Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Alberta, Canada T2N 4N1
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ABSTRACT |
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A hallmark feature of intestinal inflammation is the recruitment and extravasation of numerous cell types from the blood to the afflicted site. Much of what we know about the mechanisms of leukocyte recruitment to splanchnic organs comes from an extensive series of studies on neutrophils in the mesenteric microvasculature. In this themes article, we highlight the important findings from these experiments but also emphasize some of the limitations. In fact, there is a growing body of evidence that neutrophil recruitment may be quite different in the mesentery than in other splanchnic organs. For example, the molecular mechanisms underlying neutrophil recruitment into the liver are quite different than the mesentery and are dependent on the type of inflammatory disease. We also discuss the effect of modulating leukocyte recruitment to splanchnic organs in chronic inflammation and emphasize that the approaches that have been successful in acute inflammation may be less effective in such conditions as inflammatory bowel disease (IBD). One obvious reason for this observation is the growing body of evidence to suggest that the initiation and maintenance of IBD is, in part, due to dysregulated or inappropriately activated populations of infiltrating T lymphocyte subsets. Therefore, we also discuss some interesting new approaches to limiting lymphocyte recruitment into the inflamed intestine either by targeting T helper (Th)1 vs. Th2 lymphocytes or perhaps by allowing the recruitment of regulatory T cells. Inhibiting specific adhesion molecules or specific chemokine receptors may work in this regard.
lymphocyte; intestine; liver; neutrophils; adhesion molecules
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INTRODUCTION |
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A HALLMARK FEATURE OF INTESTINAL
inflammation is the recruitment of various types of leukocytes to the
afflicted site. Neutrophils are the predominant cell type in acute
inflammation, whereas mononuclear cells are the major cells recruited
in chronic inflammation. The key factor in the recruitment of these
cells, regardless of the type of inflammation, is the expression of
functional adhesion molecules on the surface of endothelium of small
postcapillary venules. Figure 1
summarizes the cascade of events involved in leukocyte recruitment
including a role for selectins (E-selectin, P-selectin, and L-selectin)
and the 4-integrin (
1- or
7-integrin) as key molecules regulating the initial
tethering and rolling step. Once the rolling is initiated, chemokines
presented on the surface of endothelium engage their receptors on the
surface of leukocytes and activate integrins (
1-,
2-, or
7-integrin) to cause firm
adhesion. The emigration process out of the vasculature then makes use
of numerous additional proteins including PECAM-1, CD99, and JAMs. The
driving force behind research in this area is the appreciation that
interference of the recruitment process may very likely lead to
therapeutic benefit. The major aim of this themes article is to very
briefly summarize some of the milestones and highlights in adhesion and
intestinal inflammation, to draw attention to some of the negative and
controversial results, and to provide an opinion on directions that
should be explored further. For details on adhesion and intestinal
inflammation, we draw the readers attention to excellent reviews on the
topic (22, 27).
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TARGETING NEUTROPHILS |
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Granger and Parks (6) in the early 1980s first demonstrated that ischemia of the intestine followed by reperfusion was closely associated with impairment of both the microvascular barrier and the mucosal barrier and that this pathology was dependent on oxygen free radicals. Subsequent studies demonstrated that neutrophils, a major source of oxygen free radicals, were essential for the development of the postischemic microvascular dysfunction (9). Indeed, neutrophils were demonstrated to accumulate in the postischemic intestine, and depletion of circulating neutrophils resulted in a reduction in the ischemia-reperfusion-associated vascular dysfunction. Similar observations have since been made in other splanchnic organs including postischemic stomach, pancreas, liver, and mesentery.
Although the mesentery is structurally and functionally quite different
from other gastrointestinal organs, we and others have used it as a
prototype tissue to study the basic mechanisms of leukocyte recruitment
in vivo. This is done primarily because the mesentery is a translucent
tissue and permits transillumination. Therefore, intravital microscopy
permits the direct visualization of postcapillary venules within this
tissue. Intravital microscopy of the mesentery has clearly demonstrated
that the rolling is indeed dependent on selectins, and the adhesion is
dependent on the 2-integrins (16).
Moreover, inhibition of rolling indeed inhibits adhesion and inhibition
of rolling, or adhesion will inhibit microvascular dysfunction
(18). In addition to ischemia-reperfusion, the
mesentery has been used to examine the molecular mechanisms of
leukocyte recruitment associated with numerous other intestinal pathologies (22). For example nonsteroidal
anti-inflammatory drugs induce ulceration and neutrophil recruitment in
the stomach and small bowel. Radiation-induced enteritis is also
associated with neutrophil recruitment. In addition, various bacterial
toxins, including those isolated from H. pylori, C. difficile, and even lipopolysaccharide from E. coli,
clearly induce intestinal inflammation. In each case, direct exposure
of the mesentery to any of the aforementioned procedures or noxious
stimuli also results in profound neutrophil recruitment in the
mesenteric microcirculation. Although antiadhesion therapy reduces the
neutrophil recruitment and vascular dysfunction within the mesentery,
key experiments to demonstrate that this prevents inflammation in, for
example, the intestine in many cases have not been completed. This is
undoubtedly an issue that warrants further experimentation.
Clearly, the mesenteric microvasculature has functioned as an extremely
important tool to elucidate molecular mechanisms associated with
leukocyte recruitment. However, the limited amount of antiadhesion work
completed in other splanchnic organs raises some concerns about the use
of the mesentery. For example, Kurtel and colleagues (19)
clearly demonstrated that the neutrophil recruitment response to
ischemia-reperfusion appears to be very similar in various parts of the intestinal tract including the small and large bowel (muscularis layer, mucosa, and serosa), and the results are
comparable with the mesentery. Moreover, the
anti-2-integrin antibody inhibited neutrophil
recruitment into each of the aforementioned compartments, and
microvascular dysfunction was clearly abrogated in the intestine with
anti-
2-integrin therapy. By contrast, the same
concentration of
2-integrin that inhibited neutrophil
recruitment into the intestine did not reduce the mucosal barrier
dysfunction, suggesting that the circulating neutrophils could not
account for all pathology in the intestinal mucosal compartment
(15).
Interestingly, an assessment of the intestine revealed that
relative to other organs there was always a very significant number of
neutrophils within the interstitium. These cells were only transiently
in the interstitium (passing from vasculature to lumen of the bowel),
because treatment of animals with anti-2-integrin antibody for 72 h resulted in abolition of all neutrophils within the mucosal compartment (presumably neutrophil migration into the
intestinal lumen is a constitutive, homeostatic event). When the
neutrophil-depleted intestine was subjected to
ischemia-reperfusion, the intestine remained devoid of
neutrophils and no mucosal barrier dysfunction occurred
(15). Clearly, interstitial (tissue) neutrophils within
the intestine contributed to the intestinal mucosal dysfunction associated with ischemia-reperfusion and must also be
considered when designing novel therapy.
The leukocyte recruitment responses within the liver are also quite
different from the mesentery, at least in part due to very significant
architectural differences between the hepatic and mesenteric
microvasculature. The liver has a dual blood supply that includes the
venous blood from the intestinal tract via the portal (presinusoidal)
venules and arterial blood entering via the hepatic arterioles.
Convergence of these two blood supplies occurs at the sinusoids, which
then drain the blood into the central (postsinusoidal) venules. It has
been suggested that leukocyte recruitment in portal and central venules
is very similar to that found in mesenteric and cremasteric venules,
whereas the sinusoids use a very different mechanism (31,
31). Indeed, although the sinusoids are the major site for
leukocyte recruitment in acute inflammation, leukocyte recruitment in
inflamed sinusoids was not diminished in P-selectin-deficient mice,
P/E-selectin double-deficient mice, and P/E-selectin double-deficient
mice given L-selectin or 4-integrin antibody (5,
31). Essani et al. (3) and Jaeschke and colleagues
(13, 14) have also reported that neither ICAM-1 nor
2-integrins were very important in leukocyte recruitment
in liver in a sepsis model (13). In addition, the liver
sinusoidal endothelial cells lack the capacity to express E-selectin,
P-selectin, PECAM-1, CD34, and VE-cadherin, induction of VCAM-1 is
lower than on other vessels, and yet ample adhesion occurs in
sinusoids. One possibility is that the low blood flow rates through
these vessels and the constitutively high levels of ICAM-1 (relative to
other vascular beds) permit direct adhesion of leukocytes within
sinusoids (28). However, ICAM-1 inhibition has not always
worked in the liver. Moreover, other less well-studied adhesion
molecules such as vascular adhesion protein (VAP)-1, found expressed
constitutively on sinusoidal endothelium, may potentially mediate the
leukocyte recruitment in sinusoids (21). Because the
leukocytes and sinusoids have similar diameters, an alternative
possibility is that the physical constraints (the narrow sinusoids)
rather than true adhesion may be important in leukocyte sequestration
in sinusoids.
Clearly in most acute liver inflammation, selectins, and even integrins, are not essential for leukocyte recruitment. By contrast, an important role for selectins in liver in ischemia-reperfusion has been reported, and substantial numbers of leukocytes adhere in both the postsinusoidal and the sinusoidal venules (17). Because the majority of blood that perfuses the liver initially drains the intestine, ischemia-reperfusion of the liver would also have induced ischemia-reperfusion in the intestine. Therefore, if the antiselectin therapy reduced injury in the intestine, this may have reduced the injury downstream in the liver. Indeed, Horie et al. (10) reported that ischemia-reperfusion of the intestine caused significant liver damage and that this was eliminated with antiselectin approaches. When ischemia-reperfusion was performed exclusively in the liver (intestine was removed), the results suggested that the liver was quite resistant to this insult. Only a small amount of leukocyte recruitment was noted in postischemic liver, and antiselectin therapy had minimal effects in sinusoids (17).
Finally, different inflammatory responses in liver may differ in the localization of leukocyte recruitment, i.e., sinusoids vs. postsinusoidal vessels. Indeed, administration of adenovirus vectors causes profound liver injury, but neutrophils were recruited almost exclusively to postsinusoidal venules, not to sinusoids (20). In this model of liver inflammation, neutrophil recruitment was amenable to antiadhesion therapy. Thus it appears that in certain inflammatory responses, leukocytes can be recruited in the postsinusoidal venules but not sinusoids, and under these conditions, antiadhesion therapy may be beneficial. These data as a whole clearly highlight the importance of exploring leukocyte recruitment in individual organs and in different inflammatory processes.
Therefore, despite the initial view that antiadhesion would be
the panacea for inflammatory diseases of the splanchnic organs, there
is a growing body of evidence that the adhesion processes may differ
among organs, among different compartments of the same organ, and even
in different acute inflammatory conditions. This is further complicated
in chronic intestinal inflammation. In the intestine, it is clear that
there exists a very delicate balance between a homeostatic,
appropriate, and even essential host response against intestinal flora
vs. an overexuberant inappropriate immune response. However, modulation
of the immune balance, with the intent of dampening immune response,
has often led to initiation or exacerbation of intestinal inflammation.
This is best exemplified by spontaneous development of inflammatory
bowel disease (IBD) in at least eight different mutant mouse systems
(see Table 1). Along the same lines, the
absence of selectins has resulted in exacerbation of intestinal
inflammation in some models of colitis. Surprisingly, neutrophil
recruitment was either not depressed or even enhanced in some of these
models, suggesting the induction of other mechanisms of neutrophil
recruitment. Indeed, the possibility that 4-integrin may
be upregulated on neutrophils in chronic inflammatory diseases or even
in acute systemic diseases (sepsis) raises the possibility that this
adhesion molecule could contribute to neutrophil recruitment in IBD.
This is important, because
4-integrin can support
rolling and adhesion and can bypass the necessity for selectins as well
as
2-integrins (see Fig. 1). Indeed, monoclonal antibodies against the
4-integrin attenuated the
spontaneous colitis in the cotton-top tamarin (24).
Whether this is due to inhibition of mononuclear cell recruitment or
mononuclear cell and neutrophil recruitment remains unclear but does
require some assessment.
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TARGETING LYMPHOCYTES |
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To date, a significant emphasis has been on targeting the
more overt inflammatory processes including neutrophil recruitment. However, it is well documented that a plethora of cells infiltrate the
inflamed mucosa. In fact, many studies of enterocolitis have implicated
T lymphocytes as the primary mediator in IBD based on 1)
increased T cell numbers in affected tissue, 2) the state of
activation of T cells at these sites, and 3) their
production of numerous proinflammatory cytokines [see recent review by
Strober et al. (29)]. Bacterial flora stimulate the
development of the intestinal immune system, and, under normal
conditions, tolerance to this enteric bacteria is generated. Once the
balance of regulatory and proinflammatory T cells is perturbed,
pathogenic intestinal inflammation develops and is self-reinforcing due
to the proinflammatory cytokine milieu generated via a feedback loop
between T cells and antigen-presenting cells. The direct demonstration
that effector T lymphocytes are reactive to conventional antigens of
the enteric bacteria was described by Powrie and coworkers
(25). In 1993, they observed that adoptive transfer of
CD4+CD45RBhigh T cells to severe combined
immunodeficient (SCID) recipients induced intestinal inflammation. In
addition, Sundberg and colleagues (30) observed that
within weeks of life, C3H/HeJBir mice develop a spontaneous colitis
that coincided with 1) the time of bacterial colonization
and 2) the presence of T cells producing IL-2 and IFN-
[a T helper (Th) type 1 (Th1) cell response]. An adhesive mechanism
of action has now been identified, because blocking studies showed that
4
7 helps direct the migration (homing) of CD4+CD45RBhigh lymphocytes to the intestine
(23). However, this is a very specific controlled mouse
model, wherein specific lymphocytes home to the intestine via a very
specific adhesive mechanism. Whether such a specific mechanism exists
in IBD remains unclear.
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T CELL DICHOTOMY IN IBD |
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By way of mouse models, it is becoming increasingly evident
that mucosal inflammation reflects a remarkably wide variety of causes
(as exemplified in Table 1). It is also clear that 1) the
driving force of the inflammation is the mucosal microflora and
2) the inflammation is predominantly mediated by either an excessive Th1 or Th2 T cell response. Indeed, in Crohn's disease (CD)
patients, an overproduction of Th1 cytokines, such as IFN-, TNF-
,
and IL-12, by CD4+ T cells has been implicated in disease
development, and anti-TNF-
therapy is one of the most effective
treatments to date. In contrast, the amelioration of ulcerative colitis
(UC) severity, with antibodies to Th2 cytokines, e.g., IL-4, implies
that this is a Th2-mediated disease. These observations imply that both
CD4+ Th1 and Th2 cells can function as effector cells in
IBD. Therefore, studying the effector T lymphocyte populations that
home to the chronically inflamed intestine and the adhesive mechanisms
used (particularly if they are different) has important implications for understanding IBD.
As previously stated, therapeutic strategies targeting adhesion molecules (i.e., selectins and CAMs) have limited efficacy in different models of colitis. Furthermore, whether this form of therapy is effective long term in chronic disease states is still not known. An alternative approach may be to encourage the recruitment of counterreactive cells to the inflamed site. The Th1-Th2 paradigm suggests that Th1 and Th2 cells counterbalance each other. For example, although Th1 cells promote a Th1-type inflammation, it has been proposed that Th2 cells, which secrete IL-4, protect disease development by dampening the activity of Th1 cells. Therefore, simply inhibiting Th1 but not Th2 cell recruitment could alleviate Th1-mediated disease. However, an increasing number of studies using well-defined, phenotypically committed Th1 and Th2 cells expressing identical T cell receptors does not support this hypothesis. Recently Iqbal and coworkers (12) observed that mice colonized with E. coli, producing ovalbumin, before injection of either Th1- or Th2-polarized lymphocytes (activated in vitro with the same ovalbumin), developed intestinal inflammation. In this study, both Th1 and Th2 cells induced IBD, which developed at the same rate and to equivalent severity but with a distinct pattern of inflammation. Th1-induced lesions contained predominantly lymphocyte, monocyte, and macrophage infiltrates. By contrast, in Th2-induced lesions, >40% of the infiltrating cells were eosinophils. This study showed that either effector T cell population could induce a pathogenic response to the same antigenic stimulus. Furthermore, whether the combination of Th1 and Th2 cells would decrease disease progression or severity is not known. Other studies have also shown that Th1 and Th2 cells, or their mediators, are not counterreactive. First, Th1-type colonic inflammation was shown to be exacerbated by treatment with IL-4 (4), and second, the introduction of Th1 cells into Th2 cell-induced asthma significantly increased airway inflammation (8). These observations suggest that the Th1-Th2 paradigm, which predicts that Th2 cells can suppress Th1-mediated effects and vice versa, may be more complex in IBD than initially appreciated. Regulation of T cell-mediated inflammation may require other cells.
There is increasing evidence that another lymphocyte subset is involved
in T cell homeostasis. These CD4+CD25+ T
regulatory (Treg) cells are defined by their unique profile of cytokine
production and make high levels of transforming growth factor- and
IL-10 but no IFN-
, TNF-
, IL-4, or IL-2 (7). Furthermore, experimental systems have revealed a functional
interregulation between the CD45RBhigh and
CD45RBlow CD4+ T cells. As previously
mentioned, transfer of CD45RBhigh CD4+ T cells
to SCID mice led to the development of a Th1-mediated intestinal
inflammation. Notably, cotransfer of the
CD4+CD45RBlow T cell population prevented
disease induction by the CD45RBhigh cells
(25). Annunziato and coworkers (1) recently
published that Treg cells showed poor or no proliferation in mixed
lymphocyte culture and suppressed in a dose-dependent fashion the
proliferation response to allogeneic stimulation of
CD4+CD25
T cells. In essence, these
CD4+CD25+ cells are a phenotypically and
functionally distinct population of regulatory T cells capable of
controlling inflammation via their production of IL-10 and TGF-
.
Treg cells have therefore been suggested to play a pivotal role in
intestinal homeostasis, and it is conceivable that increased
recruitment of Treg cells to sites of inflammation might ameliorate
chronic diseases such as IBD.
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TARGETING CHEMOKINES |
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Although chemokines and their receptors are considered to be
mediators of inflammation and tissue injury in inflammatory diseases, their precise role in the pathophysiology of gastrointestinal diseases
remains incompletely understood. Just as CD and UC are characterized by
a differential expression of polarized inflammatory cytokines, their T
cells are also characterized by different chemokine receptors. CD and
the mouse models that are likened to it (e.g., IL-10 knockout and IL-2
knockout) contain, in their inflammatory milieu, Th1 cells expressing
the chemokine receptors CXCR3, CCR5, and CCR7. In contrast, UC patients
and their correlative mouse models (exemplified by
TCR/
and oxazolone) contain Th2 cells that express
specific chemokine receptors (CCR4, CCR3, CCR8, and CXCR4) that differ
from those expressed by the Th1 cells (2). Treg cells also
have a particular chemokine receptor profile. They express the
chemokine receptors CCR8 and CCR4 and chemotaxis to their respective
ligands CCL22, CCL1, and CCL17 (11). Notably, CCR4 and
CCR8 are also expressed on Th2 cells, implying that further
investigation is required to better characterize these cells before we
can encourage only Treg recruitment to sites of inflammation. The
observation that both UC and CD were partly ameliorated with the
treatment of IFN-
(which promotes Treg cell proliferation) supports
the notion that Treg cells can indeed suppress intestinal inflammation
and that this, as a therapeutic approach, is worth pursuing
(26).
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CONCLUDING REMARKS |
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It is unclear whether traditional antiadhesion approaches (e.g., antiselectins and anti-integrins) will work. However, as we gain a better understanding of cellular recruitment in splanchnic organs, traditional antiadhesion therapy may become useful. Alternatively, encouraging the recruitment of Treg cells to the inflamed intestine while negatively targeting other populations of leukocytes could potentially be used in therapy to modulate immune responses in vivo. Clearly, the sooner we identify distinct adhesive differences between the effector and regulatory CD4+ T cells (for either increased subset proliferation or homing), the sooner we may be able to develop these new therapeutic strategies.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. Kubes, Dept. of Physiology and Biophysics, Univ. of Calgary, 3330 Hospital Dr. NW, Calgary, AB, Canada T2N 4N1 (E-mail: pkubes{at}ucalgary.ca).
10.1152/ajpgi.00023.2003
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Annunziato, F,
Cosmi L,
Liotta F,
Lazzeri E,
Manetti R,
Vanini V,
Romagnani P,
Maggi E,
and
Romagnani S.
Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes.
J Exp Med
196:
379-387,
2002
2.
Bonecchi, R,
Bianchi G,
Bordignon PP,
D'Ambrosio D,
Lang R,
Borsatti A,
Sozzani S,
Allavena P,
Gray PA,
Mantovani A,
and
Sinigaglia F.
Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s.
J Exp Med
187:
129-134,
1998
3.
Essani, NA,
Fisher MA,
Farhood A,
Manning AM,
Smith CW,
and
Jaeschke H.
Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure.
Hepatology
21:
1632-1639,
1995[ISI][Medline].
4.
Fort, MM,
Lesley R,
Davidson NJ,
Menon S,
Brombacher F,
Leach MW,
and
Rennick DM.
IL-4 exacerbares disease in a Th1 cell transfer model of colitis.
J Immunol
166:
2793-2800,
2001
5.
Fox-Robichaud, A,
and
Kubes P.
Molecular mechanisms of TNF-stimulated leukocyte recruitment into the hepatic circulation.
Hepatology
31:
1123-1127,
2000[ISI][Medline].
6.
Granger, DN,
and
Parks DA.
Role of oxygen radicals in the pathogenesis of intestinal ischemia.
Physiologist
26:
159-164,
1983[Medline].
7.
Groux, H,
Rouleau M,
Bacchetta R,
and
Roncarolo MG.
T-cell subsets and their cytokine profiles in transplantation and tolerance.
Ann NY Acad Sci
770:
141-148,
1995[ISI][Medline].
8.
Hansen, G,
Berry G,
DeKruyff RH,
and
Umetsu DT.
Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation.
J Clin Invest
103:
175-183,
1999
9.
Hernandez, LA,
Grisham MB,
Twohig B,
Arfors KE,
Harlan JM,
and
Granger DN.
Role of neutrophils in ischemia-reperfusion-induced microvascular injury.
Am J Physiol Heart Circ Physiol
253:
H699-H703,
1987
10.
Horie, Y,
Wolf R,
Anderson DC,
and
Granger DN.
Hepatic leukostasis and hypoxic stress in adhesion molecule-deficient mice after gut ischemia/reperfusion.
J Clin Invest
99:
781-788,
1997
11.
Iellem, A,
Mariani M,
Lang R,
Recalde H,
Panina-Bordignon P,
Sinigaglia F,
and
D'Ambrosio D.
Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells.
J Exp Med
194:
847-853,
2001
12.
Iqbal, N,
Oliver JR,
Wagner FH,
Lazenby AS,
Elson CO,
and
Weaver CT.
T helper 1 and T helper 2 cells are pathogenic in an antigen-specific model of colitis.
J Exp Med
195:
71-84,
2002
13.
Jaeschke, H.
Cellular adhesion molecules: regulation and functional significance in the pathogenesis of liver diseases.
Am J Physiol Gastrointest Liver Physiol
273:
G602-G611,
1997
14.
Jaeschke, H,
Farhood A,
Bautista AP,
Spolarics Z,
Spitzer JJ,
and
Smith CW.
Functional inactivation of neutrophils with a Mac-1 (CD11b/CD18) monoclonal antibody protects against ischemia-reperfusion injury in rat liver.
Hepatology
17:
915-923,
1993[ISI][Medline].
15.
Kubes, P,
Hunter JA,
and
Granger DN.
Ischemia/reperfusion-induced feline intestinal dysfunction: importance of granulocyte recruitment.
Gastroenterology
103:
807-812,
1992[ISI][Medline].
16.
Kubes, P,
Jutila M,
and
Payne D.
Therapeutic potential of inhibiting leukocyte rolling in ischemia/reperfusion.
J Clin Invest
95:
2510-2519,
1995[ISI][Medline].
17.
Kubes, P,
Payne D,
and
Woodman RC.
Molecular mechanisms of leukocyte recruitment in postischemic liver microcirculation.
Am J Physiol Gastrointest Liver Physiol
283:
G139-G147,
2002
18.
Kurose, I,
Anderson DC,
Miyasaka M,
Tamatani T,
Paulson JC,
Todd RF,
Rusche JR,
and
Granger DN.
Molecular determinants of reperfusion-induced leukocyte adhesion and vascular protein leakage.
Circ Res
74:
336-343,
1994[Abstract].
19.
Kurtel, H,
Zhang S,
Tso P,
and
Granger DN.
Granulocyte accumulation in postischemic intestine: role of leukocyte adhesion glycoprotein CD11/CD18.
Am J Physiol Gastrointest Liver Physiol
262:
G878-G882,
1992
20.
Li, Y,
Muruve DA,
Collins RG,
Lee SS,
and
Kubes P.
The role of selectins and integrins in adenovirus vector-induced neutrophil recruitment to the liver.
Eur J Immunol
32:
3443-3452,
2002[ISI][Medline].
21.
McNab, G,
Reeves JL,
Salmi M,
Hubscher S,
Jalkanen S,
and
Adams DH.
Vascular adhesion protein 1 mediates binding of T cells to human hepatic endothelium.
Gastroenterology
110:
522-528,
1996[ISI][Medline].
22.
Panes, J,
and
Granger DN.
Leukocyte-endothelial cell interactions: molecular mechanisms and implications in gastrointestinal disease.
Gastroenterology
114:
1066-1090,
1998[ISI][Medline].
23.
Picarella, D,
Hurlbut P,
Rottman J,
Shi X,
Butcher E,
and
Ringler DJ.
Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells.
J Immunol
158:
2099-2106,
1997[Abstract].
24.
Podolsky, DK,
Lobb R,
King N,
Benjamin CD,
Pepinsky B,
Sehgal P,
and
deBeaumont M.
Attenuation of colitis in the cotton-top tamarin by anti-4 integrin monoclonal antibody.
J Clin Invest
92:
372-380,
1993[ISI][Medline].
25.
Powrie, F,
Leach MW,
Mauze S,
Caddle LB,
and
Coffman RL.
Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice.
Int Immunol
5:
1461-1471,
1993[Abstract].
26.
Ruther, U,
Nunnensiek C,
Muller HA,
Bader H,
May U,
and
Jipp P.
Interferon alpha (IFN alpha 2a) therapy for herpes virus-associated inflammatory bowel disease (ulcerative colitis and Crohn's disease).
Hepatogastroenterology
45:
691-699,
1998[ISI][Medline].
27.
Springer, TA.
Traffic signals of lymphocyte recirculation and leukocyte emigration: the multistep paradigm.
Cell
76:
301-314,
1994[ISI][Medline].
28.
Steinhoff, G,
Behrend M,
Schrader B,
Duijvestijn AM,
and
Wonigeit K.
Expression patterns of leukocyte adhesion ligand molecules on human liver endothelia. Lack of ELAM-1 and CD52 inducibility on sinusoidal endothelia and distinct distribution of VCAM-1, ICAM-1, ICAM-2, and LFA-3.
Am J Pathol
142:
481-488,
1993[Abstract].
29.
Strober, W,
Fuss IJ,
and
Blumberg RS.
The immunology of mucosal models of inflammation.
Ann Rev Immunol
20:
495-549,
2002[ISI][Medline].
30.
Sundberg, JP,
Elson CO,
Bedigian H,
and
Birkenmeier EH.
Spontaneous, heritable colitis in a new substrain of C3H/HeJ mice.
Gastroenterology
107:
1726-1735,
1994[ISI][Medline].
31.
Wong, J,
Johnston B,
Lee SS,
Bullard DC,
Smith CW,
Beaudet AL,
and
Kubes P.
A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature.
J Clin Invest
99:
2782-2790,
1997