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C57BL/6J x bm12)F1 Mice1
,
*
Division of Digestive and Liver Diseases, Departments of Internal Medicine and
Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235; and
Dallas Veterans Affairs Medical Center, Dallas, TX 75216
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B6 x B6.C-H-2bm12
(bm12))F1 GVHD model. Briefly, 5 x
106 splenic CD4+ T lymphocytes from
B6.TNFR2-/- or control B6 mice were transferred with
1–2 x 106 T cell-depleted B6 bone marrow
cells (BMC) to irradiated MHC class II-disparate (bm12 x
B6)F1 mice. Weight loss, intestinal inflammation, and the
surface expression of CD45RB (memory marker) on intestinal and splenic
lymphocytes were assessed. IL-2 and IFN-
mRNA levels in intestinal
lymphocytes were assessed by nuclease protection assays.
A significant reduction in weight loss and intestinal inflammation was
observed in recipients of the
TNFR2-/-CD4+ SpC. Similarly, a
significant decrease was noted in T cell numbers and in
CD45RBlow (activated/memory) expression on intestinal but
not CD4+ T cells in recipients of
TNFR2-/-CD4+ spleen cells. IL-2 and IFN-
mRNA levels were reduced in the intestine in the recipients of
TNFR2-/- splenic CD4+ T cells. These results
indicate that TNF-TNFR2 interactions are important for the development
of intestinal inflammation and activation/differentiation of Th1
cytokine responses by intestinal lymphocytes in MHC class II-disparate
GVHD while playing an insignificant role in donor T cell activation in
the spleen. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B6D2)F1 GVHD
model, CD4+ T cells play a prominent role in the
pathogenesis (2, 3).
TNF-TNFR interactions appear to be important in the development of GVHD
(4, 5, 6, 7). In previous studies, TNF blockade has been noted
to ameliorate the development of intestinal GVHD in the
DBAB6D2F1 MHC class I- and II-disparate model
(6) in which TNF and its family members appear to
influence intestinal inflammation induced by GVHD by promoting a Th1
cytokine profile (IL-2, IFN-
) (8). Additional studies
have suggested that TNF signaling through the 55-kDa TNFR1 expressed on
both donor and host cells is important in the initiation of GVHD
(4, 5). For example, B6D2F1
recipients of TNFR1-deficient B6 spleen cells (SpC) have significantly
reduced morbidity and mortality compared with recipients of control B6
or TNFR2-deficient (B6.TNFR2-/-) donor SpC in
the B6B6D2F1 MHC class I- plus II-disparate
murine GVHD model (4). Moreover, in early acute GVHD
induced by transfer of donor SpC and bone marrow cells (BMC) into fully
MHC-disparate recipients deficient in the TNF-p55-kDa (TNFR1) receptor,
there was an attenuation of lethal GVHD when compared with normal
recipients, but no effect on development of intestinal GVHD
(5). In contrast to studies implicating TNFR-TNFR1
interactions in selected aspects of GVHD pathogenesis in MHC class I-
and II-disparate GVHD models, the 75-kDa TNFR (TNFR2) has not been
implicated in the evolution of GVHD. However, in vitro, TNF-TNFR2
interactions have been found to promote MHC class II-stimulated T cell
alloresponses while TNF-TNFR1 interactions promoted MHC class
I-stimulated T cell alloresponses (9).
The purpose of these studies were to determine whether the expression of the 75-kDa TNFR2 located on donor CD4+ T cells is important for the initiation and progression of MHC class II-disparate intestinal GVHD. In brief, the results demonstrate that TNF-TNFR2 interactions on donor CD4+ T cells are important in the pathogenesis of the wasting associated with acute GVHD and in the generation of histopathological lesions of intestinal GVHD. Furthermore, reduced severity of GVHD generated by transfer of TNFR2-deficient donor CD4+ T cells is associated with diminished intestinal T cell activation and reduced intestinal Th1 cytokine responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J and B6.C-H-2bm12 (bm12) and C57BL/6-Tnfr2tm1Mwm (B6.TNFR2-/-) were obtained from The Jackson Laboratory (Bar Harbor, ME) and maintained in a specific pathogen-free environment. B6 males and bm12 females were bred to produce an F1 strain (B6 x bm12F1).
Transplantation
On the day of transplantation, the age- and sex-matched B6 x bm12F1 (H-2b/bm12) recipients were irradiated (900 cGy) and 2 h later were injected via the lateral tail vein with donor cells. Briefly, 4–5 x 106 CD4+ T cell-enriched SpC and 2–3 x 106 BMC from age- and sex-matched control B6 mice or B6.TNFR2-/- mice were injected into the lateral tail vein of these lethally irradiated allogeneic B6 x bm12F1 mice as previously described (1).This transplantation regimen has been documented previously to result in complete chimerism in this strain combination (10). In other experiments, 4 x 106 splenic CD4+ T lymphocytes from B6.TNFR2-/- and control B6 mice were transferred with 1–2 x 106 T cell-depleted B6 BMC to irradiated MHC class II-disparate B6 x bm12F1 mice. In other experiments, 4–5 x 106 splenic CD4 T lymphocytes from control B6 mice were transferred with 1–2 x 106 T cell-depleted B6 or B6.TNFR2-/- BMC to irradiated MHC class II-disparate B6 x bm12F1 mice. Recipients were maintained on acidified (pH 2) antibiotic (neomycin, 100 mg/L, and polymyxin B, 10 mg/L) H2O for 7 days after transplantation. Splenic B6 or B6.TNFR2-/-CD4+ T cells were enriched as previously described (1). Briefly, SpC were incubated with anti-CD8 Abs, anti-RBC, and B cell Abs (J11D.2) for 30 min at 4°C, then incubated with an adsorbed rabbit complement at 37°C for 30 min and then passed over a nylon wool column (11).
Histological scoring of intestinal GVHD
Individual recipients of either the control B6 or the experimental B6.TNFR2-/- SpC were evaluated according to the scoring system used by Snover (12) and Bottomly et al. (13). The large intestine was isolated by removing all of the intestine distal to the appendix and 2-cm sections were cut, fixed in Formalin, and then stained with H&E. Peyer’s patches were removed from the small intestine and then 2-cm sections from the entire small intestine were cut from the duodenum to the ileum, fixed in Formalin, and stained with H&E. Specifically, intestinal GVHD was reported as grade I with evidence of increased apoptosis, grade II with evidence of cystically dilated crypts containing necrotic debris with individual crypt loss, grade III with loss of multiple crypts with preservation of surface epithelium, and grade IV with complete loss of epithelium (data not observed in this study). The pathologist reviewing the slides was not aware of the types of SpC that the mouse had received.
Preparation of lamina propria lymphocytes
Mucosal lymphocytes were isolated and prepared according to a modification of a previously published method (8, 14, 15). Large intestines and small intestines were removed and placed in 15-ml tubes containing HBSS without Ca2+ and Mg2+ (Life Technologies, Gaithersburg, MD). Each intestine was carefully cleaned and flushed of its fecal content. Peyer’s patches were removed from the small intestines. The small and the large intestines were opened longitudinally and then cut into six 0.5-cm pieces. To isolate the lamina propria lymphocytes (LPL), the intestinal tissue was vigorously pipetted, transferred to 17 x 100-mm polypropylene tubes, and shaken for 20 min at 37°C in complete RPMI 1640 supplemented with 1% FCS containing dispase at 1.5 mg/ml (Sigma-Aldrich, St. Louis, MO). The tissue suspensions were collected and passed through nylon mesh, and the cells were pelleted by centrifugation at 600 x g. The cells were layered over Ficoll-Hypaque and the lymphocytes were removed from the interface, resuspended in staining buffer (0.5 L HBSS, 0.5 L PBS, 2% BSA, and 0.02% sodium azide), and counted using a Coulter counter (8).
Isolation of SpC
SpC were harvested by surgically removing the spleen and then mincing and disrupting the spleen over a funnel covered with nylon mesh and washing repeatedly with HBSS into a 50-ml conical tube (11). After the suspension was centrifuged at 600 x g for 10 min, the cell pellet was resuspended in staining buffer (0.5 L HBSS, 0.5 L PBS, 2% BSA, and 0.02% sodium azide) and cells were counted using a Coulter counter.
Flow cytometric analysis of splenic and intestinal lymphocytes
LPL were obtained from individual mice and in some experiments
LPL from two to three mice from the same experimental group were pooled
before flow cytometric analysis. Since we had six to nine mice in each
experimental group, we were able to prepare two to three pools from
each experimental group for analysis. These pooled lymphocytes were
suspended in staining buffer (0.5 L HBSS, 0.5 L PBS, 2% BSA,
and 0.02% sodium azide). mAb used to characterize LPL populations
included fluorescein-conjugated anti-CD3
clone 145-2C11,
biotinylated anti-CD4 clone RM4-4, FITC anti-CD8 clone
53-6.7, FITC anti-CD45RB clone 16A, and PE anti-CD4 Ab (all
from BD PharMingen, San Diego, CA). mAb were added to cell
suspensions at 4°C and incubated for 20 min. After staining with the
primary Ab, samples were washed in PBS at 4°C. Avidin fluorescein was
added as a secondary staining reagent for the biotinylated mAb. In some
experiments, the cells were doubled stained with PE anti-CD4 Ab and
FITC anti-CD45 Ab. After mAb staining and washing, all samples were
fixed in PBS containing 1% paraformaldehyde and stored at 4°C until
flow cytometric analysis as previously described (11).
Flow cytometric analysis was performed on a FACscan flow cytometer (BD
Biosciences, Mountain View, CA).
Multiprobe RNase protection assay
A multiprobe RNase protection assay system (Riboquant; BD
PharMingen) that generated a series of a cytokine templates (IL-4,
IL-10, Il-13, IL-15, IL-9, IL-2, IFN-, and GAPDH standard), each of
distinct length and each representing a sequence in a distinct cytokine
mRNA species, was used in analyzing small and large intestine LPL RNA
from B6 x bm12F1 mice that had received the
control B6 CD4+ T lymphocytes and from mice that
had received the
B6.TNFR2-/-CD4+ T
lymphocytes. The mouse cytokine templates utilized a T7
polymerase-directed synthesis of a high specific activity
32P-labeled antisense RNA probe set. The probe
set was hybridized in excess to target small and large intestinal LPL
RNA in solution, after which free probe and other ssRNA were digested
with RNases (8). The remaining RNase-protected probes were
purified, resolved on polyacrylamide gels, and quantified by phosphor
imaging.
Statistical analysis
The results were analyzed by the Mann Whitney U rank sum nonparametric test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous publications have reported that intestinal GVHD is
present after transfer of B6 SpC into lethally irradiated MHC class
II-disparate B6 x bm12F1 recipients
(10) and that TNF-TNFR2 interactions promote MHC class
II-stimulated T cell alloresponses (9). To assess whether
the wasting disease induced by B6B6 x
bm12F1 GVHD is dependent upon TNF-TNFR2
interactions on donor T cells, weights were assessed 11–14 days after
transplantation. In the initial experiments, B6
CD4+ T cells and BMC and
B6.TNFR2-/-CD4+ T cells
and BMC were transferred to B6 x bm12F1
mice. A significant weight difference was noted 14 days after
transplantation in recipients of B6.TNFR2-/-
donor cells (15.3 +/- 1.22 g; n = 3) vs
recipients of control B6 donor cells (11.95 +/- 1.5 g;
n = 3). The initial weights of the animals were not
different.
To assess whether the weight difference was associated with TNFR2
deficiency on the donor T cells or donor BMC, B6
CD4+ T cells or
B6.TNFR2-/-CD4+ T cells
were transferred with B6 T cell-depleted BMC. A significant weight
difference was noted between the recipients of the
B6.TNFR2-/-CD4+ SpC
(20.33 ± 2.67 g (n = 6)) in which no
significant decline from pretransplant weight was observed vs
recipients of B6 CD4+ T cells (mean weight,
14.64 ± 3.53 g (n = 7)) in which an average
of 10.82% weight loss was observed. (Fig. 1
).
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). More of the large
intestines isolated from the B6 x bm12F1
recipients of the B6 CD4+ T cells had evidence of
grade II or higher GVHD (7 of 10) than recipients of the
B6.TNFR2-/-CD4+ T cells
(2 of 9; Fig. 3). Histological changes in
the B6B6 x bm12F1 mice were clearly
related to allogeneic responses as the large intestines of the
syngeneic controls had no GVHD changes. These results
indicate that TNF-TNFR2 interactions on alloreactive donor
CD4+ T cells are important for the development of
both intestinal GVHD and the wasting disease associated with GVHD in B6
B6 x bm12F1 mice.
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To determine whether lack of TNFR2-TNF interactions on non-T cell-derived donor BMC were important for the development of GVHD, 4–5 x 106 splenic CD4 T lymphocytes from control B6 mice were transferred with 1–2 x 106 T cell-depleted B6 or TNFR2-/- BMC to irradiated MHC class II-disparate B6 x bm12F1 mice. Twelve days after transplant, weights of recipients of B6 CD4+ T cells and either TNFR2-/- T cell-depleted BMC or B6 T cell-depleted BMC were assessed. The weights were similar for the TNFR2-/- BMC recipients (mean, 18.3 g (n = 3) (15.9% decrease) vs control B6 recipients (21.65 g (n = 2) (7.25% decrease). Intestinal histopathology also was similar in both groups (data not shown).
Fewer T cells were isolated from the small intestine in recipients of the B6.TNFR2-/-CD4+ T cells than from the recipients of the B6 CD4+ T cells
In addition to the analysis of colonic GVHD detailed in Fig. 3
, there was evidence of loss of villous architecture and gland drop-out
in the small intestines of B6 B6 x
bm12F1 GVHD mice (Fig. 4). To assess whether recipients of the
B6.TNFR2-/-CD4+ T cells
had lesser degrees of T cell infiltrates in the intestine than in the
recipients of the control B6 CD4+ T cells,
intestinal lymphocytes were removed from the small intestines of
B6 x bm12F1 recipients. Of interest,
recipients of the B6 CD4+ T cells had a large
variance in intestinal lymphocyte counts (3.3 ± 3.7 x
106) while the recipients of the
TNFR2-/-CD4+ T cells were
consistently low (0.67 ± 0.59 x 106).
The recipients of the syngeneic donor cells had counts similar to those
of the recipients of TNFR2-/- donor cells
(0.6 ± 0.57). To determine the absolute number of CD3
and CD4+ T cells, these counts were multiplied by
the percentage of cells that stained positive with anti-CD3 and
anti-CD4 Abs. As demonstrated by the data displayed in Table I, significantly fewer
CD3+ and CD4+ T cells were
obtained from the B6 x bm12F1 recipients of
the B6.TNFR2-/-CD4+ T
cells than from recipients of the B6 CD4+ T cells
,whereas recipients of syngeneic donor cells had even fewer CD3 and
CD4+ T cells isolated. These data indicate that
TNF-TNFR2 interactions are critical for the infiltration and expansion
of the CD4+ T cells in the small intestine.
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The level of expression of the CD45RB surface marker on T cells
has been reported to be associated with prior T cell activation (memory
T cells) (14, 15, 16, 17). Specifically, high levels of the CD45RB
surface marker has been observed on T cells that have no prior exposure
to Ags (naive), whereas those T cells with low levels of this marker on
their surface have prior exposure to Ags (activated or memory cells).
Intestinal LPL were isolated as described in Materials and
Methods. FACS analysis revealed that >75% of these intestinal
LPL were CD4+ T cells. The percentage of
CD45RBlowCD4+ T cells in
B6 x bm12F1 recipients of the B6
CD4+ T cells and of the
B6.TNFR2-/-CD4+ T cells
was examined to determine whether the lack of
B6.TNFR2-/- on donor CD4+
T cells affected the percentage of memory T cells in the lamina propria
of GVHD small intestines. A lower percentage and absolute number of
CD4+CD45RBlow memory T
cells was present in the recipients of
the B6.TNFR2-/-CD4+ T
cells (Fig. 5, A and
B), suggesting that
TNFR2-TNF interactions on donor CD4+ T cells may
be necessary for alloantigen-induced activation and/or memory T cell
development in this model of intestinal GVHD.
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To determine whether TNF-TNFR2 interactions were deterring the
expansion or differentiation of donor T cells at extraintestinal sites,
such as the spleen, total SpC counts were measured from mice that had
received the
B6.TNFR2-/-CD4+ T cells
and mice that had received the control B6 SpC. Eleven to 14 days after
transplant, similar number of cells (5.5 x
106 (n = 12 vs (6.47 x
106 (n = 12; Fig. 6) and of CD3+ T
lymphocytes (Table II) were obtained from
the spleens isolated from the recipients of the control B6 or B6.
TNFR2-/-CD4+ donor T
cells (p = 0.56). These results suggest that
TNF-TNFR2 interactions on donor CD4+ T cells are
not affecting the migration and expansion of donor T cell in the
spleens of lethally irradiated B6 x
bm12F1 mice.
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A significant reduction in intestinal IL-2 and IFN- mRNA
expression was observed in recipients of the TNFR2-deficient
CD4+ T cells
To assess the level of in vivo cytokine expression during
intestinal GVHD, mRNA isolated from small intestinal sections extracted
from recipients of the
TNFR2-/-CD4+ T cells or
from recipients of B6 CD4+ T cells was probed
with a multiprobe RNase protection assay system. After hybridization of
the radioactive-labeled probe set to small intestinal mRNA, the
radioactive counts for each cytokine mRNA were quantitated by phosphor
imaging and then standardized to the control L32 RNA counts.
Significantly lower levels of IL-2 (p = 0.019)
and IFN- mRNA (p = 0.007) were observed in
small intestine mRNA isolated from recipients of the
TNFR2-/-CD4+ T cells than
from controls (Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) interactions amplify
allospecific T cell responses to MHC class II differences and play a
critical role in the activation and differentiation of Th1 cytokine
responses by intestinal lymphocytes during MHC class II-disparate
GVHD.
TNF is a highly pleiotropic cytokine that plays a role in both innate
and adaptive immune responses via signaling mediated by two distinct
receptors (18). Intracellular signaling through TNFR may
lead to either apoptosis (programmed cell death) or to cell activation
and/or growth mediated through NF-
B and c-Jun kinase activation
(18). The role of TNF in GVHD has been recognized in
multiple experimental models (4, 6, 8, 17, 19). Initial
assessments of the mechanism underlying these observations focused on
the role of TNF- as an effector of host cytotoxicity during acute
GVHD (4, 17). As TNF cytotoxicity as well as many
additional acute inflammatory effects of TNFR signaling are
predominately linked to TNFR1 signaling (5, 18), initial
studies of the role of TNF in GVHD assessed the course of acute GVHD in
TNFR1-deficient recipients of MHC class I- plus II- disparate donor
cells (5). In such studies, absence of TNFR1 on host cells
was associated with a delay in mortality from acute GVHD but had no
effect on histological patterns of GVHD in the intestinal tract or
liver (5).
Other, more recent, studies have focused on the role of TNFR signaling
in donor T cells in the B6B6D2F1 and
B6B6C3F1 class I plus II MHC-disparate mouse
GVHD models (4) where CTL effector mechanisms play a
prominent role in determining GVHD mortality rates (4, 20, 21). In these GVHD models, TNFR1 deficiency, but not TNFR2
deficiency on donor T cells, was associated with decreased GVHD
mortality and clinical severity that correlated with decreased T cell
proliferative IL-2 and CTL responses. Effects on gut GVHD in these
studies were not reported.
Despite the large amount of data arguing for a predominant role for TNFR1 signaling in mediation of many of the TNF effects during acute GVHD, other findings have indicated that mechanisms underlying intestinal GVHD may be different from those leading to lethal GVHD in class I MHC-disparate murine models. In previous studies from our and other laboratories, CD4+ T cell responses have been found to play a major role in generating both small (22, 23) and large (2, 3, 6, 8) intestinal GVHD lesions. In addition, TNF inhibition during GVHD has been associated with both diminished severity of colonic mucosal injury (6) and with decreased intestinal CD4+ T cell activation and Th1 cytokine responses (8). In contrast to the prominent role that TNFR1 signaling has been found to play in propagation of CD8+ T cell allogeneic responses (4, 9), TNFR2 signaling has been found to enhance in vitro class II MHC alloantigen-stimulated CD4+ alloproliferative and Th1 cytokine responses (9). The present in vivo studies have confirmed the prominent role that TNFR2 signaling plays in CD4+ T cell responses to MHC class II alloantigens.
Furthermore, this is an important study in determining the role of TNFR2 in TNF-associated pathology. TNFR2 has been implicated in systemic toxicity of TNF and in TNF-mediated skin necrosis (24). Recently, the interaction between membrane-bound TNF and TNFR2 has been shown to be crucial in the development of experimental cerebral malaria (25). Our studies are the first to implicate TNFR2 signaling in the development of intestinal GVHD.
Of interest, however, when T cell responses in the spleen were examined
for differences in control vs TNFR2-deficient T cell expansion and
activation during GVHD, a lesser role for TNFR2 signaling was noted.
CD4+ T cell numbers and activation markers were
unaffected by lack of TNFR2 signaling (Fig. 7 and Table II in present
studies), and when Th1 cytokine responses were assessed (data not
shown) levels of IL-2 and IFN- mRNA were not found to be
consistently diminished in the spleens of recipients of TNFR2-deficient
donor T cells. These results indicate that, whereas TNFR2 signaling is
critical for the development of intestinal GVHD, TNFR2 signaling likely
plays a minor or insignificant role in GVHD responses at other sites.
Of note, in phase I and II trials of a monoclonal anti-TNF Ab for
therapy of acute GVHD in humans, TNF inhibition was associated with
more profound effects on intestinal GVHD than on GVHD in other organs
(26). In other animal studies using a LPS antagonist to
reduce but not totally ablate TNF responses during acute GVHD,
significant improvement in intestinal pathology was noted following
inhibition of LPS-induced TNF responses without impairment of either
donor T cell responses in the spleen or systemic graft vs leukemia
responses (17). In light of these observations, it is
reasonable to speculate that therapies directed at selective blocking
of TNF-TNFR2 actions during GHVD may prove beneficial in ameliorating
intestinal GHVD while having lesser effects on graft vs leukemia
responses or other GVHD responses that evolve in extraintestinal
sites.
In conclusion, TNF-TNFR2 interactions are important for the differentiation and activation of donor CD4+ T cells in the intestine during the development of MHC class II GVHD. Furthermore, the present findings demonstrate that TNF-TNFR2 interactions on donor CD4+ T cells are important in the pathogenesis of the histopathological lesions of intestinal GVHD and the wasting associated with acute intestinal GVHD. Of note, however, TNF-TNFR2 interactions appear not to play a significant role in T cell activation in the spleen and thus therapeutic strategies that selectively target various TNF signaling pathways may have different effects on graft-versus-host alloimmune responses that evolve in various organ sites.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Geri R. Brown, Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235-9151. E-mail address: gbrown{at}chop.swmed.edu
3 Abbreviations used in this paper: BMT, bone marrow transplantation; GVHD, graft-vs-host disease; SpC, spleen cell; BMC, bone marrow cell; LPL, lamina propria lymphocyte.
Received for publication November 6, 2001. Accepted for publication January 10, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor plays a critical role in T cell alloreactivity. J. Immunol. 164:656. antibody for the treatment of refractory severe acute graft-versus-host disease. Blood 79:3362.This article has been cited by other articles:
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  B. R Blazar and W. J Murphy Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD) Phil Trans R Soc B, September 29, 2005; 360(1461): 1747 - 1767. [Abstract] [Full Text] [PDF]
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 R. El-Asady, R. Yuan, K. Liu, D. Wang, R. E. Gress, P. J. Lucas, C. B. Drachenberg, and G. A. Hadley TGF-{beta}-dependent CD103 expression by CD8+ T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease J. Exp. Med., May 16, 2005; 201(10): 1647 - 1657. [Abstract] [Full Text] [PDF]
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 G. R. Brown, E. L. Lee, J. El-Hayek, K. Kintner, and C. Luck IL-12-Independent LIGHT Signaling Enhances MHC Class II Disparate CD4+ T Cell Alloproliferation, IFN-{gamma} Responses, and Intestinal Graft-versus-Host Disease J. Immunol., April 15, 2005; 174(8): 4688 - 4695. [Abstract] [Full Text] [PDF]
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 C.-K. Min, Y. Maeda, K. Lowler, C. Liu, S. Clouthier, D. Lofthus, E. Weisiger, J. L. M. Ferrara, and P. Reddy Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation Blood, November 15, 2004; 104(10): 3393 - 3399. [Abstract] [Full Text] [PDF]
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C. A. Wysocki, S. B. Burkett, A. Panoskaltsis-Mortari, S. L. Kirby, A. D. Luster, K. McKinnon, B. R. Blazar, and J. S. Serody Differential Roles for CCR5 Expression on Donor T Cells during Graft-versus-Host Disease Based on Pretransplant Conditioning J. Immunol., July 15, 2004; 173(2): 845 - 854. [Abstract] [Full Text] [PDF]
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 M. I. Kafrouni, G. R. Brown, and D. L. Thiele The role of TNF-TNFR2 interactions in generation of CTL responses and clearance of hepatic adenovirus infection J. Leukoc. Biol., October 1, 2003; 74(4): 564 - 571. [Abstract] [Full Text] [PDF]
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 G. Ramesh and W. B. Reeves TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure Am J Physiol Renal Physiol, October 1, 2003; 285(4): F610 - F618. [Abstract] [Full Text] [PDF]
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G. R. Brown, E. L. Lee, and D. L. Thiele TNF Enhances CD4+ T Cell Alloproliferation, IFN-{gamma} Responses, and Intestinal Graft-Versus-Host Disease by IL-12-Independent Mechanisms J. Immunol., May 15, 2003; 170(10): 5082 - 5088. [Abstract] [Full Text] [PDF]
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