Cancer Research
Center, Seattle, WA). The percentage of specific lysis was
calculated using the standard formula.33
Isolation of minor H antigen-specific CD8+ and
CD4+ T-cell clones.
T-cell lines exhibiting recipient-specific cytolytic activity were
cloned by limiting dilution in 96-well round-bottom plates. Each well
received 200 µL of a cell suspension containing 5 × 104/mL Collection and processing of leukemic samples.
Samples of PB and/or BM were obtained from patients with acute
myelogenous leukemia (n = 10), acute lymphoblastic
leukemia (ALL; n = 2), or chronic lymphocytic leukemia (CLL; n = 2), all of whom had either primary refractory disease or
relapse after conventional chemotherapy or allogeneic BMT. All leukemic
samples (PB and/or BM) contained greater than 90% malignant
cells as judged by morphologic criteria on Wright-Giemsa-stained
specimens. Leukemic cells were isolated by Ficoll-Hypaque density
gradient centrifugation. When not used immediately after isolation, the
cells were cryopreserved in RPMI-HEPES with 20% human serum and 10%
dimethyl sulfoxide for subsequent use. PHA blast
preparations from leukemic patients were prepared as described above.
Flow cytometry on these cell populations before use showed that they
consisted of greater than 90% CD3+ cells.
Flow cytometric analysis of CTL clones and leukemic cells.
T-lymphocyte lines and clones were analyzed by two-color flow
cytometry for expression of CD3, CD4, and CD8 using fluorescein isothiocyanate (FITC)-conjugated anti-CD3 and either phycoerythrin (PE)-conjugated anti-CD4 or anti-CD8 (all from Becton Dickinson, Mountain View, CA). Samples of leukemic blasts were analyzed for expression of class I MHC by staining with the anti-pan class I MHC
monoclonal antibody W6/32 followed by FITC-conjugated goat-antimouse Ig
(Becton Dickinson). AML samples were also stained with PE-conjugated anti-CD13 or anti-CD33 (Becton Dickinson) and ALL and CLL samples were
stained with FITC-conjugated anti-CD19 (Caltag, San Francisco, CA) or
FITC-conjugated anti-CD20 (Becton Dickinson). Analysis was performed on
a FACScalibur flow cytometer with CellQuest software (Becton
Dickinson).
Cytotoxic minor H antigen-specific T-cell lines can be generated from a
majority of HLA-matched donor/recipient pairs.
To generate donor T cells reactive with recipient minor H antigens,
responder PBMC were isolated between 14 and 156 days after transplant
from the PB of 10 transplant recipients with donor engraftment, and
cultured as described in the Materials and Methods. Lines from 8 of the
10 donor/recipient pairs exhibited preferential lytic activity against
recipient EBV-LCL compared with donor EBV-LCL (Fig 1). Three cycles of stimulation with
irradiated recipient PBMC were generally required to first detect
significant cytotoxicity against recipient targets, and the cytotoxic
activity of these polyclonal T-cell lines was increased by
restimulating the lines with irradiated recipient-derived EBV-LCL for 2 or 3 additional cycles (data not shown). In this small series of
patients, the ability to isolate recipient-specific cytolytic T cells
did not appear to correlate with the development of clinically
significant GVHD. Recipient-specific cytolytic T-cell lines were
generated from 6 of the 7 patients with acute GVHD of grade II or
greater and from 2 of the 3 patients with mild (grade I) GVHD.
Characterization of cell surface phenotype and isolation of minor H
antigen-specific cytotoxic T-cell clones.
Analysis of the cell surface phenotype of the 8 T-cell lines with
preferential lytic activity against recipient but not donor EBV-LCL
showed a mixed population of
CD3+CD4+CD8 Determination of class I MHC restriction for
CD3+CD8+ CTL-defined human minor H
antigens.
Minor H antigens recognized by CD8+ CTL are presumed to be
encoded by allelic forms of polymorphic genes that differ in nucleotide sequence between the donor and recipient and give rise to unique antigenic peptide epitopes. Such CTL-defined minor H antigens have
previously been characterized by determining the class I MHC-restricting allele and the frequency of the minor H antigen in a
population of individuals expressing this class I MHC
allele.29,34 To determine whether the minor H antigens
recognized by the CD8+ CTL clones generated in our study
correspond to previously described minor antigens or represent distinct
specificities, the MHC-restricting elements for each of the 56 CD8+ CTL clones were identified by assessing the lytic
activity of the T-cell clones against a panel of EBV-transformed B-cell
lines derived from unrelated individuals, each of whom shared only one class I MHC allele with the donor and recipient. Seven different class
I MHC alleles were identified to present minor H antigens to the CTL
clones isolated in this study. These included HLA-A2 and HLA-B7, which
were described in earlier studies as restricting elements for minor H
antigen-specific CTL, as well as HLA-A3, -A11, -B8, -B53, and -Cw7,
which have not previously been described as restricting alleles for
minor H antigen-specific CTL (Table 2).
Representative data identifying the class I MHC-restricting alleles for
four of the CTL clones are shown in Fig 2.
Recognition of hematopoietic and nonhematopoietic cells by
CD3+CD8+ minor H antigen-specific CTL clones.
To determine if any of the 17 minor H antigens identified by the CTL
isolated in this study were selectively presented by hematopoietic
cells, CTL clones were tested for lytic activity against recipient
hematopoietic target cells including both EBV-LCL and PHA blasts and
against recipient dermal fibroblasts as a representative nonhematopoietic target cell. CD8+ CTL specific for 5 of
the 17 minor H antigens lysed the hematopoietic target cells as well as
fibroblasts (Table 2). Representative data for two of these clones are
shown in Fig 3A and B. However, CD8+ CTL specific for the remaining 12 minor H antigens
lysed only the hematopoietic targets but not fibroblasts.
Representative data for two of these clones are shown in Fig 3C and D. CTL clones recognizing these 12 minor H antigens with restricted tissue
expression were isolated from 4 of the 8 T-cell lines in which T-cell
cloning was performed and the class I MHC-restricting elements for
these clones included HLA-A2, -A3, -B7, -B8, -B53, and -Cw7 (Table 2).
Lysis of leukemic cells by CTL clones specific for tissue-restricted
minor H antigens.
The HLA-B53-restricted CD8+ CTL clones isolated from
donor/recipient pair no. 8 showed significant lysis of leukemic cells from the recipient (data not shown). To determine if the clones with
limited tissue reactivity derived from other recipients also lysed
leukemic cells, samples were obtained from 14 HLA-A3+,
HLA-B7+, or HLA-B8+ patients with primary
refractory or relapsed AML (n = 10), ALL (n = 2), or CLL (n = 2). Flow
cytometric analysis of the PB and/or BM mononuclear cells
obtained from the 10 individuals with AML showed that greater than 90%
of the cells were either CD13+ and/or
CD33+ and PBMC from the 4 patients with lymphoid leukemia
contained greater than 90% CD19+ and/or
CD20+ cells. The leukemic samples were stained for surface
expression of class I MHC with the monoclonal antibody W6/32 to
determine if complete or partial loss of class I MHC might interfere
with the presentation of minor H antigens to CTL. None of the 14 leukemic samples contained a significant population of class I
MHClow or class I MHCnegative cells (data not
shown).
The CD3+CD8+ class I MHC-restricted minor H
antigen-specific CTL clones characterized in this study significantly
expand the spectrum of CTL-defined human minor H antigens. Comparison
of the results of class I MHC restriction, phenotype frequencies, and
distribution of tissue expression for the 17 minor H antigens identified here with those obtained for previously described minor H
antigens suggests that the antigens described here represent novel
specificities.8,28-30 Similarity exists between two of the
HLA-A2-restricted antigens defined by clones ATT-3 and ATT-5 and the
previously described HA-5 minor H antigen.28,29 These three
minor H antigens are all restricted by HLA-A2 and are detected in
hematopoietic cells but not fibroblasts. Clones ATT-3 and ATT-5 recognize distinct specificities as determined by differential recognition of HLA-A2+ target cells from the panel of
unrelated donors, but it is conceivable that one of these minor H
antigens could be identical to HA-5. The population frequency of 0.07 reported for HA-5 is lower than the frequencies of 0.17 and 0.28 we
obtained for the minor H antigen defined by ATT-3 and ATT-5,
respectively, although this disparity could be due to the different
panel of EBV-LCL used in our analysis. HLA-B7-restricted minor H
antigens have also been described in previous studies, but insufficient
data were reported on the frequency of these antigens in the population
and their tissue expression to determine if any correspond to one of
the six distinct HLA-B7-restricted minor H antigens defined by the CTL
clones generated and characterized in our study.34,35
Submitted June 24, 1997;
accepted October 28, 1997.
The authors thank Jennifer Michaels for assistance in preparation of
the manuscript and Suzanne Xuereb for technical assistance with many of
the experiments described in this report.
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Abstract
Introduction
Abstract
-irradiated PBMC cryopreserved from the recipient pretransplant.
) or donor-derived (
)
EBV-LCL targets in a standard 4-hour 51Cr release assay at
an effector to target (E:T) ratio of 20:1.
and
CD3+CD4
