|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-07-2109.
TRANSPLANTATION
From the Departments of Pediatrics, and Medicine,
Memorial Sloan-Kettering Cancer Center, New York, NY; the Department of
Pathology, Thomas Jefferson Medical Center, Philadelphia, PA; the
Department of Pathology, Immunology and Laboratory Medicine, University
of Florida, Gainesville; and the Department of Immunology, Weill
Medical College of Cornell University, New York, NY.
Previous studies in murine bone marrow transplantation (BMT)
models using neutralizing anti-tumor necrosis factor (TNF) antibodies or TNF receptor (TNFR)-deficient recipients have demonstrated that TNF
can be involved in both graft-versus-host disease (GVHD) and
graft-versus-leukemia (GVL). TNF in these GVHD and GVL models was
thought to be primarily produced by activated monocytes and macrophages, and the role of T cell-derived TNF was not determined. We
used TNF Tumor necrosis factor (TNF) is the original
member of what is now known as the TNF superfamily. Signaling through 2 different receptors (TNFR1 or p55TNFR and TNFR2 or p75TNFR), it
modulates complex events in malignant growth, infection, inflammation,
and immunity. As a type I inflammatory cytokine, TNF has an important role in the pathophysiology of a variety of inflammatory
diseases.1 The inhibition of TNF has emerged as an
effective novel therapy for a number of autoimmune
diseases.1-3 Although TNF can be expressed in a
membrane-anchored form and secreted by activated T cells,4 the specific role of T cell-derived TNF (as opposed to TNF derived from monocytes/macrophages or natural killer [NK] cells) in
inflammatory disease models has been less well studied.
The role of TNF as an effector molecule of cytotoxic T cells is poorly
defined. Although most of the cytolytic activity of cytotoxic
lymphocytes (CTL) can be accounted for by the classic pathways of
perforin/granzyme and Fas/FasL, CTLs deficient for both pathways
exhibit residual cytolytic activity,5 which has been
ascribed to TNF in its membrane-anchored or secreted form.
TNF has been recognized as an important inflammatory cytokine of the
"cytokine storm," which is an important element in the pathogenesis
of graft-versus-host disease (GVHD).6 In murine BMT
models, blockade of the TNF pathway with anti-TNF antibodies or by
using TNF receptor-deficient recipients has resulted in diminished GVHD
and graft-versus-leukemia (GVL).7-9 Serum TNF levels have
been reported to be elevated in patients with acute GVHD and clinical
trials have shown improvement of GVHD during treatment with anti-TNF
antibodies.10,11
Previous murine studies demonstrated an important role for TNF in
the development of GVHD and the GVL effect. It was presumed that most
of the TNF responsible for GVHD and GVL activity was derived from host
or donor monocytes/macrophages due to the pretransplantation conditioning regimen and GVHD, although the experiments using anti-TNF
antibodies or TNF receptor-deficient recipients could not distinguish
between different sources of TNF. In this study we decided to examine
the specific role of donor T cell-derived TNF in GVHD, and GVL, which
had not been addressed before.
Using wild-type (wt) and TNF Cell line and antibodies
Antimurine CD16/CD32 Fc block (2.4G2) and fluorochrome-labeled
antimurine CD3 (145-2C11), antimurine CD4 (RM4-5), antimurine CD8
(53-6.7), antimurine CD62L (MEL-14), antimurine CD122 (TM-B1), antimurine CD25 (PC61), antimurine Ly-9.1 (30C7), antimurine CD45R/B220 (RA3-6B2), antimurine CD90.2 (53-2.1), antimurine CD44 (IM7), antimurine TNF (MP6-XT22) and antimurine IFN- Mice and BMT
Leukemia induction, assessment of leukemic death vs death from GVHD, and GVHD organ pathology Animals received 2 × 104 32Dp210 cells intravenously in a separate injection on day 0 of BMT. Survival was monitored daily, and ear-tagged animals in coded cages were individually scored weekly for 5 clinical parameters (weight loss, hunched posture, decreased activity, fur ruffling, and skin lesions) on a scale from 0 to 2. A clinical GVHD score was generated by summation of the 5 criteria scores (0-10) as first described by Cooke et al.14 Every animal that died during the course of the experiment underwent autopsy and the cause of each death after BMT was determined as previously described15,19: (1) any spleen weight of more than 0.3 g (a previously determined cut-off point that never occurs with GVHD alone) or (2) a spleen weight of less than 0.3 g with evidence of leukemic infiltration on histopathology of the liver and spleen (obtained from every animal with a spleen weight of < 0.3 g and reviewed by veterinary pathologist Dr Hai Nguyen, Cornell University, New York, NY) were considered death from leukemia. In addition, the weekly determined GVHD scores correlated with death from GVHD. GVHD target organ pathology for bowel (terminal ileum and ascending colon), liver and skin (tongue and ear) was asessed by one individual (J.M.C. for liver and intestinal pathology, G.F.M. for cutaneous pathology) in a blinded fashion on formalin-preserved, paraffin-embedded and hematoxylin/eosin-stained histopathology sections with a semiquantitative scoring system. Briefly, bowel and liver were scored for 19 to 22 different parameters associated with GVHD as previously described16,17 and skin was evaluated for the number of dyskeratotic and apoptotic cells as previously published.18Flow cytometric analysis, intracellular cytokine staining, and CFSE staining Splenocytes were washed, incubated with CD16/CD32 Fc block, subsequently incubated with primary antibodies, washed, resuspended and analyzed on a FACScan flow cytometer (Becton Dickinson, San Jose, CA) with CellQuest software (Becton Dickinson). For intracellular cytokine staining, splenocytes were initially incubated in a mixed lymphocyte reaction (MLR) with irradiated (2000 cGy) allogeneic (C3HxB6) stimulator cells for 5 days, then harvested, and restimulated for 15 hours with either allogeneic or syngeneic irradiated stimulator cells (T-cell depleted, to reduce contamination with cytokine-expressing stimulator cells) in the presence of Brefeldin A (10 µg/mL; Sigma, St Louis, MO). Alternatively (in an attempt to measure cytokine production of in vivo preactivated cells), splenic donor T cells were harvested from recipients of allogeneic BMT (wt B6 TCD-BM + 2 × 106 splenic T cells into lethally irradiated C3HxB6) on day 14 and subsequently restimulated for 15 hours with irradiated (2000 cGy) syngeneic (B6) or allogeneic (C3HxB6) TCD stimulators. Subsequently, cells were washed, stained with primary (surface) fluorochrome-conjugated antibodies, fixed and permeabilized with the Cytofix/Cytoperm Kit (Pharmingen), and stained with secondary (intracellular cytokine) PE-conjugated antibody. Activated CD4+ memory cells were gated as CD4+, CD44+, and CD62L ; CD8+ memory
cells were gated as CD8+, CD44+,
CD122+. FACS analysis was carried out as described above.
For CFSE staining, RBC-lysed splenocytes of B6 wt and
TNF/ background were positively selected with anti-CD5
microbeads (Miltenyi, Auburn, CA), stained in 2.5 µM
carboxyfluorescein diacetate succinimidyl ester (CFSE) and
25 × 106 of stained cells were transplanted into
allogeneic (C3HxB6) recipients. Splenocytes from these animals were
harvested 72 hours later, stained with fluorochrome-conjugated
antibodies for surface antigens and FACS analysis was carried out
as above.
Proliferation assays To measure proliferation in response to mitogen, RBC-lysed B6 splenocytes of wt or TNF/ origin (3 individual animals
per group) were incubated (in quadruplicates for each condition per
animal) in 96-well plates at 2 × 105 cells per well in
complete cell culture medium (as described above) ± 2.5 µg/mL
Concanavalin A (ConA; Sigma) for 72 hours. For the last 20 hours of the
incubation 1 µCi/well (0.037 MBq/well) of H-3-thymidine (NEN,
Boston, MA) was added. Cells were harvested with a Filtermate 196 harvester (Packard, Meriden, CT), fixed with 70% Ethanol, and
H-3-thymidine incorporation was measured on a Topcount NXT
microscintillation counter (Packard, Meriden, CT) after the addition of
scintillation fluid ("Microscint-20"; Packard). Fold increase over
incubation with medium alone was calculated for each animal, and
average and SE for 3 animals per group is shown. To measure
proliferation in response to alloantigen, effector cells were prepared
as described in the previous paragraph and incubated for 96 hours in the presence of allogeneic (C3HxB6) or syngeneic (B6)
irradiated (2000 cGy) RBC-lysed splenocytes. The effector-to-stimulator
ratio was 1:2. H-3-thymidine incorporation was measured as
described before.
ELISA Enzyme-linked immunosorbent assay (ELISA) for serum IFN- and
TNF levels was performed according to the manufacturer's instructions with 2 different assay kits from R&D (Minneapolis, MN) and Endogen (Woburn, MA), with similar results.
Statistics Statistical analysis of GVHD scores, thymocyte and splenocyte number, and proliferation assays was performed with the nonparametric unpaired Mann-Whitney U test, whereas the Mantel-Cox log-rank test was used for survival data. A P value of .05 or less was considered statistically significant.
TNF is expressed upon alloactivation of wt but not
TNF / T cells: when used as
effectors in this assay, they were unable to express TNF in response to
allogeneic stimuli (Figure 1A; < 0.5% positive cells in this setting
are likely to be due to some residual cytokine-secreting T cells in the
TCD stimulator population). Similar results were obtained when the
CD122+/CD44+ population of activated/memory
CD8+ cells was gated (data not shown). The percentage of
TNF-secreting activated/memory cells is in the typical range that we
have shown previously in similar settings.19
Donor T cells and CD4+ T cells require TNF for maximum GVHD induction To assess the importance of donor T cell-derived TNF in the development of GVHD, we used splenic T cells from TNF-deficient B6 mice (TNF/) as donor T cells in a well-established murine
parent-into-F1 model (mismatched for MHC classes I and II):
B6-into-C3HxB6. Lethally irradiated C3HxB6 recipients all received T
cell-depleted (TCD) bone marrow (BM) from wt B6 mice and only the
source of the donor T-cell inoculum (wt or TNF/)
differed between groups. Recipients of wt T cells demonstrated greater
morbidity (weight loss and clinical GVHD score) (data not shown) and
significantly greater mortality than recipients of TNF/
T cells (Figure 1B). Because we had previously shown that induction of
GVHD in this model is modulated primarily by donor CD4+ T
cells,19 we also tested the contribution of TNF to GVHD
induced with a highly purified CD4+ donor cell inoculum
(Figure 1C). Again, we saw a profound effect of donor T cell-derived
TNF on mortality from GVHD. More than 80% of animals receiving
TNF/ cells survived past day 100, whereas all animals
receiving wt CD 4 cells died of GVHD by day 50. This is in agreement
with data from studies using TNF receptor-deficient
recipients8 or administration of anti-TNF antibodies after
BMT,7,9,17,20 which also showed a reduction of mortality
from GVHD with blockade of the TNF pathway (in some studies this effect
occurred only with higher radiation doses17,21). However,
these studies were not able to determine the source of TNF that was
responsible for induction of GVHD. It was thought that TNF is released
mainly from damaged or activated host macrophages. Although our data do
not exclude the possibility that host macrophage-derived TNF also
contributes to the pathophysiology of GVHD, in our model we are able to
show a major role of donor T cell-derived TNF, with experimental
groups differing exclusively in TNF status of donor T cells.
Small and large bowel as well as thymus, but not liver, are target organs of TNF-mediated GVHD To determine the contribution of TNF to specific GVHD-associated target organ pathology, recipients of wt and TNF/ T
cells were killed on day 28 after BMT and organs were harvested. When
small bowel and large bowel histopathology was assessed with a
semiquantitative score that has previously been validated in human and
experimental GVHD,16,17 recipients of wt T cells had
significant small and large bowel GVHD, whereas the intestinal GVHD
scores in recipients of TNF/ T cells were similar to
those of controls, which had received only TCD-BM (Figure 1D). The
total body irradiation that is administered to all animals (including
controls) is responsible for some baseline histological damage, which
is reflected in the low scores of control animals. These data suggest
that donor T cell-derived TNF plays an important role in intestinal
GVHD. Liver pathology on the other hand was not significantly different
between animals receiving wt vs. TNF/ cells. This
pattern of target organ GVHD is consistent with observations by Piguet
et al,22 Hattori et al7 and Cooke et
al20 who administered monoclonal anti-TNF antibody and
found amelioration of intestinal GVHD, whereas liver GVHD has been
found to be mediated mostly through Fas/FasL.7,23 The use
of antibodies in these studies resulted in blockade of any TNF/TNF
receptor interaction, without discriminating between different sources
of TNF, and could have resulted in a broader inhibition of TNF than in
our studies. We and others24,25 have previously
demonstrated that thymic GVHD is associated with a decrease in thymic
cellularity. Here we found significantly higher thymic cellularity in
recipients of TNF/ T cells than in recipients of wt T
cells (Figure 1E), indicating that TNF contributes to thymic GVHD. We
also analyzed on day 28 after BMT skin GVHD in recipients of wt and
TNF/ cells and found levels of skin GVHD which did not
significantly differ between groups (data not shown). This would
suggest that donor T cell-derived TNF is not required for skin GVHD.
Previous studies using anti-TNF antibodies found a decrease in skin
GVHD7,22 and these results in combination with our data
would suggest that the TNF which is involved in skin GVHD is not
derived from donor T cells but other effector cells of donor or host
origin. In conclusion, our data indicate the relevance of TNF
originating from the donor T cell for overall mortality and morbidity,
as well as for GVHD-associated intestinal and thymic pathology.
TNF is required for graft-versus-leukemia activity of donor T cells In allogeneic BMT, donor T cells are not only the cause of GVHD, they are also important effectors of a graft-versus-leukemia effect.26 The perforin/granzyme and to a lesser degree the Fas/FasL pathway have been found by us and others to be important mediators of this effect.9,19 To test the relevance of TNF as an additional donor T cell effector pathway for graft-versus-leukemia activity, we inoculated BMT recipients at the time of transplantation with 32Dp210 cells (a murine leukemia cell line derived by transfection of the human bcr/abl oncogene into a murine myeloid cell line of H-2k background12) and monitored survival from leukemia and/or GVHD. We found that mice, which received bone marrow without the addition of T cells, succumbed rapidly to leukemia as expected (Figure 2). Recipients of wt T cells survived significantly longer, with most of the mortality due to GVHD and not leukemic death (see table insert in Figure 2). Recipients of TNF/ T cells died
significantly earlier than recipients of wt T cells and almost
exclusively from leukemia, indicating that donor T cell-derived TNF is
an important effector of graft-versus-tumor (GVT) activity. Previous
studies using anti-TNF antibody had demonstrated increased leukemic
relapse when this pathway was blocked, but again could not determine
what the source of the TNF was.9,21 Hill et
al21 also demonstrated an increased rate of leukemic death
when donor T cells lacked the p55TNFR, suggesting that TNF signals via
this receptor on donor T cells for optimal CTL generation. Our study
suggests another, more direct mechanism for TNF-mediated GVL activity:
Donor T cells use soluble or membrane-anchored TNF to exert their
antileukemic activity.
Decreased GVHD and GVL activity of TNF / T cells to induce
GVHD could be due to impaired proliferation of these alloreactive
cells. To test this hypothesis, we compared the ability of
TNF/ T cells to proliferate in response to allogeneic
stimulation in vitro and in vivo. TNF/ T cells did not
differ significantly in their ability to proliferate in response to
ConA (Figure 3A) or in a 5-day MLR with
irradiated allogeneic C3HxB6 stimulator cells (Figure 3B). Equally,
when we compared the number of splenic T cells of donor origin on day 7 and day 14 in recipients of donor TCD-BM and T cells, we found no
significant difference between animals that had received wt T cells and
animals that had received TNF-deficient T cells (Figure 3C). To test
for differences in activation status of TNF/ T cells,
we stained in vivo allo-activated CD8+ T cells (which were
also CFSE stained so that their early divisions could be tracked) with
CD25 and CD122 and found the same pattern of up-regulation of CD25 and
CD122 over the course of the first divisions in both
TNF/ and wt cells (Figure 3D). Similar data were
obtained in CD4+ T cells (not shown). Finally, we examined
IFN- secretion in vitro on a per cell basis (Table
1) as well as in vivo serum levels after
BMT (Table 2).
B6 splenocytes of wt or TNF On day 0, lethally irradiated C3HxB6 mice received
5 × 106 TCD BM cells with or without the addition of
2 × 106 T cells as indicated. Serum was obtained by
cardiac bleed on days 7 and 14 after BMT from 3 or 4 animals per group,
and ELISA for TNF and IFN- No significant differences between wt and TNF In conclusion, our data demonstrate for the first time a critical role for donor T cell-derived TNF in 2 core phenomena of the pathophysiology of BMT: it contributes to GVHD and GVL effect via a local pathway. Although previous data have indicated a role for TNF in GVHD and GVL, the demonstration of the donor T cell as a novel and highly relevant source of TNF and the evidence that its effect does not depend on serum level, but rather functions in a paracrine mode or as a membrane-bound molecule in T cell-target interactions contributes to the further delineation of the mechanism of GVHD and GVL and opens a field for further studies. This is particularly timely as the new TNF antagonists Etanercept and Infliximab are currently in clinical trials for the treatment of human GVHD and early positive results have been reported.29
We wish to thank Dr Michael Marino for TNF
Submitted July 22, 2002; accepted October 23, 2002.
Prepublished online as Blood First Edition Paper, November 7, 2002; DOI 10.1182/blood-2002-07-2109.
Supported by grants HL69929 and HL72412 from the National Institutes of Health (M.R.M.v.d.B.), a Special Fellowship of the Leukemia and Lymphoma Society (C.S.), a Damon Runyon Scholar Award of the Cancer Research Fund, a scholarship of the V Foundation, and an award of the Wendy Will Case Cancer Fund (M.R.M.v.d.B.).
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: Marcel R. M. van den Brink, Department of Medicine, Box 111, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York NY 10021; e-mail: m-van-den-brink{at}ski.mskcc.org.
1. Kollias G, Douni E, Kassiotis G, Kontoyiannis D. On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Immunol Rev. 1999;169:175-194[CrossRef][Medline] [Order article via Infotrieve].
2.
Choy EHS, Panayi GS.
Cytokine pathways and joint inflammation in rheumatoid arthritis.
N Engl J Med.
2001;344:907-916 3. Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis. 1999;5:119-133[Medline] [Order article via Infotrieve].
4.
Kinkhabwala M, Sehajpal P, Skolnik E, et al.
A novel addition to the T cell repertory. Cell surface expression of tumor necrosis factor/cachectin by activated normal human T cells.
J Exp Med.
1990;171:941-946
5.
Braun MY, Lowin B, French L, Acha-Orbea H, Tschopp J.
Cytotoxic T cells deficient in both functional fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease.
J Exp Med.
1996;183:657-661 6. Ferrara JL, 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].
7.
Hattori K, Hirano T, Miyajima H, et al.
Differential effects of anti-Fas ligand and anti-tumor necrosis factor alpha antibodies on acute graft-versus-host disease pathologies.
Blood.
1998;91:4051-4055 8. Speiser DE, Bachmann MF, Frick TW, et al. TNF receptor p55 controls early acute graft-versus-host disease. J Immunol. 1997;158:5185-5190[Abstract].
9.
Tsukada N, Kobata T, Aizawa Y, Yagita H, Okumura K.
Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation.
Blood.
1999;93:2738-2747
10.
Herve P, Flesch M, Tiberghien P, et al.
Phase I-II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease.
Blood.
1992;79:3362-3368 11. Racadot E, Milpied N, Bordigoni P, et al. Sequential use of three monoclonal antibodies in corticosteroid-resistant acute GVHD: a multicentric pilot study including 15 patients. Bone Marrow Transplant. 1995;15:669-677[Medline] [Order article via Infotrieve]. 12. Matulonis U, Salgia R, Okuda K, Druker B, Griffin JD. Interleukin-3 and p210 BCR/ABL activate both unique and overlapping pathways of signal transduction in a factor-dependent myeloid cell line. Exp Hematol. 1993;21:1460-1466[Medline] [Order article via Infotrieve].
13.
Marino MW, Dunn A, Grail D, et al.
Characterization of tumor necrosis factor-deficient mice.
Proc Natl Acad Sci U S A.
1997;94:8093-8098
14.
Cooke KR, Kobzik L, Martin TR, et al.
An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation, I: the roles of minor H antigens and endotoxin.
Blood.
1996;88:3230-3239 15. Teshima T, Hill GR, Pan L, et al. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. J Clin Invest. 1999;104:317-325[Medline] [Order article via Infotrieve]. 16. Crawford JM. Graft-versus-host disease of the liver. In: Ferrara JLM,Deeg HJ,Burakoff SJ, eds. Graft-vs.-Host-Disease. New York, NY: Marcel Dekker; 1997:315-336.
17.
Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL.
Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines.
Blood.
1997;90:3204-3213 18. Ferrara J, Guillen FJ, Sleckman B, Burakoff SJ, Murphy GF. Cutaneous acute graft-versus-host disease to minor histocompatibility antigens in a murine model: histologic analysis and correlation to clinical disease. J Invest Dermatol. 1986;86:371-375[CrossRef][Medline] [Order article via Infotrieve].
19.
Schmaltz C, Alpdogan O, Horndasch KJ, et al.
Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect.
Blood.
2001;97:2886-2895 20. Cooke KR, Hill GR, Crawford JM, et al. Tumor necrosis factor-alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J Clin Invest. 1998;102:1882-1891[Medline] [Order article via Infotrieve]. 21. Hill GR, Teshima T, Gerbitz A, et al. Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia. J Clin Invest. 1999;104:459-467[Medline] [Order article via Infotrieve].
22.
Piguet PF, Grau GE, Allet B, Vassalli P.
Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease.
J Exp Med.
1987;166:1280-1289
23.
van Den Brink MR, Moore E, Horndasch KJ, et al.
Fas-deficient lpr mice are more susceptible to graft-versus-host disease.
J Immunol.
2000;164:469-480
24.
Baker MB, Altman NH, Podack ER, Levy RB.
The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice.
J Exp Med.
1996;183:2645-2656 25. van den Brink MR, Moore E, Ferrara JL, Burakoff SJ. Graft-versus-host-disease-associated thymic damage results in the appearance of T cell clones with anti-host reactivity. Transplantation. 2000;69:446-449[CrossRef][Medline] [Order article via Infotrieve]. 26. Porter DL, Antin JH. The graft-versus-leukemia effects of allogeneic cell therapy. Annu Rev Med. 1999;50:369-386[CrossRef][Medline] [Order article via Infotrieve].
27.
Holler E, Kolb HJ, Moller A, et al.
Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation.
Blood.
1990;75:1011-1016 28. Ruuls SR, Hoek RM, Ngo VN, et al. Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation. Immunity. 2001;15:533-543[CrossRef][Medline] [Order article via Infotrieve]. 29. Kobbe G, Schneider P, Rohr U, et al. Treatment of severe steroid refractory acute graft-versus-host disease with infliximab, a chimeric human/mouse antiTNFalpha antibody. Bone Marrow Transplant. 2001;28:47-49[CrossRef][Medline] [Order article via Infotrieve].
© 2003 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  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. Zhang, A. Barber, and C. L. Sentman Chimeric NKG2D Modified T Cells Inhibit Systemic T-Cell Lymphoma Growth in a Manner Involving Multiple Cytokines and Cytotoxic Pathways Cancer Res., November 15, 2007; 67(22): 11029 - 11036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Borsotti, A. R. K. Franklin, S. X. Lu, T. D. Kim, O. M. Smith, D. Suh, C. G. King, A. Chow, C. Liu, O. Alpdogan, et al. Absence of donor T-cell-derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity Blood, July 15, 2007; 110(2): 783 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Chatzidakis, G. Fousteri, D. Tsoukatou, G. Kollias, and C. Mamalaki An Essential Role for TNF in Modulating Thresholds for Survival, Activation, and Tolerance of CD8+ T Cells J. Immunol., June 1, 2007; 178(11): 6735 - 6745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vodanovic-Jankovic, P. Hari, P. Jacobs, R. Komorowski, and W. R. Drobyski NF-{kappa}B as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145 Blood, January 15, 2006; 107(2): 827 - 834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Welniak, D. V. Kuprash, A. V. Tumanov, A. Panoskaltsis-Mortari, B. R. Blazar, K. Sun, S. A. Nedospasov, and W. J. Murphy Peyer patches are not required for acute graft-versus-host disease after myeloablative conditioning and murine allogeneic bone marrow transplantation Blood, January 1, 2006; 107(1): 410 - 412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C. Hildebrandt, K. M. Olkiewicz, S. Choi, L. A. Corrion, S. G. Clouthier, C. Liu, J. S. Serody, and K. R. Cooke Donor T-cell production of RANTES significantly contributes to the development of idiopathic pneumonia syndrome after allogeneic stem cell transplantation Blood, March 15, 2005; 105(6): 2249 - 2257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C. Hildebrandt, L. A. Corrion, K. M. Olkiewicz, B. Lu, K. Lowler, U. A. Duffner, B. B. Moore, W. A. Kuziel, C. Liu, and K. R. Cooke Blockade of CXCR3 Receptor:Ligand Interactions Reduces Leukocyte Recruitment to the Lung and the Severity of Experimental Idiopathic Pneumonia Syndrome J. Immunol., August 1, 2004; 173(3): 2050 - 2059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C. Hildebrandt, K. M. Olkiewicz, L. A. Corrion, Y. Chang, S. G. Clouthier, C. Liu, and K. R. Cooke Donor-derived TNF-{alpha} regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation Blood, July 15, 2004; 104(2): 586 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C. Hildebrandt, U. A. Duffner, K. M. Olkiewicz, L. A. Corrion, N. E. Willmarth, D. L. Williams, S. G. Clouthier, C. M. Hogaboam, P. R. Reddy, B. B. Moore, et al. A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation Blood, March 15, 2004; 103(6): 2417 - 2426. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
C3FeB6F1/J). Recipients of TNF
with 2 different assays