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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2197-2207
Cytotoxic T-Lymphocyte-Defined Human Minor Histocompatibility
Antigens With a Restricted Tissue Distribution
By
Edus H. Warren,
Philip D. Greenberg, and
Stanley R. Riddell
From the Fred Hutchinson Cancer Research Center, Seattle, WA; and the
University of Washington, Seattle, WA.
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ABSTRACT |
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.
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INTRODUCTION |
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
 -irradiated PBMC cryopreserved from the recipient pretransplant.
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.
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MATERIALS AND METHODS |
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).
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Table 1.
Characteristics of the 10 Allogeneic BMT Donor/Recipient
Pairs Recruited for This Study, Including Gender of Recipient and Donor, Recipient's Class I MHC Typing, Recipient's Diagnosis, Source
of Donor Hematopoietic Stem Cells, Regimen Used for GVHD Prophylaxis, and Acute GVHD Status of the Recipient
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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 -irradiated (35 Gy) PBMC obtained from the
recipient pretransplant. The cell lines were restimulated with
-irradiated recipient PBMC at 7 and 14 days after the initial
stimulation and the media was supplemented with interleukin-2 (10 to 15 U/mL) after each restimulation. The resulting T-cell lines were
expanded by restimulation at weekly intervals with irradiated EBV-LCL
derived from the recipient pretransplant. After 4 to 6 weeks, the
cultures were tested for cytolytic activity against donor- and
recipient-derived EBV-LCL and/or PHA blast targets.
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 -irradiated (65 Gy) recipient-derived EBV-LCL as
antigen-presenting cells (APC), 2.5 × 105/mL
-irradiated (35 Gy) PBMC as feeder cells, and 2 cells/mL (0.4 cells/well) of responder T cells. In some experiments, CD4+
T cells were depleted from the T-cell lines before cloning by adherence
to tissue culture flasks coated with anti-CD4 monoclonal antibody
(Applied Immune Sciences, Santa Clara, CA). After 13 to 14 days, wells
exhibiting T-cell growth were identified by microscopy and aliquots of
the well were screened for lytic activity against donor- and
recipient-derived EBV-LCL or PHA blast targets. T-cell clones with
lytic activity against only recipient-derived targets were expanded in
vitro for further analysis of phenotype and function.
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).
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RESULTS |
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.
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| Fig 1.
Cytolytic activity of T-cell lines generated from 10 donor/recipient pairs against recipient- and donor-derived EBV-LCL
targets. Lines were tested 4 to 6 weeks after initial stimulation for
lytic activity against recipient-derived ( ) 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.
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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 and
CD3+CD4CD8+ cells in all
cases (data not shown). To determine if CD8+ T cells
contributed to the cytolytic activity against recipient target cells
and whether multiple minor H antigen specificities were being
recognized by each line, T-cell clones were isolated in limiting
dilution cultures from the 8 T-cell lines using recipient EBV-LCL as
APC. In 5 of the cloning experiments (donor/recipient pairs no. 1, 2, 3, 4, and 5; Table 1) the T cells were plated without prior selection
for CD4+ or CD8+ T cells. A total of 527 T-cell
clones were isolated from 4 of these 5 T-cell lines. Fifty-four of the
T-cell clones exhibited cytolytic activity for recipient but not donor
EBV-LCL; 25 of these T-cell clones were
CD3+CD4+CD8 and 29 were
CD3+CD4CD8+. Fourteen of the
25 cytolytic CD3+CD4+CD8
clones were derived from donor/recipient pair no. 1, between whom a
major mismatch at DR (DR6 v DR8) was present, suggesting that
these clones may recognize MHC determinants rather than minor H
determinants. Because the focus of our study was to identify minor H
antigens presented by class I MHC molecules, further characterization of the cytolytic CD3+CD4+CD8
clones was not performed. Of the 29 CD3+CD4CD8+ CTL clones
isolated in these initial experiments, 1 was obtained from
donor/recipient pair no. 1, 2 from pair no. 2, 23 from pair no. 4, and
3 from pair no. 5.
The small number of
CD3+CD4CD8+ minor H
antigen-specific CTL clones obtained from 3 of these 5 T-cell lines
with recipient-specific cytolytic activity suggested that enrichment of
CD8+ T cells before cloning may be necessary to improve the
efficiency with which
CD3+CD8+CD4 T-cell clones
reactive with recipient minor H antigens are isolated. Thus, 3 subsequent T-cell lines derived from donor/recipient pairs no. 7, 8, and 10 (Table 1), respectively, were depleted of CD4+ T
cells and the remaining cells plated at limiting dilution. A total of
357 T-cell clones were isolated from 2 of these T-cell lines (pairs no.
7 and 8) and screened for cytolytic activity against recipient- but not
donor-derived EBV-transformed B-cell targets. Nine clones from donor
recipient/pair no. 7 and 18 clones from donor/recipient pair no. 8 exhibited cytolytic activity against recipient-but not donor-derived
target cells. These 27 minor H antigen-specific clones were all
CD3+CD4CD8+.
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.
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| Fig 2.
Identification of class I MHC-restricting elements for
four representative CD8+ minor H antigen-specific CTL
clones. Each CTL clone was assayed for lytic activity against a panel
of EBV-LCL target cells derived from unrelated individuals each of whom
shared only one class I MHC allele with the donor/recipient pair from
whom the clone was derived. Lytic activity at an E:T ratio of 20:1
against recipient-derived LCL, donor-derived LCL, and LCL derived from
unrelated individuals who shared the indicated HLA-A or HLA-B allele
with the recipient and the donor is plotted for (A) HLA-A3-restricted
clone DRN-7, (B) HLA-B7-restricted clone DRN-11, (C)
HLA-B8-restricted clone MRR-2, and (D) HLA-B53-restricted clone
DJG-24.
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The proportion of individuals in the population that express the gene
encoding the minor H antigen can be estimated by evaluating the lytic
activity of each CTL clone against a large panel of EBV-transformed
B-cell targets bearing the relevant class I MHC-restricting allele. For
36 of the 56 clones, an estimate of the phenotype frequency of the
minor H antigen in the population was established by evaluating the
lysis of EBV-transformed B cells derived from at least 10 unrelated
individuals bearing the class I MHC-restricting allele. In some cases,
individual CTL clones that used the same class I MHC-restricting
element exhibited a different pattern of reactivity against the panel
of unrelated EBV-LCL, indicating that distinct minor H antigens were
being recognized. For example, four minor H antigen specificities
presented by HLA-A2 and six specificities presented by HLA-B7 could be
identified by the panel of CTL clones restricted by these alleles
(Table 2). The population frequencies of the four HLA-A2-restricted
minor H antigens were 0.17, 0.28, 0.47, and 0.70, respectively (Table
2).29 The population frequencies of the six
HLA-B7-restricted minor H antigens ranged from 0.31 to 0.92 (Table 2).
Twenty-three CD8+ CTL clones were generated from
donor/recipient pair no. 4 and all recognized a minor H antigen
presented by HLA-B8. When these CTL were tested against a panel of 16 EBV-LCL derived from HLA-B8+ donors, they lysed 10 of 10 EBV-LCL from male donors (>60% specific lysis) but 0 of 6 EBV LCL
from female donors (<3% specific lysis), suggesting that the minor H
antigen recognized by these clones was encoded or regulated by a gene
on the Y chromosome.
The analysis of MHC restriction and population phenotype frequency
defined at least 17 distinct minor H antigenic specificities, each of
which was recognized by one or more of the CD8+ CTL clones
generated in this study (Table 2). Multiple CTL clones with identical
MHC restriction and patterns of reactivity against the panel of target
cells were frequently isolated from a single patient. However, none of
the 17 minor H antigens identified in this study was recognized by T
cells derived from more than one patient (Table 2). Thus, this analysis
indicates that there is a large number of minor H antigen disparities
recognized by CD8+ CTL and potentially involved in GVH and
GVL reactions after MHC-matched sibling BMT and suggests that isolation
of minor H antigen-specific T cells from additional donor/recipient
pairs will identify many new specificities.
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).
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| Fig 3.
Recognition of EBV-LCL, PHA blasts, and fibroblasts
derived from single donors by four different CD8+ minor H
antigen-specific CTL clones. EBV-LCL, PHA blasts, and fibroblasts
derived from minor H antigen-positive individuals were used as targets
in 51Cr release assays at E:T 20:1 for (A)
HLA-A2-restricted clone PAM-13, (B) HLA-A2-restricted clone ATT-1,
(C) HLA-A3-restricted clone DRN-7, and (D) HLA-B53-restricted clone
DJG-24.
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Surprisingly, CD8+ CTL clones recognizing the male-specific
(H-Y) minor H antigen presented by HLA-B8 lysed hematopoietic target cells but not dermal fibroblasts derived from the same donors (Fig 4). This was not due to a failure of
these fibroblasts to present antigens or be lysed by CTL, because a CTL
clone specific for an HLA-A2-restricted minor H antigen lysed the same
fibroblasts as efficiently as hematopoietic cells (data not shown).
Pretreatment of the male fibroblast targets with 500 U/mL
interferon- (IFN-) for 48 or 72 hours did not significantly
sensitize them to lysis by any of these HLA-B8-restricted clones (Fig
4). These results differ from those obtained with the HLA-A1-,
HLA-A2-, and HLA-B7-restricted male-specific (H-Y) CTL clones
described by other investigators, which efficiently lysed both
hematopoietic and fibroblast target cells derived from male
donors.28
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| Fig 4.
The male-specific minor H antigen recognized by
HLA-B8-restricted CTL clones is detected in hematopoietic cells but
not fibroblasts. Lytic activity of a representative HLA-B8-restricted
male-specific CTL clone (MRR-23) against EBV-LCL (), dermal
fibroblasts (), and IFN--treated fibroblasts (500 U/mL for 48 hours; ) derived from four unrelated HLA-B8+ male
donors. The effector to target ratio is 20:1.
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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).
Four CTL clones which recognized distinct minor H antigens presented by
either HLA-A3, -B7, or -B8 were tested for their ability to lyse
leukemic cell targets from this panel in vitro. The HLA-A3-restricted clone DRN-7 was assayed against 11 different HLA-A3+ AML,
ALL, and CLL samples. Significant lytic activity was observed against 5 of 7 AML samples, 1 of 2 ALL samples, and 1 of 2 CLL samples, and this
lytic activity was inhibited in the presence of the anti-pan class I
MHC antibody W6/32 (Fig 5A). Clone DRN-7 was also tested for lytic activity against PHA blast populations derived from the same panel of leukemic patients, and lysed PHA blast
targets from the 7 patients against whom significant antileukemic activity was also seen, but exhibited negligible lysis of PHA blasts
from the patients against whom no antileukemic activity was
demonstrable (data not shown).
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| Fig 5.
CD8+ minor H antigen-specific CTL clones
demonstrate cytolytic activity against leukemic blasts in vitro that is
blocked by antibody to class I MHC. Activity of HLA-A3-restricted
clone DRN-7 (A) and HLA-B7-restricted clones ATT-4 (B) and ATT-7 (C)
against panels of leukemic cells in the absence () or presence ()
of anti-pan class I MHC antibody W6/32 at 25 µg/mL. The target cell panel in (A) was derived from 11 different HLA-A3+
patients: 7 with AML, 2 with ALL, and 2 with CLL. The target cell panel
in (B) and (C) was derived from 5 different HLA-B7+
patients: 4 with AML and 1 with CLL. E:T was 20:1 in all experiments.
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The HLA-B7-restricted clones ATT-4 and ATT-7, which are specific for
minor H antigens present in 92% and 85% of the population, respectively, were tested for lytic activity against 4 AML samples and
1 CLL sample. Both clones demonstrated significant lytic activity against all of the leukemic targets, and this lytic activity was significantly reduced in the presence of the W6/32 antibody (Fig 5B and
C). PHA blast targets derived from the leukemic donors were also lysed
(data not shown). Three HLA-B8-restricted, H-Y-specific clones from
donor/recipient pair no. 4 were assayed against a panel of 2 male and 3 female HLA-B8+ AML samples. Significant lytic activity was
seen against the male but not the female AML targets (data not shown).
| |
DISCUSSION |
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
The HLA-B8-restricted, male-specific H-Y antigen defined by the CTL
clones obtained from donor/recipient pair no. 4 is distinguishable from
H-Y antigens described by other investigators.28 CTL clones specific for the HLA-A2- and HLA-B7-restricted H-Y antigens recognize epitopes derived from the human homologue of the murine SMCY gene and
lyse both hematopoietic cells and fibroblasts.28,36,37 In
contrast, the HLA-B8-restricted H-Y antigen is expressed in hematopoietic cells including EBV-transformed B cells, PHA blasts, and
HLA-B8+ AML blasts, but is not expressed sufficiently for
CTL recognition in either untreated or IFN--treated fibroblasts.
These results suggest that the peptide epitope recognized by these
H-Y-specific clones is encoded by a gene distinct from SMCY that is
presumably located on the Y chromosome and whose transcription,
translation, and/or processing is regulated in a
tissue-specific fashion.
In the setting of MHC-matched allogeneic BMT, recipient minor H
antigens that are expressed on hematopoietic cells including leukemic
cells but are not widely distributed on nonhematopoietic tissues could
potentially be targets for adoptive therapy with donor-derived CTL
clones to induce GVL activity without causing GVHD. Twelve of the 17 CTL-defined minor H antigens described in this report are detected in
recipient hematopoietic cells but not in skin fibroblasts. These 12 tissue-restricted antigens are presented by common class I MHC
alleles,31 including HLA-A2, -A3, -B7, -B8, and -Cw7, and
several are present in phenotype frequencies that suggest that BMT
donor/recipient pairs will often be discordant for one or more of these
minor H antigens. In the cohort of patients in this study,
CD3+CD8+ CTL clones recognizing
tissue-restricted minor H antigens were isolated from 4 of the 8 donor/recipient pairs in whom T-cell cloning was attempted, and it is
conceivable that analysis of a larger number of clones would identify
such CTL in a higher fraction of patients. Two of the 4 donor/recipient
pairs from whom clones with tissue-specific reactivity were isolated
(pairs no. 4 and 8) did not develop clinically significant GVHD, in
agreement with some38,39 but not all40 previous
studies. CD8+ CTL specific for 6 of the tissue-restricted
minor H antigens displayed lytic activity against leukemic cells in
vitro. CTL defining 4 distinct tissue-resticted minor H antigens were
tested against panels of leukemic cells bearing the appropriate
MHC-restricting allele and were shown to lyse leukemias of both myeloid
and lymphoid phenotypes, demonstrating that, in addition to normal
hematopoietic cells such as T cells, B cells, and monocytes, the
antigens recognized are expressed in leukemic blasts. Thus, our results
significantly extend the number of minor H antigens that could
potentially be targeted with CD3+CD8+ CTL
clones to selectively induce GVL and demonstrate that a large proportion of BMT patients would be candidates for adoptive T-cell therapy.
A critical issue for the development of this approach to GVL therapy is
to demonstrate that expression of the genes encoding candidate target
minor H antigens is truly limited to hematopoietic cells. Dermal
fibroblasts and keratinocytes have been used as nonhematopoietic target
cells because they can be readily obtained from a skin biopsy and
cultured in vitro. However, defining the expression of minor H antigens
in other tissues using in vitro cytolytic assays is limited by the
difficulties inherent in obtaining and culturing samples from other
tissue sites. Moreover, data from such in vitro assays could
underestimate the expression of minor antigens in tissues in vivo and
thus the potential for inducing or aggravating GVHD. Indeed, a recent
study identified a significant association of a mismatch of the
tissue-restricted HA-1 minor H antigen between donor and recipient with
the occurrence of grade II or higher GVHD in adult BMT
recipients.41 Thus, the identification of the genes
encoding minor H antigens is necessary to permit a comprehensive
definition of gene expression in different tissues using molecular
techniques. Biochemical methods have been used to isolate and sequence
the peptide epitopes bound to MHC molecules and this technology has
recently been applied to identify the sequence of human minor H antigen
peptides.36,37,42 However, the short peptide sequence
obtained with this approach, typically 8 to 11 amino acids in length,
does not ensure that the gene encoding the antigen will be identified
in available databases. A second approach to identifying genes encoding
CTL-defined antigens is based on cDNA expression cloning. In this
method, cDNA expression libraries are prepared from antigen-positive
cells and divided into small pools; these pools are then cotransfected
with a plasmid encoding the class I restricting allele into
antigen-negative target cells, and CTL are used to screen the
transfectants.43-46 This strategy has been used to identify
several genes encoding CTL-defined antigens expressed by melanoma cells
and is being adapted in our laboratory to identify genes encoding
CTL-defined minor H antigens.
The results of this and other studies have established that minor H
antigen-specific CTL clones are cytotoxic for leukemic blasts in vitro,
but the extent to which in vitro cytolytic activity will correlate with
in vivo antileukemic activity is unknown. New insights into the biology
of human AML underscore the potential for the results of in vitro
cytotoxicity assays to be misleading. The transplantation of human AML
cells into NOD/SCID mice has revealed a hierarchy of cells in the
leukemic population with differing potential for establishing leukemic
engraftment.47,48 These studies have identified a putative
leukemic stem cell that is CD34+, CD38,
present in exceedingly low frequency (<1 in 105 cells) in
PB or BM samples from AML patients, and capable of establishing
leukemic hematopoiesis in NOD/SCID mice.47,48 This suggests
that T cells used in immunotherapy of AML will have to eliminate this
rare AML stem cell. The activity of CD8+ minor H
antigen-specific CTL clones against the putative AML stem cell cannot
easily be addressed with in vitro cytotoxicity assays because of the
rarity of this cell, but should be evaluable by analyzing the effect of
CTL on leukemic engraftment in the NOD/SCID mouse. Preliminary studies
have shown that CTL clones generated in this study prevent engraftment
of human AML in the NOD/SCID model (Bonnet and Warren, manuscript in
preparation).
The results of this study suggest that there will be a large number of
distinct human minor H antigens that could be targets for GVL therapy,
and it may not be feasible in all circumstances to pursue gene
identification and studies of antileukemic activity in the NOD/SCID
mouse model. The ability to genetically modify human T-cell clones with
the Herpes simplex virus thymidine kinase gene to confer an
inducible toxic phenotype could permit the in vivo elimination of
adoptively transferred T cells if they caused severe
GVHD.49-51 This strategy should allow
clinical evaluation of the antileukemic activity of minor H
antigen-specific T-cell clones for patients with relapse of AML or ALL
after allogeneic BMT.
| |
FOOTNOTES |
Submitted June 24, 1997;
accepted October 28, 1997.
Supported by grants from the National Institutes of Health (Grant No.
CA18029), the Lady Tata Memorial Trust (E.H.W.), and the Florence A. Carter Fellowship from the American Medical Association-Education and
Research Fund (E.H.W.).
Address reprint requests to Edus H. Warren, MD, PhD, Program in
Immunology, M-758, Clinical Research Division, Fred Hutchinson Cancer
Research Center, 1124 Columbia St, Seattle, WA 98104.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
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