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3 and LTß in Inflammation Elucidates Potential Mechanisms of Mesenteric and Peripheral Lymph Node Development1
Department of Epidemiology and Public Health and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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transgene under the control of the rat insulin promoter results in
inflammation at the sites of transgene expression. LT transgene
expression results in expression of the adhesion molecules VCAM, ICAM,
peripheral node addressin (a marker of peripheral lymph nodes), and
mucosal addressin cellular adhesion molecule (a marker of mucosal
lymphoid tissue, including mesenteric lymph nodes). In this study to
determine the mechanisms by which LT promotes inflammation and lymphoid
tissue organization, we analyzed the regulation of expression of
adhesion molecules and chemokines in LT transgenic mice. The results
demonstrate that LT3 induces expression of the adhesion molecules
VCAM, ICAM, and mucosal addressin cellular adhesion molecule as well as
the chemokines RANTES, IFN-inducible protein-10, and monocyte
chemotactic protein-1, while LTß is required for the induction of
peripheral node addressin that may contribute to the recruitment of
L-selectinhigh CD44low naive T cells. These
data provide candidate mediators of LT-induced inflammation as well as
potential mechanisms by which LT and LTß may differentially
promote the development of mesenteric and peripheral lymph
nodes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LT (TNFß) is a member of the TNF family of cytokines that also
includes TNF- and LTß. LT is produced as both a secreted LT
homotrimer as well as an LTß heterotrimeric complex expressed on
the surface of activated lymphocytes. LT3 interacts with both TNFR1
and TNFR2, while the LT1ß2 complex interacts with LTßR (reviewed
in 6). In addition to its proinflammatory effects, LT plays a
critical role in lymphoid organ development. Mice genetically deficient
in LT lack peripheral and mesenteric lymph nodes (LN) and Peyer’s
patches (PP) and have a disrupted splenic architecture (7, 8). These
effects are mediated in part by the LTß heterotrimeric complex, as
mice genetically deficient in LTß also have a disrupted splenic
architecture and lack PP and peripheral LN (9, 10). However,
interestingly, these mice still have mesenteric LN, suggesting a
possible role for LT3 in promoting the development of these lymph
nodes. Data obtained with various combinations of knockout mice and
agonist Abs now suggest that LT3 acting through TNFR1 and LTß
can contribute to the development of the mesenteric LNs (11, 12).
We have developed a mouse model of chronic inflammation in which LT is expressed under the control of the rat insulin promoter (RIPLT) (13). These mice develop inflammation of the pancreas and kidney at the sites of transgene expression. In addition, these infiltrates exhibit the characteristics of lymphoid tissue noted above, including lymphoid aggregates, the presence of APC (macrophages, follicular dendritic cells, and interdigitating dendritic cells), and high endothelial venules that express the lymph node addressins MAdCAM and PNAd (3). Our data are consistent with the idea that this local infiltrate can respond to antigenic challenge as the B cells produce Abs and undergo class switching after immunization with exogenous Ag (3). The similarities between RIPLT-inflamed tissues and lymphoid tissue, whose development is also driven by LT, suggests that the mechanisms of lymphoid neo-organogenesis observed in chronic inflammation may be similar to those of lymphoid organogenesis during embryonic development.
In the present study we have employed the RIPLT mouse model to
investigate the mechanisms by which chronic inflammation is initiated
and becomes organized into lymphoid tissue. Toward that end, we have
analyzed the regulation of adhesion molecule and chemokine expression
in RIPLT mice. The data presented here demonstrate that LT, in the
absence of LTß, induces the expression of the adhesion molecules
VCAM, ICAM, and the mucosal addressin, MAdCAM, while LTß may
contribute to the recruitment of naive T cells at least in part through
its ability to induce the peripheral node addressin, PNAd. Further, the
LT transgene induces the expression of several chemokines at the
sites of transgene expression. This effect is dependent upon
interaction with TNFR1, not LTßR. These data provide insight into the
mechanisms by which LT mediates both pathogenic and developmental
processes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice transgenic for the rat insulin promoter driving the murine
lymphotoxin- gene (RIPLT) have previously been described (13). These
mice were bred to mice deficient in RAG2 (RAG2-/-;
provided by Dr. David Schatz) (14), TNFR1 (TNFR1-/-;
provided by Dr. Werner Lesslauer) (15), or LTß
(LTß-/-) (9). All animals were housed under specific
pathogen-free conditions at Yale University (New Haven, CT). At least
three mice of each genotype were analyzed between 5 and 12 wk of age.
RNase protection analysis
Total RNA was isolated from the kidneys of 5-wk-old mice using Tri-Reagent (Molecular Research Center, Cincinnati, OH) according to the manufacturer’s recommendations. Chemokine mRNA levels were determined using the Riboquant Multiprobe RNase Protection Assay System (PharMingen, San Diego, CA). 32P-labeled riboprobes were synthesized from the plasmid template set using T7 polymerase, after which the DNA template was digested with DNase. Ten micrograms of total kidney RNA was hybridized with the riboprobes in a 10-µl volume overnight at 56°C. The following day, ssRNA species were removed by digestion with RNase A at 37°C for 45 min. Following phenol/chloroform extraction, the protected RNA species were ethanol precipitated, resuspended in loading buffer, and electrophoresed on a 5% polyacrylamide gel. Protected chemokine probes were visualized by autoradiography of the dried gel, and the level of mRNA expression was quantified by densitometric analysis using ImageQuant software (Molecular Dynamics, Sunnyvale, CA).
Protein analysis
Chemokine protein expression in the kidney was assessed by ELISA. Lysates of whole kidney were prepared by homogenization in lysis buffer containing 1 mM PMSF (Sigma, St. Louis, MO), 100 µg/ml soybean trypsin inhibitor (Sigma), 100 µg/ml aprotinin (Sigma), 100 µg/ml leupeptin (Boehringer Mannheim, Indianapolis, IN), 1% Nonidet P-40 (Sigma), and 0.1% deoxycholate (Sigma) in calcium- and magnesium-free PBS. RANTES protein was measured using sandwich ELISA purchased from R&D Systems (Minneapolis, MN), and monocyte chemoattractant protein-1 (MCP-1) was measured with matched Ab pairs purchased from PharMingen according to the manufacturer’s recommendations. Data were normalized to the amount of total protein in the kidney lysate as determined by bicinchoninic acid protein assay (Pierce, Rockford, IL). Reagents were not available to measure IP-10 protein levels.
Immunohistochemistry
Pancreas and kidney were dissected and immediately snap-frozen in OCT compound (Miles, Elkhart, IN). Sections of 5 µm were cut and stored at -20°C. Sections were air-dried for 10 min at room temperature, fixed in 100% acetone, and blocked with 3% BSA in 0.1 M phosphate buffer. Primary Abs were diluted in 1% BSA in 0.1 M phosphate buffer and incubated for 1–2 h at room temperature. Biotinylated species-specific secondary Abs (Vector, Burlingame, CA) diluted 1/250 were then incubated for 30 min at room temperature, followed by alkaline phosphatase-conjugated AB (Vector) for 30 min according to the manufacturer’s recommendations. Biotinylated primary Abs were reacted directly with AB complex. Enzymatic reactivity was visualized using Vector Red with 100 mM levamisole added to inhibit endogenous alkaline phosphatase activity. In all experiments a species-specific irrelevant Ab was used as a control for nonspecific reactivity. Tissues were counterstained with 3% methyl green. Dr. Eugene Butcher provided Abs to PNAd (MECA 79) and MAdCAM (MECA 367) as cell culture supernatants that were used at a dilution of 1/5. Rabbit anti-factor VIII-specific Ab was purchased from Dako (Carpinteria, CA) and was used at a dilution of 1/200. Biotinylated hamster anti-MCP-1 was purchased from PharMingen and was used at a concentration of 50 µg/ml. The macrophage marker BM8 was purchased from Accurate (Westbury, NY) and was used at a concentration of 5 µg/ml.
Statistics
Data were analyzed by Student’s t test, and p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The RIPLT transgene induces an infiltrate in both the pancreas and
kidney, which are the sites of transgene expression. This infiltrate
consists of memory and naive T cells (16), B cells, macrophages, and
dendritic cells (3). We have previously determined that the LTß
complex contributes to the recruitment of CD44low,
L-selectinhigh naive cells as fewer of these cells were
detected in the kidneys of RIPLT.LTß-/- than in those
of RIPLT wild-type (wt) mice (16). Since alterations in the expression
of adhesion molecules on the inflamed vasculature contribute to the
recruitment of naive and memory cells (17), we analyzed the
regulation of MAdCAM, PNAd, ICAM, and VCAM in RIPLT.wt and
RIPLT.LTß-/- animals. We have previously demonstrated
that the adhesion molecules ICAM and VCAM are up-regulated in the blood
vessels near the islets of RIPLT.wt animals (3) as are the
vascular addressins MAdCAM and PNAd (Fig. 1
, A and C). ICAM,
VCAM, and MAdCAM expression were also induced by the RIPLT transgene in
RAG2-/- mice in the absence of a lymphocytic infiltrate
(3) as well as in vitro by recombinant murine and human LT (18, 19).
Here we evaluated whether adhesion molecule expression in vivo was
regulated by LT3 or the LTß complex. Comparable levels of
MAdCAM were expressed within the vessels of the inflamed pancreas in
RIPLT.wt and RIPLT.LTß-/- mice (Fig. 1, A
and B). However, in RIPLT.LTß-/- mice, no
expression of PNAd was apparent (Fig. 1D) despite the
detection of vessels in a serial section with an Ab to factor VIII that
reacts with endothelial cells (Fig. 1F). Furthermore,
although PNAd expression was detected in RIPLT.wt kidneys in the
vessels near the infiltrate (Fig. 1G), no PNAd expression
was detected in the kidneys of RIPLT.LTß-/- mice (Fig.
1H). ICAM and VCAM were expressed at a similar level in
RIPLT.LTß-/- inflamed tissues compared with their
expression in RIPLT.wt tissues (data not shown). These data together
suggest that LT3, not LTß, is required for MAdCAM-1, VCAM-1,
and ICAM-1 expression in RIPLT-inflamed tissues. In contrast, LTß
is required for PNAd expression. LT may induce adhesion
molecules through multiple receptors. One candidate is TNFR1.
RIPLT.TNFR1-/- mice lack the infiltrate observed in
RIPLT.wt mice (16), and the expression of VCAM-1, ICAM-1, and
MAdCAM-1 was markedly reduced in these mice (data not shown),
suggesting a role for TNFR1 in the induction of adhesion molecule
expression by LT3.
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The recruitment of leukocytes is also regulated through
the expression of individual chemokines (20). To determine which
chemokines may participate in the recruitment of infiltrating cells to
RIPLT-inflamed tissues, we performed multiprobe RNase protection
analysis with a set of chemokine probes that detects lymphotactin
(Ltn), RANTES, eotaxin, MIP-1, MIP-1ß, MIP-2, IP-10, MCP-1, and
TCA-3 on RNA purified from the RIPLT kidney. These analyses indicated
that the levels of RANTES, IP-10, and MCP-1 mRNA were all elevated in
the inflamed kidney compared with those in nontransgenic littermates
(Fig. 2). Densitometric analyses in which
the levels of chemokines were normalized to the housekeeping gene GAPDH
indicated that RANTES mRNA levels were elevated 6.5-fold above those in
wt controls, while IP-10 and MCP-1 mRNA levels were increased 18- and
30-fold, respectively (Fig. 3A). There was no consistent
increase in the other chemokines analyzed, including MIP-1,
MIP-1ß, and Ltn, although these were also variably elevated in some
experiments. To determine which chemokines were induced directly by LT
and which were secondary to inflammation, we analyzed the chemokine
profile in RIPLT mice on a RAG2-/- background. We have
previously shown that these mice, which lack mature B and T cells, have
a much reduced infiltrate in the pancreas and kidney. Densitometric
analysis of the autoradiogram shown in Fig. 2 as well as data from
other experiments indicated that IP-10 and MCP-1 mRNA expression was
elevated 3-fold above the level detected in nontransgenic littermates.
RANTES mRNA, however, was not induced, indicating that at least some of
its expression was secondary to inflammation (Figs. 2 and 3B). The infiltrate also influenced IP-10 and MCP-1
production, as these mRNAs were further increased following
infiltration by T and B lymphocytes.
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To determine whether the elevations in chemokine mRNA levels
resulted in increases in protein production, we measured RANTES and
MCP-1 protein expression from whole kidney lysates of RIPLT and
nontransgenic mice. As shown in Fig. 4,
nontransgenic mice express very low levels of RANTES protein (60
pg/ml). The RIPLT transgene induced the RANTES protein level to 3.6
ng/ml (p < .001). Similarly, kidneys of
nontransgenic animals expressed a baseline level of MCP-1 (5.4 ng/ml),
and this was elevated in the kidney lysates of RIPLT animals to 20.6
ng/ml (p < 0.02).
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Chemokines can be produced by both inflammatory cells as well as
nonhemopoietic resident cells. To investigate which cells were the
source of chemokines in RIPLT-induced inflammation, we performed
immunohistochemistry for the chemokine MCP-1 in the pancreas of LT
transgenic and nontransgenic littermates. Frozen sections of the
pancreas were unreactive with a biotinylated isotype control Ab (Fig. 5A), and no MCP-1 reactivity
was detected in the pancreas of nontransgenic mice (Fig. 5B). However, the RIPLT.wt pancreas stained intensely for
MCP-1 (Fig. 5C). This MCP reactivity was restricted to the
islets; the lymphocytic infiltrate that surrounds the islets was not
reactive for MCP-1. To further discriminate between MCP-1 production by
inflammatory cells vs resident cells, we analyzed the expression of
this chemokine in RIPLT.RAG2-/- mice. As shown in Fig. 5, MCP-1 expression in these animals was similarly restricted to the
islets of Langerhans (Fig. 5D).
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, E and F), suggesting a directed migration of
macrophages to the islets. This is in contrast to the situation
observed in nontransgenic animals in which macrophages were distributed
randomly throughout the pancreas (Fig. 5H). Chemokine expression is dependent upon TNFR1, but not LTß receptor
We have previously demonstrated that TNFR1 is essential for the
induction of RIPLT-induced inflammation, whereas TNFR2 plays no obvious
role in RIPLT-induced inflammation (16). To determine whether the
mechanism of TNFR1-mediated inflammation included up-regulation of the
chemokines, we analyzed the chemokine expression pattern in
RIPLT.TNFR1-/- mice. While the baseline expression of
RANTES, IP-10, and MCP-1 mRNAs in TNFR1-/- mice was
comparable to that in wild-type animals, none of these chemokines was
up-regulated in RIPLT.TNFR1-/- transgenic littermates
(Fig. 6), indicating an essential role
for that receptor in the induction of these chemokines.
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ß has been reported to induce RANTES expression in
melanoma cells (25). To analyze whether LTß contributes to the
induction of RANTES and/or other chemokines in the RIPLT model, the
chemokine expression profile was analyzed in
RIPLT.LTß-/- mice. The mRNA expression profile of these
chemokines in RIPLT.LTß-/- mice was comparable to that
in RIPLT.wt mice (Fig. 7), with a similar
up-regulation of RANTES, IP-10, and MCP-1. Densitometric analysis of
shorter exposures of the gel shown in Fig. 7 demonstrated equivalent
levels of RANTES, IP-10, and MCP-1 mRNA expression in
RIPLT.LTß-/- kidneys compared with that in
RIPLT.LTß+/- littermates and with that in RIPLT.wt
kidneys. In addition, immunohistochemical analysis of
RIPLT.LTß-/- pancreas indicated that MCP-1 protein was
expressed within the islets of Langerhans in the same pattern as that
detected in RIPLT.wt mice (data not shown). These data suggest that
LTß is not needed for the induction of RANTES, IP-10, and MCP-1 in
RIPLT mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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3 and LTß differentially
regulate adhesion molecule expression. LT3 induces the up-regulation
of the adhesion molecules VCAM-1, ICAM-1, and MAdCAM, while the
LTß complex is required for the induction of the adhesion molecule
PNAd that may contribute to the recruitment of
L-selectinhigh naive T cells to the infiltrate. We
further demonstrate that LT3, not LTß, induces expression of
the chemokines RANTES, IP-10, and MCP-1. These data elucidate the
mechanisms of LT-induced inflammation and also potential pathways of
LT-induced lymphoid organogenesis. They suggest that LT3 may promote
the development of all LN in part through the induction of MAdCAM-1,
while LTß may promote the development of peripheral lymph nodes by
inducing a distinct set of inflammatory mediators that includes PNAd.
Adhesion molecule induction is a necessary event in the recruitment of
inflammatory cells to sites of inflammation. In fact, the nature of the
inflammatory response is regulated in part by the expression of
adhesion molecules (17). These studies demonstrate that both LT3 and
LTß regulate adhesion molecule expression in endothelial cells. We
have previously demonstrated that RIPLT mice crossed onto a
RAG2-/- background lacking mature lymphocytes still
express VCAM, ICAM, and MAdCAM in the absence of a lymphocytic
infiltrate, suggesting that the LT transgene itself induces the
expression of these molecules. The data presented here, which
demonstrate persistent expression in the absence of LTß, support a
role for LT3 in the induction of these inflammatory mediators and
are consistent with in vitro data in which recombinant murine LT3
induces the expression of VCAM, ICAM, and MAdCAM in a murine
endothelial cell line (18). VCAM and ICAM have been shown to mediate
the adhesion of macrophages and T cells to endothelial cells both in
vitro and in vivo at sites of inflammation (reviewed in 26), while MAdCAM has been shown to mediate the trafficking
of both naive and memory T cells to mesenteric LN and PP (27). The
expression of MAdCAM within the RIPLT-inflamed tissues may contribute
to the recruitment of the naive mucosal lymphoid cells to tissues of
both RIPLT.wt and RIPLT.LTß-/- mice. Interestingly, the
LTß complex is necessary for the expression of the L-selectin
ligand PNAd within RIPLT-inflamed tissues. This adhesion molecule is a
marker for peripheral LN and has been demonstrated to mediate the
recruitment of L-selectin+ naive T cells. In fact,
expression of this adhesion molecule correlates with the recruitment of
L-selectinhigh naive T cells into the inflamed kidney (16).
The absence of PNAd expression in the inflamed vasculature of
RIPLT.RAG2-/- mice (3) further suggests that production
of LTß by the infiltrating lymphocytes may induce the expression
of this vascular addressin.
The similarities between RIPLT-induced inflammation and LT-induced
lymphoid organ development suggest that these two processes may have
overlapping mechanisms. We have shown that LT3 is a potent inducer
of MAdCAM expression in vivo (this study) and in vitro (18). It has
previously been demonstrated that MAdCAM is expressed on high
endothelial venules in the developing mesenteric LN and peripheral LN
of perinatal animals (28), while PNAd is induced following population
of the LN by a CD4+CD3-LTß+
cell (29). In addition, treatment of LT-/- mice with
an agonist Ab to LTßR induces the formation of pLN with a transient
induction of PNAd (12), further supporting the idea that LTß is an
important inducer of PNAd in vivo. We propose that induction of MAdCAM
by LT3 may be an early event in the development of all lymph nodes,
and while PNAd expression is not essential for LN development (30), the
LTß/LTßR interaction may induce additional mediators that are
critical for LN development.
The present study also demonstrates that a select group of chemokines
is up-regulated in response to the LT transgene. IP-10 and MCP-1 are
regulated directly by LT or a downstream cytokine, as they are
induced in RIPLT.RAG2-/- mice that lack a mature T and B
cell infiltrate. These particular chemokines may play a role in the
initiation of LT-induced inflammation, since both have been shown to
recruit T cells in vitro (31, 32). In addition, MCP-1 is a potent
chemotactic agent for monocytes and macrophages (21, 22, 23, 24).
In the RIPLT model, MCP-1 is produced in the islets of Langerhans, and
its expression correlates with the accumulation of macrophages that
both encircle and infiltrate the islet. Of particular note is the
ability of the islets themselves to produce chemokines in response to
LT. Inflammation of the pancreas can occur following microbial
infection or as part of the autoimmune process in IDDM. In the latter
case, the pancreas is infiltrated by macrophages and lymphocytes that
inappropriately recognize the islet cells as foreign and destroy them.
However, the mechanisms by which the cells are initially recruited to
the islets are unknown. Our results demonstrate that the islets
themselves can produce the chemokine MCP-1, which may then contribute
to the recruitment of inflammatory cells. Immunohistochemical analysis
does not definitively demonstrate the source of chemokine production,
as these molecules are matrix binding proteins and adhere to both
matrix and to surrounding cells that express the appropriate chemokine
receptors. The nature of the MCP-1-producing cells is not known. It
could be produced by the -cells, the ß-cells, underlying stroma,
and/or the infiltrating macrophages. It appears that the islets
themselves, rather than the infiltrating cells, are producing MCP-1.
While macrophages reside within RIPLT-inflamed islets, they and the
macrophages with the same morphologic and histochemical phenotype
(BM8+) surrounding the islet are not immunoreactive for
MCP-1. We consider it unlikely that the chemokines would be selectively
produced by the infiltrating macrophages.
These studies support our previous observations that the LT3/TNFR1
interaction is crucial for the inflammatory process observed in RIPLT
mice (16). The induction of IP-10 and MCP-1 by LT3 in this in vivo
model is also supported by the recent demonstration of induction of
these same chemokines by LT treatment in a murine endothelial cell line
(18). Although recombinant LTß was shown to induce RANTES and IL-8
expression through the LTßR in a human melanoma cell line (25), and
LTß may contribute to chemokine production in vivo as well, we did
not find that LTß was necessary for the induction of RANTES,
IP-10, or MCP-1 in RIPLT-induced inflammation. It is possible that
additional chemokines not analyzed in this study are induced by LT
and/or LTß and may also contribute to the inflammation observed.
However, to definitively elucidate the precise role of the chemokines
in LT-induced inflammation, further studies, including the use of
blocking Abs or the generation of RIPLT mice deficient in the various
chemokine genes, will need to be performed.
LT-induced expression of chemokines may also play a role in lymphoid
organogenesis. One chemokine receptor, BLR1, is involved in
compartmentalization of B cells within lymphoid tissue and the
development of lymph nodes (33), possibly through interaction with a
recently identified ligand (34, 35). Several other chemokines have also
recently been shown to be preferentially expressed within lymphoid
tissue (BLC, SLC, ELC, and DC-CK1) and may play a role in regulating
the migration of cells within the lymphoid compartment. It has recently
been shown that LT, LTß, and TNF- contribute to the expression
of BLC, and that LT and LTß contribute to the expression of SLC
and ELC within the spleen (36). With this in mind, it will be
interesting to determine whether LT can induce these
lymphoid-associated chemokines in inflammation and/or whether
LT-induced IP-10 or MCP-1 plays a role in lymphoid organ development.
In summary, these data demonstrate that LT induces the expression of a select set of chemokines and adhesion molecules at the site of transgene expression. While LTß is not required for expression of these chemokines, it is required for induction of the peripheral node addressin PNAd in RIPLT-inflamed tissues. These results suggest that LT contributes to inflammatory processes in the adult mouse and lymphoid organogenesis during development through regulation of adhesion molecule and chemokine expression.
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Acknowledgments |
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Footnotes |
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2 Current address: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104.
3 Current address: Department of Genetic Technologies, Central Research Division, Pfizer, Inc., Groton, CT 06340.
4 Address correspondence and reprint requests to Dr. Nancy H. Ruddle, Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College St., P.O. Box 208034, New Haven, CT 06520-8034. E-mail address:
5 Abbreviations used in this paper: MS, multiple sclerosis; IDDM, insulin-dependent diabetes mellitus; LT, lymphotoxin; MAdCAM, mucosal addressin cellular adhesion molecule; PNAd, peripheral node addressin; LN, lymph node; PP, Peyer’s patch; RIP, rat insulin promoter; RAG, recombination-activating gene; MCP, monocyte chemotactic protein; IP-10, IFN-inducible protein-10; wt, wild type; Ltn, lymphotactin; MIP, macrophage inflammatory protein.
Received for publication December 11, 1998. Accepted for publication March 3, 1999.
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Q. Wu, Y.-X. Fu, and R. D. Sontheimer Blockade of Lymphotoxin Signaling Inhibits the Clinical Expression of Murine Graft-versus-Host Skin Disease J. Immunol., February 1, 2004; 172(3): 1630 - 1636. [Abstract] [Full Text] [PDF]
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A. E. Juedes, P. Hjelmstrom, C. M. Bergman, A. L. Neild, and N. H. Ruddle Kinetics and Cellular Origin of Cytokines in the Central Nervous System: Insight into Mechanisms of Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis J. Immunol., January 1, 2000; 164(1): 419 - 426. [Abstract] [Full Text] [PDF]
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D. V. Kuprash23, M. B. Alimzhanov2, A. V. Tumanov2, A. O. Anderson, K. Pfeffer, and S. A. Nedospasov TNF and Lymphotoxin {beta} Cooperate in the Maintenance of Secondary Lymphoid Tissue Microarchitecture But Not in the Development of Lymph Nodes J. Immunol., December 15, 1999; 163(12): 6575 - 6580. [Abstract] [Full Text] [PDF]
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Q. Wu, Y. Wang, J. Wang, E. O. Hedgeman, J. L. Browning, and Y.-X. Fu The Requirement of Membrane Lymphotoxin for the Presence of Dendritic Cells in Lymphoid Tissues J. Exp. Med., September 6, 1999; 190(5): 629 - 638. [Abstract] [Full Text] [PDF]
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