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Departments of Pediatrics, Microbiology-Immunology, and Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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4 integrin adhesion molecules can mediate
leukocyte rolling, the contribution of these receptors to lymphocyte
migration to inflammation was examined. The recruitment of
111In-labeled spleen T cells to intradermal sites injected
with IFN-
, TNF-, LPS, poly inosine-cytosine, and Con A was
measured in the rat, and the effect of blocking mAbs to E-selectin,
P-selectin, very late activation Ag-4 (VLA-4), and LFA-1 was determined
on this T cell migration in vivo. Anti-E-selectin and
anti-P-selectin mAbs each inhibited 10–40 and 20–48%,
respectively, of the T lymphocyte migration to the inflammatory sites,
depending on the stimulus. Blocking VLA-4 inhibited 50% of the
migration to all of the lesions except Con A. Treatment with both
anti-VLA-4 and anti-E-selectin mAbs inhibited up to 85% of the
lymphocyte accumulation, while P-selectin and VLA-4 blockade in
combination was not more effective than VLA-4 blockade alone in
TNF-, IFN-, LPS, and poly inosine-cytosine lesions. Inhibiting
E-selectin, P-selectin, and VLA-4 together nearly abolished lymphocyte
migration to all inflammatory sites. Anti-LFA-1 mAb strongly inhibited
lymphocyte accumulation by itself, and this inhibition was not
significantly further reduced by E- or P-selectin blockade. Thus, T
cell migration to dermal inflammation is dependent on E-selectin,
P-selectin, and VLA-4, likely because these three receptors are
required for rolling of memory T lymphocytes, but VLA-4 and E-selectin
are especially important for lymphocyte infiltration in these
tissues. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Based on previous studies, it is clear that the integrins LFA-1
(L
2; CD11a/CD18) and
very late activation Ag-4
(VLA-4)3
(41; CD49d/CD29)
mediate T lymphocyte recruitment to cutaneous inflammatory reactions
including delayed-type hypersensitivity (DTH) (1, 3, 4, 5, 6, 7, 8).
LFA-1 and VLA-4 can mediate firm adhesion of lymphocytes to
endothelium, and 4 integrins have been shown
to also mediate the rolling of lymphocytes on vascular endothelial
cells in vitro and in postcapillary venules in vivo (9, 10). The members of the selectin family of adhesion molecules,
including E- and P-selectin expressed on endothelium at sites of
inflammation, have also been shown to mediate the rolling of
lymphocytes on vascular endothelium in vitro (11, 12, 13).
However, the importance of E- and P-selectin in recruitment of T
lymphocytes to inflamed tissues is less well understood. E-selectin may
be especially important for T lymphocyte migration to cutaneous
inflammation, because a subset of T cells found enriched in human
inflammatory dermatoses expresses a specific ligand for E-selectin,
i.e., the cutaneous lymphocyte Ag (CLA) (14, 15). In vitro
stimulated and adoptively transferred T cells of the Th1 phenotype in
the mouse express ligands for P-selectin and/or E-selectin
(16). These T cells have been shown in the mouse to use
P-selectin for migration to inflammatory sites, such as DTH
reactions and arthritic joints, and to peritoneal inflammation
(16, 17, 18, 19). A subset of unactivated T lymphocytes also
expresses P-selectin glycoprotein ligand-1, which, when properly
glycosylated, can bind to P-selectin (20).
Although the above studies suggest a role for these selectins in T
lymphocyte or lymphoblast recruitment, the contribution of E- and
P-selectin to resting T lymphocyte migration to sites of inflammation,
such as the skin in vivo, in response to cytokines, cytokine inducers,
and polyclonal activators has not been investigated. Furthermore, the
relative contribution of adhesion molecules involved in rolling of
lymphocytes, i.e., E- and P-selectin and the 4
integrin, VLA-4, has not been systematically examined or compared with
the role of LFA-1, which mediates primarily firm adhesion and
transmigration rather than leukocyte rolling. The studies presented in
this work demonstrate a variable role in T cell recruitment for both
E-selectin and P-selectin depending on the inflammatory stimulus, a
marked contribution of the integrin VLA-4, and a substantially greater
contribution for E-selectin in combination with VLA-4 than P-selectin
in mediating T lymphocyte migration to dermal inflammation to most
stimuli.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male Lewis strain rats of 200–250 gm (Harlan Sprague-Dawley,
Indianapolis, IN) were used in all experiments. Rat IFN- was
generously provided by Dr. P. Van Der Meide (TNO Primate Center,
Rijswijk, The Netherlands) and murine rTNF- was a kind gift from
Genentech (South San Francisco, CA). Escherichia coli 0111B4
LPS was from List Biologicals (Campbell, CA), and poly
inosine-cytosine (poly(I:C)) and Con A were purchased from
Sigma-Aldrich (St. Louis, MO). mAbs used included TA-2, a mAb to rat
4, and TA-3, a mAb to rat LFA-1
(L specific) (5, 21). RME-1 is a
mAb against rat E-selectin and mAb RMP-1 recognizes rat P-selectin
(22, 23); these are mouse IgG mAbs generated in our
laboratories, and each of these blocks the adhesion function of its
respective Ags based on in vitro and in vivo studies
(22, 23, 24). Isotype control mAb was mAb B9 (IgG) reactive
with pertussis toxin (25).
In vivo migration assay
Spleen T lymphocytes were isolated from donor rats as previously described (5). Briefly, the spleen was minced to obtain a cell suspension and RBCs were lysed with 0.84% NH4Cl. T cells were purified by passage through a nylon wool column. The recovered cells were 91–93% CD2+, 2–4% surface Ig+, <2% neutrophils and monocytes, and contained 60–65% CD4+8- and 30–35% CD4-8+ lymphocytes.
The T lymphocytes were labeled with 111In-labeled
oxine and their in vivo migration was measured as previously described
(5). Briefly, 5 x 107 cells
suspended in 0.5 ml of medium were labeled with 3.5 µCi of
111In-labeled oxine for 10 min, washed, and
resuspended for injection. Immediately afterward, where indicated, mAbs
RME-1 and/or RMP-1 (1–2 mg), TA-2 (2 mg), TA-3 (3 mg), or B9 (2 mg),
as a control, were administered i.v. The skin on the back of the animal
was then shaved and 0.05 ml of test sample containing 300 U of IFN-,
10 ng of TNF-, combinations of these two cytokines, 100 ng of LPS,
200 ng of poly(I:C), or 10 µg of Con A were injected intradermally,
using 30-gauge needles, into duplicate or triplicate skin sites. Each
of these stimuli has been previously shown to recruit T lymphocytes to
dermal sites over 6–20 h (26, 27). Diluent medium (RPMI
1640, 0.1% pyrogen free human serum albumin) was injected in control
skin sites. Animals were sacrificed 20 h later, the skin on their
backs was removed, and the injected areas were punched out with a
leather punch. This produced a circular piece of tissue 12 mm in
diameter with a standard surface area. At time of sacrifice, samples of
blood, spleen, cervical, axillary, and mesenteric lymph nodes, and
Peyer’s patches were taken. All samples were analyzed for
111In content in a Wallac Wizard III gamma
radioisotope counter (Wallac, Gaithersburg, MD). Results are
expressed as cpm of 111In accumulated per 20-h
migration period per 106 cpm injected on labeled
cells.
Immunofluorescence flow cytometry
The expression of ligands for E-selectin and P-selectin on T cells was determined using mouse E-selectin and mouse P-selectin chimera constructs fused to human µ-chain (kind gift from Drs. J. Lowe and L. Stoolman, University of Michigan, Ann Arbor, MI) as reported previously (28). Briefly, the purified T cells were incubated (45 min at 4°C) with either E- or P-selectin chimera constructs in immunofluorescence buffer. Binding was detected by using sequential incubation with biotin-labeled mouse anti-human µ-chain (Zymed Laboratories, San Francisco, CA) followed by washing and incubation with streptavidin-conjugated PE (Sigma-Aldrich). Controls included chimera plus 10 mM EDTA during the staining procedure to eliminate cation-dependent binding.
For double staining of IL-2R and selectin ligands, T cell IL-2R expression was determined using mAb MRC OX-39 (Serotec, Oxford, U.K.), followed by F(ab')2 sheep anti-mouse IgG-conjugated FITC (Sigma-Aldrich). The sheep anti-mouse IgG was then blocked with 5% mouse serum and staining was conducted as above with the E-selectin and P-selectin chimeras. Samples were read immediately in a FACSCalibur flow cytometer (BD Biosciences, Mountain View, CA) with appropriate FL-1/FL-2 compensation. Twenty thousand lymphocytes were analyzed per sample.
Statistics
Data were expressed as means ± SEM of multiple animals. ANOVA and Student’s unpaired t test were used to compare the differences between means.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The intensity of T lymphocyte accumulation in response to the
different stimuli varied considerably, as shown in Fig. 1
. The response to TNF- and IFN-
was the weakest, despite using an optimal dose for each stimulus.
However, the combination of TNF- with IFN- induced a synergistic
increase in lymphocyte recruitment. The response to Con A was the
greatest, with LPS and poly(I:C) inducing intermediate responses. There
was little effect of E-selectin or P-selectin mAb treatment on the
TNF-, IFN-, or TNF- plus IFN- responses, or on the LPS or
poly(I:C) stimuli when only E- or P-selectin Ab was used. In contrast,
the response to Con A was especially inhibited by anti-P-selectin
treatment. In addition, the response to LPS, poly(I:C), and especially
Con A was inhibited by simultaneous blockade of E- and P-selectin with
little effect of this combination of selectin blockade on the TNF-
and IFN- responses.
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shows the results normalized to the
control response obtained with each stimulus. Treatment with mAb to
E-selectin alone significantly inhibited the recruitment induced by
TNF-, LPS, and Con A, with no effect on the response to IFN-,
TNF- plus IFN-, or poly(I:C). Ab to P-selectin, in contrast,
inhibited the response to the combination of TNF- plus IFN- and
also significantly inhibited the response to LPS, poly(I:C), and Con A.
Blocking both E- and P-selectin also had no effect on IFN--induced
migration, and there was no additive effect by dual selectin blockade
on TNF- and TNF- plus IFN- responses, which were only modestly
(30–40%) inhibited. T cell recruitment induced by LPS and Con A was
especially strongly inhibited by E- plus P-selectin blockade, with a
60–70% reduction of the response to these stimuli.
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VLA-4 has been reported to mediate capture and rolling of
lymphocytes (9, 10). Therefore, the contribution of VLA-4
in E-selectin- and P-selectin-independent T lymphocyte migration was
evaluated. As shown in Fig. 3, blocking
VLA-4 significantly inhibited T cell recruitment induced by TNF-,
IFN-, TNF- plus IFN-, LPS, and poly(I:C) by 42–56%. In
contrast, VLA-4 blockade had no effect on the response to Con A. When
anti-VLA-4 was combined with mAb to E-selectin, there was a marked
reduction of the lymphocyte migration to all of the stimuli, with
80% inhibition of the recruitment to most of the inflammatory sites.
In almost all cases a much greater inhibition was observed with this
combination than with either anti-VLA-4 or anti-E-selectin
alone. Once again the response to Con A was most resistant to
inhibition with VLA-4 plus E-selectin blockade, inhibiting T cell
recruitment by only 40%.
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). Blockade of P-selectin did not
significantly potentiate the inhibition of migration observed in the
presence of blocking VLA-4 to most of the stimuli and was substantially
less effective than blockade of E-selectin plus VLA-4 (Fig. 3
).
Anti-P-selectin treatment did not potentiate the inhibition by
anti-VLA-4 mAb on the response to TNF-, IFN-, and poly(I:C)
and had only a small effect on the response to LPS and TNF- plus
IFN-. Similarly, VLA-4 blockade, which did not affect the Con A
response, also did not potentiate the inhibitory effect of P-selectin
blockade.
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The results above showed that VLA-4 contributed substantially to T
lymphocyte migration to most of the inflammatory sites examined and
that blocking E-selectin together with VLA-4 markedly inhibited, but
did not abolish, T cell accumulation in these sites. To determine
whether P-selectin contributed to this residual lymphocyte
infiltration, the effect of blocking both E- and P-selectin plus VLA-4
was determined and compared with anti-VLA-4 and anti-VLA-4 plus
anti-E-selectin treatment (Fig. 5).
Blocking P-selectin, in addition to VLA-4 and E-selectin, was
significantly more effective at inhibiting migration to all of the
lesions than was blocking VLA-4 and E-selectin, and blocking P-selectin
reduced T lymphocyte accumulation by >90%. In most of the
inflammatory sites additional blockade of P-selectin decreased T cell
migration from 
20% of control to <10%. Even the migration to Con
A-induced inflammation was inhibited from 56% of control to <10%
when all three receptors were blocked. Thus, P-selectin appeared to
mediate a substantial part of the residual T cell migration that was
independent of VLA-4 and E-selectin function.
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Both VLA-4 and LFA-1 are important integrins mediating T cell
migration to dermal inflammation, and combined blockade of VLA-4 and
LFA-1 essentially abolishes T cell migration to dermal inflammation
(4). Therefore, the role of LFA-1 and E- and P-selectin in
T cell recruitment was examined (Fig. 6).
Blockade of LFA-1 inhibited T cell migration induced by all the stimuli
by 75–80%. Treatment with anti-P-selectin mAb did not potentiate
this inhibition, and anti-E-selectin mAb substantially (>10%)
inhibited the residual T cell recruitment to only two of the stimuli,
LPS and Con A. Furthermore, the combination of E- and P-selectin
blockade had a comparable effect to E-selectin blockade alone, and, in
response to stimuli such as TNF-, IFN-, TNF- plus IFN-, and
poly(I:C), selectin blockade did not enhance the inhibition of T cell
migration observed with LFA-1 blockade alone. Thus, it would appear
that E- and P-selectins do not mediate alternate pathways to LFA-1 in T
cell recruitment to dermal inflammation.
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The effect of mAbs to E- and P-selectin and VLA-4 on the level of
the labeled T lymphocytes in the blood and on their migration to
lymphoid tissues was determined in the above animals. As shown in Fig. 7, anti-P- and anti-E-selectin
treatment had no effect on the accumulation of labeled T cells in the
blood, spleen, cervical, axillary and mesenteric lymph nodes, and
Peyer’s patches. However, mAb to VLA-4 either alone or in the presence
of E- and P-selectin blockade partially inhibited T cell homing to the
mesenteric lymph nodes and abolished migration to Peyer’s patches in
accordance with the known dependence of migration to the gut-associated
lymphoid tissues on the 4 integrin,
47 (6, 29, 30).
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T lymphocytes from the spleen were analyzed for P- and E-selectin ligand expression using mouse P-selectin and E-selectin human µ-chain chimera. These chimeras have been shown to bind to P- and E-selectin ligands expressed on myeloid cells and T lymphoblasts (16, 28). Their binding to rat P- and E-selectin ligands was confirmed by us using rat blood monocytes and neutrophils in previous experiments (our unpublished observations). Among the spleen T lymphocytes, only 2.5 ± 1.3% (n = 4) expressed E-selectin ligand and 5.2 ± 1.5% (n = 4) expressed P-selectin ligand. The T lymphocytes were also analyzed for the activation marker CD25 (IL-2R). Only 3.6% of the T cells expressed CD25. Double staining analysis showed that of the total T cells 0.22% coexpressed CD25 and E-selectin ligand and 0.42% coexpressed CD25 and P-selectin ligand. Overall, these double-positive cells accounted for <10% of all of the E- and P-selectin ligand-positive cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF- plus IFN-, was not inhibited by E-selectin
blockade alone and was either unaffected or reduced by only 30% when
E- and P-selectin were blocked. Interestingly, these results contrast
with previous findings using blood monocytes in this model, which
showed that monocyte migration to IFN- and TNF- are highly
P-selectin dependent (31). Thus, the relative importance
of E- and P-selectin to T lymphocyte recruitment in the skin is highly
stimulus dependent as well as different from monocytes.
Our results showing a major E- and P-selectin dependence of the
migration of T cells to Con A- and LPS-induced inflammation is similar
to the findings reported in mice, in which activated T cells and Th1
lymphocyte accumulation in DTH and contact sensitivity reactions was E-
and P-selectin dependent (16, 19). The cells in these
lesions expressed ligands for P- and E-selectin which appear to be
related to the sustained level of (1, 3)fucosyltransferase VII, an
enzyme critical to selectin ligand synthesis in activated Th1 cells
(32).
Our studies highlight several important features of T lymphocyte
recruitment that extend these previous reports. In contrast to the
results with activated T cells, in which almost all of the migration to
the dermal inflammation was E- and P-selectin dependent (16, 19), a significant component of the T cell migration in these
studies was E- and P-selectin independent to all the inflammatory
stimuli examined, including Con A. As discussed below, this appears to
be the result of lymphocyte migration mediated by VLA-4. This may be a
reflection of the fact that the selectin ligands, although present on a
few unactivated T cells (2.3–4.8% in the spleen T cells used here;
see Results), are induced or up-regulated following T cell
activation by Ag or mitogen, while virtually all resting T cells
express VLA-4. Furthermore, VLA-4-mediated rolling does not require Ag
activation of the lymphocyte (6, 10). Overall, only 2.5%
of the spleen T cells expressed ligands for E-selectin and 5.2% for
P-selectin, and <10% of these cells expressed the CD25 activation
marker, suggesting that most of the selectin ligand-positive cells were
not lymphoblasts. Whether it is only these initial selectin
ligand-positive cells which use E- and P-selectin for migration in our
model or whether some T cells acquire selectin ligands during the
migration period is not yet clear. However, our results demonstrate
that, under the resting conditions used, it is clear that T cells can
use E- and P-selectin-independent mechanisms for migration as shown
especially by the recruitment to IFN-, TNF-, TNF- plus
IFN-, and the IFN inducer poly(I:C) (Fig. 2).
Our results also demonstrate a major role for VLA-4 in T cell migration
to dermal inflammation to most of the inflammatory sites examined, and
a particular cooperative interaction between VLA-4 and E-selectin,
rather than P-selectin, in T cell recruitment. Blocking VLA-4 inhibited
40–60% of the lymphocyte recruitment to TNF-, IFN-, TNF-
plus IFN-, LPS, and poly(I:C). E-selectin blockade markedly
potentiated the inhibitory effect of blocking VLA-4, even when
E-selectin blockade alone had no effect, as with, e.g., IFN-,
TNF- plus IFN-, and poly(I:C) (Fig. 3). The combination of
E-selectin and VLA-4 blocked 80–85% of the T cell migration to these
lesions (Fig. 5). In contrast, anti-P-selectin treatment had only a
small or no potentiating effect on the inhibition of lymphocyte
recruitment to most of these sites (Fig. 4). Furthermore, blocking
P-selectin, in addition to VLA-4 and E-selectin, reduced T cell
migration by only an additional 7–10% to these stimuli, suggesting
that P-selectin contributes a relatively much smaller component to the
lymphocyte migration to these inflammatory sites than does E-selectin.
However, the balance of these mechanisms appears to be influenced by
the complexity of the reaction as the response to the potent mitogen
and cytokine inducer Con A shows. T cell recruitment to this stimulus
was dependent on both E- and P-selectin and VLA-4 (Figs. 2 and 5).
Although previous reports by our group and others have shown that VLA-4 mediated T cell recruitment to dermal inflammation both alone and together with LFA-1, a role for VLA-4 as a mediator of E- and P-selectin-independent migration of resting T cells to cutaneous inflammation has not been previously demonstrated. Our findings extend to skin inflammation the observation that in CNS inflammation T cells use VLA-4, rather than E- or P-selectin, to migrate out of the blood (33, 34, 35). They also suggest that in tissues other than the CNS, VLA-4 may substantially substitute for selectins in mediating lymphocyte recruitment to some inflammatory stimuli, as seen in pulmonary inflammation with T lymphoblasts (28).
Despite the important role of VLA-4 in the T cell migration to the
skin, endothelial selectins contributed significantly to T cell
recruitment in every inflammatory lesion examined. Even in the case of
IFN-, which was not inhibited by blocking E- and P-selectin, a
selectin component was revealed when VLA-4 was blocked (Fig. 4). The
balance of VLA-4- vs selectin-mediated mechanisms appears to vary
considerably and is quite stimulus dependent, even within a given
tissue. This could be related to differences in the extent of E- and
P-selectin or VCAM-1 up regulation induced by these stimuli. However,
it is also compatible with multiple mechanisms being available to a
migrating T cell and with selective recruitment of T cell
subpopulations, which preferentially use different adhesion receptors.
Further studies are needed to define the relative contribution of these
variables.
Our studies also demonstrate that E-selectin, in particular, functions in concert with VLA-4 in T cell recruitment to most of the reactions studied. These observations agree with an important role for E-selectin in T cell migration to skin lesions, as demonstrated for DTH reactions in the pig and macaque monkey (36, 37), and with results in human skin biopsies showing that most infiltrating T cells express CLA, a carbohydrate ligand for E-selectin (14, 15). Our results also show differences in the role of E-selectin in lymphocyte recruitment to various stimuli, and the role of VLA-4 in the E-selectin-independent migration. The basis for the relatively greater importance of E-selectin than of P-selectin in most of the inflammatory sites is not clear. The rodent homolog of CLA has not been identified, but recent studies indicate that in mouse contact sensitivity reactions P-selectin glycoprotein ligand-1 on T cells is a ligand, although not the sole ligand, for E-selectin-mediated T cell recruitment (38). Our studies emphasize a greater contribution of E-selectin to T cell recruitment to skin than P-selectin.
Our findings in this study once again contrast the mechanisms of T cell migration with those of monocyte migration, the latter being P-selectin, but not E-selectin, dependent, and in particular mediated by VLA-4 and P-selectin (31). The predominant role of the VLA-4 and E-selectin mechanisms of T cell migration shown in this study is also in contrast with the requirement for P-selectin in the recruitment of leukocytes to acute inflammation in P-selectin knockout mice, with relatively normal acute inflammatory responses in E-selectin-deficient mice (39, 40).
Our findings also emphasize the marked difference between the role of
VLA-4 and LFA-1 function in vivo in dermal inflammation. E- and
P-selectin blockade did not potentiate the inhibitory effect of LFA-1
in most lesions (Fig. 6), in contrast to the enhanced inhibition in the
presence of anti-VLA-4 treatment (Fig. 5). This suggests that LFA-1
functions at a different step in the adhesion cascade in vivo than does
VLA-4 or the selectins. E- and P-selectin are primarily involved in
mediating leukocyte capture, tethering and rolling in the postcapillary
venules, a prerequisite step to firm adhesion and transendothelial
migration of leukocytes. VLA-4 has also been shown to mediate
lymphocyte capture and rolling in vitro, in addition to mediating firm
adhesion to the endothelium (1, 10, 41). LFA-1, in
contrast, mediates primarily firm adhesion and transendothelial
migration (1). Our results suggest that VLA-4, but not
LFA-1, is an important mechanism which can substitute for E- and
P-selectin-mediated capture and rolling in T cell migration to many
inflammatory stimuli in the skin.
In summary, these studies demonstrate that resting T cells can use E- and P-selectin for rapid (<20 h) migration to a range of inflammatory stimuli. Furthermore, VLA-4 is the predominant E- and P-selectin-independent mechanism for migration to skin, and VLA-4 and E-selectin in particular are complementary mechanisms operative in resting T cell migration to inflamed skin.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas B. Issekutz, Department of Pediatrics, Dalhousie University, Izaak Walton Killam Health Center, 5850University Avenue, Halifax, Nova Scotia, B3J 3G9, Canada. E-mail address: Thomas.Issekutz{at}dal.ca
3 Abbreviations used in this paper: VLA-4, very late activation Ag-4; CLA, cutaneous lymphocyte Ag; DTH, delayed-type hypersensitivity; poly(I:C), poly inosine-cytosine.
Received for publication March 14, 2001. Accepted for publication December 5, 2001.
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(1,3)-fucosyltransferase VII and (2,3)-sialyltransferase IV are up-regulated in activated CD4 T cells and maintained after their differentiation into Th1 and migration into inflammatory sites. J. Immunol. 163:3746.This article has been cited by other articles:
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 Y. Katayama, A. Hidalgo, B. C. Furie, D. Vestweber, B. Furie, and P. S. Frenette PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: evidence for cooperation between E-selectin ligands and {alpha}4 integrin Blood, September 15, 2003; 102(6): 2060 - 2067. [Abstract] [Full Text] [PDF]
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 J. R. Timoshanko, J. D. Sedgwick, S. R. Holdsworth, and P. G. Tipping Intrinsic Renal Cells Are the Major Source of Tumor Necrosis Factor Contributing to Renal Injury in Murine Crescentic Glomerulonephritis J. Am. Soc. Nephrol., July 1, 2003; 14(7): 1785 - 1793. [Abstract] [Full Text] [PDF]
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K. Yanaba, Y. Kaburagi, K. Takehara, D. A. Steeber, T. F. Tedder, and S. Sato Relative Contributions of Selectins and Intercellular Adhesion Molecule-1 to Tissue Injury Induced by Immune Complex Deposition Am. J. Pathol., May 1, 2003; 162(5): 1463 - 1473. [Abstract] [Full Text] [PDF]
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S. B. Forlow, E. J. White, K. L. Thomas, G. J. Bagby, P. L. Foley, and K. Ley T Cell Requirement for Development of Chronic Ulcerative Dermatitis in E- and P-Selectin-Deficient Mice J. Immunol., November 1, 2002; 169(9): 4797 - 4804. [Abstract] [Full Text] [PDF]
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 A. A. Kulidjian, A. C. Issekutz, and T. B. Issekutz Differential role of E-selectin and P-selectin in T lymphocyte migration to cutaneous inflammatory reactions induced by cytokines Int. Immunol., July 1, 2002; 14(7): 751 - 760. [Abstract] [Full Text] [PDF]
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