| |
|
|
|
|
|
|
|||
|
TRANSPLANTATION
From the Bone Marrow Transplantation Section,
Transplantation Biology Research Center, Surgical Service,
Massachusetts General Hospital/Harvard Medical School, Boston, MA.
The graft-versus-leukemia (GVL) effects and graft-versus-host
disease (GVHD)-inducing activity of CD8 T cells was compared in murine
recipients of wild-type (WT) or interferon Allogeneic bone marrow transplantation (BMT) is an
effective therapeutic approach for the treatment of otherwise fatal
hematologic malignancies and nonmalignant hematopoietic disorders.
Although reduced leukemic relapse rates resulting from
graft-versus-leukemic (GVL) effects have been observed in patients
receiving HLA antigen-mismatched marrow compared to HLA-identical
transplants,1-5 the high incidences of graft-versus-host
disease (GVHD) and GVHD-induced immunodeficiency present an enormous
obstacle to HLA-mismatched BMT in humans.6-8 Thus, a major
challenge is to separate beneficial GVL effects from GVHD. Although
T-cell depletion of donor marrow can inhibit GVHD, and some studies
have shown that GVL effects can be induced in recipients of allogeneic
natural killer (NK) cells9-11 or T cell-depleted (TCD)
allogeneic BMT,12,13 a strong association of leukemic
relapse with TCD BMT has been proven in a number of animal studies and
clinical trials.14-19 The high incidence of leukemic
relapse associated with T-cell depletion indicates that in addition to
GVHD, efficient GVL effects against certain leukemias are also largely
dependent on donor T cells. Thus, methods that can selectively inhibit
the GVHD-promoting activity of allogeneic T cells while preserving
allogeneic T cell-mediated GVL effects would be highly beneficial in
the use of allogeneic BMT for the treatment of leukemia.
Previous studies have shown that interferon- Mice
Bone marrow transplantation
Induction of GVH with 2C T cells was performed by intravenous injection of 10 × 106 BMCs and 12 × 106 splenocytes from WT or GKO 2C TCR transgenic B6 donors into lethally irradiated (8 Gy) BALB/c mice. Non-GVHD controls received similar numbers of BMCs and splenocytes from syngeneic donors. As described above, animals were randomized before and after BMT. FACS analysis For the measurement of donor T-cell expansion and chimerism, recipient white blood cells (WBCs) were stained for 30 minutes at 4°C with antihost H-2Kb mAb 5F1-FITC (Pharmingen) and phycoerythrin (PE)-conjugated anti-CD8 mAb (53-6.7, Pharmingen). To block nonspecific FcR binding of labeled antibodies, 10 µL of undiluted culture supernatant of 2.4G2 (rat antimouse Fc R
mAb)27 was added to the first incubation. The expression of
IFN- receptor on EL4 cells was measured by staining cells with rat
antimouse CD119-FITC (GR20, Pharmingen). FITC-labeled and
biotinylated mouse IgG2a mAb HOPC-1 and PE-labeled rat IgG2a mAb
(Pharmingen) were used as nonstaining negative control antibodies.
Cells were washed with FACS buffer (Hanks balanced salt solution
containing 0.1% bovine serum albumin [BSA] and 0.1% NaN3) between each and following the last stain, and were
analyzed on a FACScan (Becton Dickinson, Mountain View, CA).
Proliferation assay EL4 cells (2 × 103/well) and WEHI-279 cells (1 × 104/well) were incubated in triplicate in 96-well plates with various concentrations of recombinant murine IFN-
(Pharmingen) in RPMI medium supplemented with 10% fetal calf serum
(FCS; Sigma, St Louis, MO), 4% nutrient mixture
(L-glutamine, nonessential amino acids, sodium pyruvate, penicillin/streptomycin), 1% Hepes buffer, and 10 µM
2-mercaptoethanol. Cultures were pulsed with 1 µCi (0.037 MBq)
3H-thymidine 36 hours after incubation, and harvested 12 hours later. 3H-thymidine uptake was counted on a
Betaplate counter (Wallac, Gaithersburg, MD) and data are presented
as the mean ± SD (cpm) of triplicate samples. WEHI-279, a murine
lymphoma cell line that is sensitive to an antiproliferative effect of
IFN- , was used as an assay control.
The Nunc 10-mm tissue culture inserts (0.4 µm polycarbonate membrane, Nalge Nunc International, Roskilde, Denmark) were used to determine the effects of cytokines released by alloreactive T cells (ie, mixed lymphocyte reaction supernatants) on EL4 cell proliferation. BALB/c spleen cells (2 × 106 in 0.5 mL) or 0.5 mL media were added to each well of 24-well culture plates (Nalge Nunc International) containing 30 Gy-irradiated B6 spleen cells (2 × 106 in 0.5 mL). After 10-mm tissue culture inserts were placed into each well, 2.5 × 104 EL4 cells (1 mL) were added into each insert. EL4 cells were harvested on days 1, 2, 3, and 4 after incubation, and the number of viable EL4 cells in each well was counted by trypan blue exclusion. Three wells in each group were harvested at each time point and data are presented as the mean ± SD. The culture insert used in this study allows the permeation into the insert of cytokines produced by spleen cells, but blocks any spleen cell-mediated direct killing of EL4 cells. Alloreactive cytotoxic T-lymphocyte assay BALB/c spleen cells were cultured in triplicate in 96-well plates with irradiated B6 spleen cells (30 Gy), at a 1:1 ratio (8 × 105/well) in RPMI supplemented with 10% FCS, 4% nutrient mixture, 1% Hepes buffer, and 10 µM 2-mercaptoethanol for 5 days. Responder cells were mixed with 51Cr-labeled EL4 (target) cells in 96-well plates (8000 cells/well) at various ratios (50:1 to 0.78:1) and incubated for 4 hours. The supernatants were harvested and radioactivity was measured in an automatic gamma counter. The percent specific lysis was determined as follows: specific lysis (%) = [(cpm experimental cpm background)/(cpm maximum cpm background)] × 100%. Background cpm was taken as
spontaneous release from target cells in the absence of responder
cells, and maximum cpm as release by target cells treated with 0.5%
Nonidet P-40.
Statistical analysis Statistical analysis of survival data was performed with the log-rank test. The Student t test was used to determine the level of significance of differences in group means. A P < .05 was considered to be significant in both types of analysis.
IFN- in GVHD- and GVL-associated
alloresponses of allogeneic CD8 T cells, we compared these phenomena in
lethally irradiated C57BL/6 (B6) mice receiving CD4-depleted spleen
cells from WT or IFN- -deficient GKO BALB/c donors. B6 mice were
lethally irradiated (9.75 Gy) and reconstituted with 5 × 106 TCD B6 BMCs (syngeneic controls) or with TCD
BMCs (5 × 106) and CD4-depleted spleen cells
(10 × 106) from WT or GKO BALB/c mice. Some recipients
were injected with 500 EL4 cells (a B6 T-cell leukemia/lymphoma cell
line) along with the BMT inoculum. It has been demonstrated that the
GVL effect against EL4 cells is donor CD8+ cell dependent
and CD4+ cell independent.20,28 Consistent
with our previous finding that lethal acute GVHD in this strain
combination is mostly CD4 dependent,22 most B6 mice
injected with WT BALB/c CD4-depleted spleen cells survived long-term
(Figure 1A). However, injection of a
similar number of GKO BALB/c CD4-depleted spleen cells into B6 mice led
to 60% mortality by 20 days (Figure 1A). Nonleukemic recipients of GKO
BALB/c cells also showed more severe weight loss compared to
nonleukemic recipients of WT BALB/c cells (Figure 1B). The body weight
of most recipients of GKO BALB/c cells (4 of 5) decreased to less than
18 g by week 1 after BMT. However, only 1 of 5 mice that received
WT BALB/c cells showed severe weight loss (< 18 g) by week 1 and the
body weight of all surviving mice in this group recovered by week 2 after BMT. Because GVHD cannot be induced by donor spleen cells if both
CD4 and CD8 T cells are depleted in this strain combination, these
results indicate that donor-derived IFN- down-modulates systemic
GVHD induced by allogeneic CD8 T cells.
Remarkably, donor-derived IFN-
Similar results were observed in a repeat experiment. To limit the
potential for GVHD-associated mortality to interfere with the
evaluation of GVL effects, B6 recipients in this experiment were
injected with a reduced number (7.5 × 106) of BALB/c
CD4-depleted spleen cells. As shown in Figure
2A, with the exception of one nonleukemic
recipient in each of the WT and GKO allogeneic BMT groups, nonleukemic
mice survived for the duration of the experiment. However, the survival
advantage against EL4 leukemia conferred by CD4-depleted spleen cells
from GKO BALB/c mice was significantly less than that mediated by WT BALB/c CD4-depleted spleen cells (Figure 2B; P < .05 for
leukemic recipients of WT BALB/c cells compared to leukemic recipients of GKO BALB/c cells). All recipients of WT BALB/c cells were protected from leukemia-associated lethality, whereas all syngeneic recipients died of leukemia by day 32 after BMT (P < .001). Although
leukemic recipients of GKO BALB/c cells were also significantly
protected from lethality compared to syngeneic recipients
(P < .05), long-term survival was only achieved in less
than 50% of these mice. Evidence for tumor at autopsy was found in 3 of 4 leukemic recipients of GKO BALB/c cells that died by 40 days after
BMT (Exp 2 in Table 1). No tumor was detected in long-term surviving
leukemic recipients of either GKO (3 mice) or WT (7 mice) BALB/c cells.
Together, our results indicate that donor-derived IFN-
IFN- seems to be required for the absence of lethal GVHD
in this 2C BALB/c BMT model. As shown in Figure
3, administration of
10 × 106 BMCs and 12 × 106 splenocytes
from IFN- -deficient 2C donors caused severe acute GVHD, with 100%
mortality by 20 days, whereas BALB/c mice receiving similar numbers of
bone marrow and spleen cells from WT 2C mice survived
long-term.
IFN- produced
by the effector CD8 T cells plays a role in dissociating GVL effects
from systemic GVHD, we compared GVHD versus GVL effects in lethally
irradiated B6 mice receiving transplants with purified CD8+
T cells (1 × 106) from GKO or WT BALB/c mice. B6 TCD
BMCs (5 × 106) and GKO BALB/c TCD BMCs
(5 × 106) were given to all allogeneic BMT recipients
and 500 EL4 cells were injected into some groups. Coadministration of
TCD B6 BMCs into these lethally irradiated recipients of allogeneic
cells provided a marker for the evaluation of lymphohematopoietic GVH reactions (see below). Although GVHD death was not observed (during an
observation period of > 100 days) in the recipients of either WT or
GKO BALB/c CD8 T cells (Figure 4A),
significant loss of body weight was again observed in nonleukemic
recipients of GKO BALB/c (19.5 ± 0.9 g), but not in nonleukemic
recipients of WT BALB/c (20.7 ± 1.1 g) cells at week 1 after BMT
(P < .05). The average body weight of nonleukemic
recipients of syngeneic cells at week 1 after BMT was 20.7 ± 0.9 g.
However, GVL effects correlated inversely with the degree of
GVHD-related weight loss. Despite the more severe GVHD, as indicated by
weight loss in nonleukemic recipients of GKO BALB/c CD8 cells, the
survival of leukemic recipients of GKO BALB/c CD8 cells was not
significantly extended compared to that of syngeneic controls
(P = .17). In contrast, the survival of leukemic mice
transplanted with WT BALB/c CD8 cells was significantly prolonged
(Figure 4A; P < .005 compared to leukemic recipients of
syngeneic BMT or GKO BALB/c cells).
Consistent results were observed in a repeat experiment, in which
allogeneic recipients were injected with a higher number (2.5 × 106) of WT or GKO BALB/c CD8 T cells. As shown in
Figure 4B, 40% of nonleukemic recipients of GKO BALB/c CD8
cells died of GVHD, whereas all nonleukemic recipients of WT BALB/c CD8
cells survived long-term (> 100 days). In addition, the mean body
weight of nonleukemic recipients of GKO BALB/c CD8 cells was
significantly lower than that of nonleukemic recipients of WT BALB/c
CD8 cells (19 ± 1.1 g versus 21 ± 1.2 g at week 1;
P < .05). However, unlike GVHD, the potency of GKO BALB/c
CD8 T cell-mediated GVL effects was not greater than that of WT BALB/c
CD8 T cells (Figure 4B; P = .19). A significant delay in
leukemic death was seen in leukemic recipients of both WT BALB/c
(P < .0005) and GKO BALB/c (P < .005) CD8
cells compared to leukemic recipients of syngeneic BMT. Because most
nonleukemic recipients (8 of 9) were surviving by the time when all
leukemic recipients had died in recipients of GKO BALB/c CD8 cells,
leukemia, but not GVHD, was the presumed cause of death in the leukemic
group. Together, these results indicate that IFN- Discrepancy between systemic GVHD and antihost lymphohematopoietic alloreactivity in recipients of GKO BALB/c CD8 T cells Previous studies in humans and animal models have shown that lymphohematopoietic GVH reactions that selectively eliminate host lymphohematopoietic cells, including lymphoma cells, can be induced without severe systemic GVHD in allogeneic BMT recipients.33-35 To determine whether or not the loss of GVL effects in recipients of GKO CD8 T cells was due to a reduced lymphohematopoietic GVH reaction, we compared donor CD8 T-cell expansion and levels of residual host hematopoietic cells in recipients of WT or GKO allogeneic BMT along with TCD host-type BMCs. Nonleukemic recipients of WT BALB/c or GKO BALB/c CD8 cells (these are the same mice shown in Figure 4A) were bled at weeks 5 and 9 after BMT, and the levels of donor CD8 T cells and surviving host cells in the recipient WBCs were determined by FACS analysis. Because these mice were injected with 5 × 106 TCD B6 BMCs along with allogeneic cells, lymphohematopoietic GVH reactions were assessed by measuring the preservation of host-type hematopoiesis. Consistent with the increased severity of systemic GVHD as shown by weight loss, the extent of GKO donor CD8 T-cell expansion was significantly greater than that of WT CD8 T cells in B6 recipients (Figure 5A). However, this greater expansion of GKO BALB/c CD8 T cells that was associated with significant loss of recipient body weight was associated with poor alloreactivity against host lymphohematopoietic cells. The levels of host (H-2Kb+) peripheral blood cells in mice receiving transplants with GKO BALB/c CD8 T cells were similar to and higher than those in the recipients of WT BALB/c CD8 T cells at weeks 5 and 9, respectively (Figure 5B). The difference was even more significant when comparing the levels of host-type cells in non-T-cell lineages (ie, when expanded donor T cells were excluded). As shown in Figure 5C, the percentages of host B cells (ie, percent of H-2Kb+CD19+ cells in the CD19+ cell population) in recipients of GKO BLAB/c CD8 T cells were markedly higher than that in recipients of WT CD8 T cells. These results indicate that allogeneic CD8 T cells induce more severe systemic GVHD but weaker antihost hematopoietic alloreactivity (and an associated reduction in GVL effects) if they are incapable of producing IFN- .
CD4 CD8 spleen cells or IFN- -producing
BMCs or both play a role in the anti-EL4 GVL effect, which has been
shown to be donor CD8 T-cell dependent.20,28 To address
this possibility, we compared GVL effects in B6 recipients of 500 EL4
cells and 5 × 106 TCD WT BALB/c BMCs along with
different populations of WT BALB/c splenocytes: (1)
8.5 × 106 CD4-depleted spleen cells (with 16.5%
CD8+ cells); (2) 1.4 × 106 CD8+
splenocytes; (3) 7.1 × 106 TCD (ie, CD4 and CD8
cell-depleted) splenocytes; or (4) 1.4 × 106
CD8+ and 7.1 × 106 TCD splenocytes.
Syngeneic controls were injected with 5 × 106 TCD B6
BMCs and 500 EL4 cells. Consistent with previous
studies20,28 and the results described above (Figures 1
and 2), GVL effects against EL4 cells were completely abolished by
depletion of CD4+ and CD8+ splenocytes
(P = .1 for the recipients of TCD BALB/c splenocytes compared to syngeneic controls), whereas they were preserved if only
CD4+ splenocytes were depleted (P < .0005 for
the recipients of CD4-depleted BALB/c splenocytes compared to syngeneic
controls; Figure 6). Although leukemic
mortality was delayed in mice receiving TCD BALB/c BMCs plus purified
CD8+ BALB/c splenocytes compared to syngeneic controls
(P < .005), all of these mice eventually succumbed to
leukemia (Figure 6). However, the GVL effects were fully restored by
adding TCD (CD4 CD8 ) splenocytes back to
purified CD8+ splenocytes. The potency of GVL effects in
the recipients of a combination of CD8+ and TCD BALB/c
splenocytes was significantly greater than that in mice receiving
CD8+ BALB/c splenocytes only (P < .005), and
was indistinguishable from that in recipients of CD4-depleted BALB/c
splenocytes (P = .6; Figure 6). Thus, donor
CD4 CD8 splenocytes, which do not mediate
GVL effects when injected alone, act synergistically with CD8 T cells
to augment the antileukemic alloreactivity of CD8 T cells. Furthermore,
these results confirm our previous results20,28 that donor
CD4 cells do not contribute to GVL effects in this model.
IFN- has been shown to mediate antitumor effects by
directly inhibiting tumor cell growth and inducing T cell-mediated antitumor responses.36-41 To determine whether the reduced
GVL effect in leukemic recipients of GKO allogeneic cells is due to the
loss of direct inhibition of EL4 cell proliferation by donor-derived IFN- , we measured the susceptibility of EL4 cells to an
IFN- -mediated antiproliferative effect. EL4 cells were incubated
with varying concentrations of IFN- for 48 hours and cell
proliferation was assessed by tritiated thymidine incorporation.
Despite the expression of IFN- receptor on their surface (Figure
7A), the proliferation of EL4 cells was
not significantly inhibited by IFN- , while IFN- efficiently
inhibited the growth of WEHI-279, an IFN- -susceptible murine
lymphoma cell line (Figure 7B). Moreover, no suppression of EL4
proliferation was mediated by supernatants of BALB/c-anti-B6 mixed
lymphocyte reactions, suggesting that cytokines released by
alloreactive T cells are incapable of directly suppressing the growth
of EL4 cells (Figure 7C).
IFN- has been shown to augment the sensitivity of tumor
cells to cytolytic T lymphocyte (CTL) activity by up-regulating surface
expression of Fas and major histocompatibility complex (MHC) on tumor
cells.42,43 To determine whether or not IFN- affects
the expression of Fas and class I MHC on EL4 cells, we have analyzed
the cell surface expression of these molecules on EL4 cells treated
with IFN- in comparison with untreated EL4 cells. EL4 cells were
incubated with IFN- at various concentrations (7 different
concentrations from 0.78 to 50 ng/mL) for 12 to 14 hours. Both Fas and
MHC class I expression were up-regulated on EL4 cells treated with
IFN- at all concentrations compared to control EL4 cells incubated
in IFN- -free medium (Figure 8A and data not shown). The peak expression for both molecules was observed on
EL4 cells treated with IFN- in a concentration range of 6.25 to 12.5 ng/mL (Figure 8A). CTL assays revealed that EL4 cells are highly
sensitive to the killing activity of both WT and GKO BALB/c CTLs
(Figure 8B). Indeed, the levels of Fas and MHC class I expression were
high even on untreated EL4 cells (Figure 8A). Consistently, the
susceptibility of EL4 cells to alloreactive CTLs was only slightly
increased by pretreatment with IFN- (Figure 8B).
The data presented here demonstrate that IFN- The mechanism for the discrepancy between augmented systemic GVHD
(identified as weight loss and mortality) and reduced
lymphohematopoietic GVH reactions in the recipients of GKO BALB/c cells
remains to be defined. It has been proposed that Th1 cytokines are
critical for inducing acute GVHD,44 and a number of
studies have shown that IFN- However, reduced death of alloreactive donor CD8 T cells alone cannot
explain the opposing effects of IFN- Although the differentiation of cytotoxic CD8 T cells has been shown to
require help from CD4 cells,71,72 the generation of
alloreactive CD8 T cells can also be independent of CD4
help.73,74 The striking increase in GVHD mortality in
recipients of GKO CD8 T cells or 2C cells demonstrates that this
helper-independent CD8 subset is regulated by cell-autonomous IFN- The present study demonstrated that allogeneic CD8 T cells lacking the
capacity for IFN-
We thank Drs Markus Mapara and Yong-mi Kim for critical reading of the manuscript and Sharon Titus for her expert secretarial assistance.
Submitted August 14, 2001; accepted January 25, 2002.
Supported by National Institutes of Health grant RO1 CA79989, American Cancer Society grant IRG-87-007-13, and American Society for Blood and Marrow Transplantation/Orphan Medical New Investigator Award.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Yong-Guang Yang, Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, MGH East, Bldg 149-5102, 13th St, Boston, MA 02129; e-mail: yongguang.yang{at}tbrc.mgh.harvard.edu.
1. Beatty PG, Clift RA, Mickelson FM, et al. Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med. 1985;313:765-771[Abstract]. 2. Bortin MM. Bone marrow transplantation for leukemia using family donors other than HLA-identical siblings: a preliminary report from the International Bone Marrow Transplant Registry. Transplant Proc. 1987;19:2629-2631[Medline] [Order article via Infotrieve].
3.
Beatty PG, Anasetti C, Hansen JA, et al.
Marrow transplantation from unrelated donors for treatment of hematologic malignancies: effect of mismatching for one HLA locus.
Blood.
1993;81:249-253
4.
Sierra J, Storer B, Hansen JA, et al.
Transplantation marrow cells from unrelated donor for treatment of high-risk acute leukemia: the effect of leukemic burden, donor HLA-matching, and marrow cell dose.
Blood.
1997;89:4226-4235
5.
Verdonck LF, Dekker AW, Lokhorst HM, Petersen EJ, Nieuwenhuis HK.
Allogeneic versus autologous bone marrow transplantation for refractory and recurrent low-grade Non-hodgkin's lymphoma.
Blood.
1997;90:4201-4205 6. Gale RP. Graft-versus-host disease. Immunol Rev. 1985;88:193-214[CrossRef][Medline] [Order article via Infotrieve]. 7. Ringden O, Nilsson B. Death by graft-versus-host disease associated with HLA mismatch, high recipient age, low marrow cell dose, and splenectomy. Transplantation. 1985;40:39-44[Medline] [Order article via Infotrieve].
8.
Lokhorst HM, Schattenberg A, Cornelissen JJ, Thomas LLM, Verdonck LF.
Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation.
Blood.
1997;90:4206-4211 9. Uharek L, Glass B, Gaska T, et al. Natural killer cells as effector cells of graft-versus-leukemia activity in a murine transplantation model. Bone Marrow Transplant. 1993;12:S57-60. 10. Zeis M, Uharek L, Glass B, et al. Allogeneic NK cells as potent antileukemic effector cells after allogeneic bone marrow transplantation in mice. Transplantation. 1995;59:1734-1736[Medline] [Order article via Infotrieve]. 11. Asai O, Longo DL, Tian RL, Taub DD, Ruscetti FW, Murphy WJ. Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. J Clin Invest. 1998;101:1835-1842[Medline] [Order article via Infotrieve].
12.
Papadopoulos EB, Carabasi MH, Castro-Malaspina H, et al.
T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: freedom from relapse in the absence of graft-versus-host disease.
Blood.
1998;91:1083-1090
13.
Aversa F, Tabilio A, Velardi A, et al.
Treatment of high risk leukemia with T cell depleted stem cells in patients from related donors with one fully matched haplotype.
N Engl J Med.
1998;339:1186-1193 14. Martin PJ, Hansen JA, Torok-Storb B, et al. Graft failure in patients receiving T cell-depleted HLA-identical allogeneic marrow transplants. Bone Marrow Transplant. 1988;3:445-456[Medline] [Order article via Infotrieve]. 15. Poynton CH. T cell depletion in bone marrow transplantation. Bone Marrow Transplant. 1988;3:265-279[Medline] [Order article via Infotrieve]. 16. Butturini A, Gale RP. T cell depletion in bone marrow transplantation for leukemia: current results and future directions. Bone Marrow Transplant. 1988;3:185-192[Medline] [Order article via Infotrieve]. 17. Slavin S, Ackerstein A, Naparstek E, Or R, Weiss L. The graft-versus-leukemia (GVL) phenomenon: is GVL separable from GVHD? Bone Marrow Transplant. 1990;6:155-161[Medline] [Order article via Infotrieve]. 18. Sykes M. Novel approaches to the control of GVHD. Curr Opin Immunol. 1993;5:774-781[CrossRef][Medline] [Order article via Infotrieve]. 19. Uharek L, Glass B, Zeis M, et al. Abrogation of graft-vs.-leukemia activity after depletion of CD3+ T cells in a murine model of MHC-matched peripheral blood progenitor cells. Exp Hematol. 1998;26:93-99[Medline] [Order article via Infotrieve].
20.
Yang YG, Sergio JJ, Pearson DA, Szot GL, Shimizu A, Sykes M.
Interleukin-12 preserves the graft-vs-leukemia effect of allogeneic CD8 T cells while inhibiting CD4-dependent graft-vs-host disease in mice.
Blood.
1997;90:4651-4660 21. Yang YG, Dey B, Sergio JJ, Sykes M. IL-12 prevents severe acute GVHD and GVHD-associated immune dysfunction in a full MHC haplotype-mismatched murine bone marrow transplantation model. Transplantation. 1997;64:1343-1352[CrossRef][Medline] [Order article via Infotrieve].
22.
Yang YG, Dey B, Sergio JJ, Pearson DA, Sykes M.
Donor-derived interferon 23. Sha WC, Nelson CA, Newberry RD, Kranz DM, Russell RD, Loh DY. Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature. 1988;335:271-274[CrossRef][Medline] [Order article via Infotrieve].
24.
Kranz DM, Sherman DH, Sitkowsky MV, Pasternack MS, Eisen HN.
Immunoprecipitation of cell surface structures of cloned cytotoxic T lymphocytes by clone-specific antisera.
Proc Natl Acad Sci U S A.
1984;81:573-577
25.
Sykes M, Romick ML, Hoyles KA, Sachs DH.
In vivo administration of interleukin 2 plus T cell-depleted syngeneic marrow prevents graft-versus-host disease mortality and permits alloengraftment.
J Exp Med.
1990;171:645-658 26. Sykes M, Bukhari Z, Sachs DH. Graft-versus-leukemia effect using mixed allogeneic bone marrow transplantation. Bone Marrow Transplant. 1989;4:465-474[Medline] [Order article via Infotrieve].
27.
Unkeless JC.
Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors.
J Exp Med.
1979;150:580-596 28. Sykes M, Abraham VS, Harty MW, Pearson DA. IL-2 reduces graft-vs-host disease and preserves a graft-vs-leukemia effect by selectively inhibiting CD4+ T cell activity. J Immunol. 1993;150:197-205[Abstract]. 29. Dey B, Yang YG, Preffer F, et al. The fate of donor T-cell receptor transgenic T cells with known host antigen specificity in a graft-versus-host disease model. Transplantation. 1999;68:141-149[CrossRef][Medline] [Order article via Infotrieve]. 30. Korngold R, Sprent J. Surface markers of T cells causing lethal graft-vs-host disease to class I vs class II H-2 differences. J Immunol. 1985;135:3004-3010[Abstract]. 31. Vallera DA, Soderling CCB, Kersey JH. Bone marrow transplantation across major histocompatibility barriers in mice, III: treatment of donor grafts with monoclonal antibodies directed against Lyt determinants. J Immunol. 1982;128:871-875[Abstract]. 32. Palathumpat V, Dejbachsh-Jones S, Strober S. The role of purified CD8+ T cells in graft-versus-leukemia activity and engraftment after allogeneic bone marrow transplantation. Transplantation. 1995;60:355-361[Medline] [Order article via Infotrieve].
33.
Sykes M, Sheard MA, Sachs DH.
Graft-versus-host-related immunosuppression is induced in mixed chimeras by alloresponses against either host or donor lymphohematopoietic cells.
J Exp Med.
1988;168:2391-2396 34. Pelot MR, Pearson DA, Swenson K, et al. Lymphohematopoietic graft-vs-host reactions can be induced without graft-vs-host disease in murine mixed chimeras established with a cyclophosphamide-based non-myeloablative conditioning regimen. Biol Blood Marrow Transplant. 1999;5:133-143[CrossRef][Medline] [Order article via Infotrieve]. 35. Spitzer TR, McAfee S, Sackstein R, et al. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies [in process citation]. Biol Blood Marrow Transplant. 2000;6:309-320[CrossRef][Medline] [Order article via Infotrieve].
36.
Nastala CL, Edington HD, McKinney TG, et al.
Recombinant IL-12 administration induces tumor regression in association with IFN- 37. Brunda MJ, Sulich V, Bellantoni D. The anti-tumor effect of recombinant interferon alpha and gamma is influenced by tumor location. Int J Cancer. 1987;40:807-810[Medline] [Order article via Infotrieve].
38.
Sayers TJ, Wiltrout TA, McCormick K, Wiltrout RH.
Antitumor effects of alpha-interferon and gamma-interferon on a murine renal cancer (Renca) in vitro and in vivo.
Cancer Res.
1990;50:5414-5420
39.
Brunda MJ, Luistro L, Hendrzak JA, Fountoulakis M, Garotta G, Gately MK.
Role of interferon- 40. Tannenbaum CS, Wicker N, Armstrong D, et al. Cytokine and chemokine expression in tumors of mice receiving systemic therapy with IL-12. J Immunol. 1996;156:693-699[Abstract]. 41. Tan J, Crucian BE, Chang AE, et al. Interferon-gamma-inducing factor elicits antitumor immunity in association with interferon-gamma production. J Immunother. 1998;21:48-55.
42.
Bohm W, Thoma S, Leithauser F, Moller P, Schirmbeck R, Reimann J.
T cell-mediated, IFN-
43.
Sayers TJ, Brooks AD, Lee J-K, et al.
Molecular mechanisms of immune-mediated lysis of murine renal cancer: differential contributions of perforin-dependent versus Fas-mediated pathways in lysis by NK and T cells.
J Immunol.
1998;161:3957-3965 44. Ferrara JLM, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant. 1999;5:347-356[CrossRef][Medline] [Order article via Infotrieve]. 45. Allen RD, Staley TA, Sidman CL. Differential cytokine expression in acute and chronic murine graft-versus-host disease. Eur J Immunol. 1993;23:333-337[Medline] [Order article via Infotrieve]. 46. Guy-Grand D, Vassalli P. Gut injury in mouse graft-vs-host reaction: study of its occurrence and mechanism. J Clin Invest. 1986;77:1584-1595[Medline] [Order article via Infotrieve]. 47. Mowat AM. Antibodies to IFN-gamma prevent immunologically mediated intestinal damage in murine graft-versus-host reaction. Immunology. 1989;68:18-23[Medline] [Order article via Infotrieve].
48.
Ellison CA, Fischer JMM, HayGlass KT, Gartner JG.
Murine graft-versus-host disease in an F1-hybrid model using IFN- 49. Brok HP, Heidt PJ, Van der Meide PH, Zurcher C, Vossen JM. Interferon-gamma prevents graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Immunol. 1993;151:6451-6459[Abstract].
50.
Murphy WJ, Welniak LA, Taub DD, et al.
Differential effects of the absence of interferon-
51.
Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS.
Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production.
Blood.
2001;97:2923-2931 52. Welniak LA, Blazar BR, Anver MR, Wiltrout RH, Murphy WJ. Opposing roles of interferon-gamma on CD4+ T cell-mediated graft-versus-host disease: effects of conditioning. Biol Blood Marrow Transplant. 2000;6:604-612[CrossRef][Medline] [Order article via Infotrieve].
53.
Liu Y, Janeway CA.
Interferon-gamma plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance.
J Exp Med.
1990;172:1735-1739 54. Novelli F, D'Elios MM, Bernabei P, et al. Expression and role in apoptosis of the alpha- and beta-chains of the IFN-gamma receptor on human Th1 and Th2 clones. J Immunol. 1997;159:206-213[Abstract]. 55. Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol. 1996;157:3223-3227[Abstract].
56.
Willenborg DO, Fordham SA, Staykova MA, Ramshaw IA, Cowden WB.
IFN-gamma is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: a possible role for nitric oxide.
J Immunol.
1999;163:5278-5286
57.
Tarrant TK, Silver PB, Wahlsten JL, et al.
Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon-
58.
Chu CQ, Wittmer S, Dalton DK.
Failure to suppress the expansion of the activated CD4 T cell population in interferon gamma-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis.
J Exp Med.
2000;192:123-128
59.
Dalton DK, Haynes L, Chu CQ, Swain SL, Wittmer S.
Interferon gamma eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells.
J Exp Med.
2000;192:117-122
60.
Dey B, Yang YG, Szot GL, Pearson DA, Sykes M.
IL-12 inhibits GVHD through a Fas-mediated mechanism associated with alterations in donor T cell activation and expansion.
Blood.
1998;91:3315-3322
61.
Badovinac VP, Tvinnereim AR, Harty JT.
Regulation of antigen-specific CD8(+) T cell homeostasis by perforin and interferon-gamma.
Science.
2000;290:1354-1358
62.
Badovinac VP, Harty JT.
Adaptive immunity and enhanced CD8+ T cell response to Listeria monocytogenes in the absence of perforin and IFN-gamma.
J Immunol.
2000;164:6444-6452
63.
Liao F, Rabin RL, Yannelli JR, Koniaris LG, Vanguri P, Farber JM.
Human Mig chemokine: biochemical and functional characterization.
J Exp Med.
1995;182:1301-1314
64.
Luster AD, Weinshank RL, Feinman R, Ravetch JV.
Molecular and biochemical characterization of a novel gamma-interferon-inducible protein.
J Biol Chem.
1988;263:12036-12043
65.
Luster AD, Ravetch JV.
Biochemical characterization of a gamma interferon-inducible cytokine (IP-10).
J Exp Med.
1987;166:1084-1097
66.
Tran EH, Prince EN, Owens T.
IFN-
67.
Koga S, Auerbach MB, Engeman TM, Novick AC, Toma H, Fairchild RL.
T cell infiltration into class II MHC-disparate allografts and acute rejection is dependent on the IFN-
68.
Shrikant P, Mescher MF.
Control of syngeneic tumor growth by activation of CD8+ T cells: efficacy is limited by migration away from the site and induction of nonresponsiveness.
J Immunol.
1999;162:2858-2866 69. Klimpel GR, Annable CR, Cleveland MG, Jerrells TR, Patterson JC. Immunosuppression and lymphoid hypoplasia associated with chronic graft versus host disease is dependent upon IFN-gamma production. J Immunol. 1990;144:84-93[Abstract]. 70. Parfrey NA, El Sheikh A, Monckton EA, Cockfield SM, Halloran PF, Linetsky E. Interferon-gamma gene expression during acute graft-versus-host disease: relationship to MHC induction and tissue injury. J Pathol. 1999;189:99-104[CrossRef][Medline] [Order article via Infotrieve]. 71. Bennett SRM, Carbone FR, Karamalis F, Flavell RA, Miller JFAP, Heath WR. Help for cytotoxic- T-cell responses is mediated by CD40 signalling. Nature. 1998;393:478-480[CrossRef][Medline] [Order article via Infotrieve]. 72. Schoenberger SP, Toes REM, van der Voort EIH, Offringa R, Melief CJM. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature. 1998;393:480-483[CrossRef][Medline] [Order article via Infotrieve].
73.
Manning TC, Rund LA, Gruber MM, Fallarino F, Gajewski TF, Kranz DM.
Antigen recognition and allogeneic tumor rejection in CD8+ TCR transgenic/RAG(
74.
Zhang Y, Corbett AJ, Brady JL, Sutherland RM, Lew AM.
CD4 help-independent induction of cytotoxic CD8 cells to allogeneic P815 tumor cells is absolutely dependent on costimulation.
J Immunol.
2000;165:3612-3619
75.
Zeng D, Lewis D, Dejbachsh-Jones S, et al.
Bone marrow NK1.1- and NK1.1+ T cells reciprocally regulate acute graft versus host disease.
J Exp Med.
1999;189:1073-1081
76.
Raziuddin A, Longo DL, Mason L, Ortaldo JR, Bennett M, Murphy WJ.
Differential effects of the rejection of bone marrow allografts by the depletion of activating versus inhibiting Ly-49 natural killer cell subsets.
J Immunol.
1998;160:87-94
77.
Seino K, Fukao K, Muramoto K, et al.
Requirement for natural killer T (NKT) cells in the induction of allograft tolerance.
Proc Natl Acad Sci U S A.
2001;98:2577-2581 78. Mapara MY, Kim Y-M, Wang S-P, Bronson R, Sachs DH, Sykes M. Donor lymphocyte infusions (DLI) mediate superior graft-versus-leukemia (GvL) effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells. Blood. In press.
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
![]() |
H. Wang, W. Asavaroengchai, B. Yong Yeap, M.-G. Wang, S. Wang, M. Sykes, and Y.-G. Yang Paradoxical effects of IFN-{gamma} in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury Blood, April 9, 2009; 113(15): 3612 - 3619. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Chakraverty, B. Flutter, F. Fallah-Arani, H.-S. Eom, T. Means, G. Andreola, S. Schwarte, J. Buchli, P. Cotter, G. Zhao, et al. The Host Environment Regulates the Function of CD8+ Graft-versus-Host-Reactive Effector Cells J. Immunol., November 15, 2008; 181(10): 6820 - 6828. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Nishimura, J. Baker, A. Beilhack, R. Zeiser, J. A. Olson, E. I. Sega, M. Karimi, and R. S. Negrin In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity Blood, September 15, 2008; 112(6): 2563 - 2574. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Sun, M. Li, T. J. Sayers, L. A. Welniak, and W. J. Murphy Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation Blood, August 15, 2008; 112(4): 1522 - 1529. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Ramirez-Montagut, A. Chow, A. A. Kochman, O. M. Smith, D. Suh, H. Sindhi, S. Lu, C. Borsotti, J. Grubin, N. Patel, et al. IFN-{gamma} and Fas Ligand Are Required for Graft-versus-Tumor Activity against Renal Cell Carcinoma in the Absence of Lethal Graft-versus-Host Disease J. Immunol., August 1, 2007; 179(3): 1669 - 1680. [Abstract] [Full Text] [PDF] |
||||
![]() |
X.-Z. Yu, M. H. Albert, and C. Anasetti Alloantigen Affinity and CD4 Help Determine Severity of Graft-versus-Host Disease Mediated by CD8 Donor T Cells J. Immunol., March 15, 2006; 176(6): 3383 - 3390. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. M. Hubbard, J. M. Eng, T. Ramirez-Montagut, K. H. Tjoe, S. J. Muriglan, A. A. Kochman, T. H. Terwey, L. M. Willis, R. Schiro, G. Heller, et al. Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation Blood, November 1, 2005; 106(9): 3285 - 3292. [Abstract] [Full Text] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||