- Email: [email protected]
Lymphocyte homing to sites of inflammation
lymphocyte
homing
to sites of inflammation
Thomas lzaak Walton
Killam Children’s
The identification receptors, involved
the in
understanding endothelial receptors of
by monoclonal integrins,
cells
Halifax, Nova Scotia, Canada
antibodies
and gene cloning of the major
molecular
in the
molecules,
past
Opinion
few
antigen-l
These
our
lymphocytes
and
antibodies
and
soluble
the in vivo expression
of which
in Immunology
in various
types
of
1992, 4:287-293
ducible on a wide variety of cells with cytokines. ICAMis constitutively expressed on ECs and hematopoietic is cells, but not on other cells [6,7-l. Its expression not altered by cytokines [i’**,8* 1. Studies have suggested but there is a third ligand for LFA-1, and a glycoprotein of 124 kD, ICAM3, has been identified recently on leukocytes, although it is not found on ECs [9]. Thus, LFA-1 on lymphijqtes binds to ICAM- and possibly low levels of ICAM- on unstimulated ECs and, after cytokine stimulation, to the increased ICAM- on activated ECs. Anti-LFA-I inhibits a portion (4&60%) of the adhesion of lymphocytes to normal unstimulated EC and, to a smaller degree, their adhesion to activated ECs [ lO,ll].
,. Very
late activ&n
antigen-4
’
pattiway
Treatment of HUVECs with TNF-a, IL-l, or IL-4 induces the production of the vascular cell adhesion molecule (VCAM)-1 on the surface of the HUVECs [2,12-141. VCAMI is a 110 kD glycoprotein that also belongs to the Ig superfamily [15,16*-,I?]. The major form on both TNFcland IL1 stimulated HUVECs has seven domains, but there is an additional shorter form with six domains generated by alternative splicing to exclude exon 5 [16**,18-1. The role of this short VCAM is unknown. The & integrin qpl (CD49d/CD29), also known as the very late activation antigen (VLA)-4, mediates lymphocyte adhesion to VCAM-1 [ 13,191. m-4 is expressed on virtually all lymphocytes, monocytes, and eosinophils. It has been shown to bind to immobilized soluble recombinant VCAM-1 [ 201 and to the CS-1 peptide of fibronectin [ 211. Anti-VLA4 antibody inhibits adhesion of human and rat lymphocytes and lymphoblasts to cytokine activated ECs [13,19,22*,23*“]. VLA4 does not mediate resting lym
cell adhesion
activation
between
molecules,
advanced
is being recognized.
pathways function
has
for studying
importance
One of the first steps in the migration of lymphocytes out of the blood is their adhesion to endothelial cells (ECs) in the post-capillary venule. The adhesion of lymphocytes to cultured human umbilical vein endothelial cells (HUVECs) or ECs from other species has been used to model this process in vitro. Some blood lymphocytes adhere B, unstimulated ECs. This adhesion may be similar to the. binding of lymphocytes to normal ECs that is thought to precede migration of lymphocytes through normal blood vessels in the skin and other tissues. Gram-negative bacterial lipopolysaccharide (LPS) and the cytokines, tumor necrosis factor (TNF), interleukin (IL)-1, interferon (IFN)-y and IL-4 activate ECs and enhance lymphocyte adhesion [l-4]. The adhesion molecules and how they pertain to lymphocyte migration in inflammation will be the focus of this review.
The lymphocyte
adhesion
migration
years.
Introduction
Lymphocyte-endothelial
and
as reagents
the
endothelial
interactions
inflammation
Current
and
adhesion
are being applied
adhesion
Hospital,
selectins
lymphocyte of the
B. lssekutz
pathway
Lymphocytes have integrin molecules on their surface that mediate much of their adhesion to ECs. The p2 integrin, CDlla/CDlS, or lymphocyte function-activation antigen (LFA)-1, can bind to the amino-terminal domain of the intercellular adhesion molecules (ICAM)- 1 (CD54), an 85-l 10 kD glycoprotein with five tandem Ig-like domains [5]. LFA-1 can also bind to ICAM-1, a 60kD glycoprotein with two Ig domains that have homology with the two amino-terminal domains of ICAM-1. ICAM- is expressed at low levels on unstimulated ECs and is in-
Abbreviations CM-cutaneous lymphocyte-associated antigen; DTH-delayed type hypersensitivity; EC-endothelial cell; ELAM--endothelial leukocyte adhesion molecule; HW-high endothelial venule; HUVEC-human umbilical vein endothelial ICAM-intercellular
adhesion
LP!-lipopolysaccharide;
molecule;
IFN-interferon;
sle -sialyl-LewiP;
IL-interleukin;
TNF-tumor W-very
@ Current
necrosis factor;
late activation
Biology
LFA-lymphocytic VCAM-vascular
function-associated cell adhesion
cell;
antigen;
molecule;
antigen.
Ltd ISSN 0952-7915
287
288
lymphocyte
activation
and effector
functions
phocyte adhesion to unstimulated ECs, but 5&60’% of the increased adhesion observed after stimulation of ECs with IL-2, TNI-a, IFN-y, and LPS is mediated by VLA4. IL-4 stimulated adhesion occurs entirely through VCAMI [3,4]. VIA4 in combination with LFA-1 appears to account for most of the integrin-mediated lymphocyte adhesion to ECs observed in vitro [ 23**,24**]. Another integrin closely related to VLA-4 (c1,&) is CL&~, also known as lymphocyte Peyer’s patch adhe(LPAM1) [ 251. This integrin mediates sion molecule-l lymphocyte adhesion to Peyer’s patch high endothelial venules (HEVS) in the mouse. Recently, a human integrin p7 was cloned and it is likely that it is the homologue of BP in the mouse and can associate with a4 [ 26,271. a& may mediate adhesive interactions with activated ECs in some tissues.
The selectin
then appears to be stabilized and enhanced by the p2 integrins of the neutrophil [37]. With regard to lymphocytes, it was shown that resting, unstimulated T lymphocytes also bind to E-selectin on cytokine-activated HUVECs [23**,38] and immobilized soluble E-selectin, and that the adherent T cells are mainly CD4+ memory cells [ 230*,39*]. Elegant studies by Picker et al. [40,41*0] have shown that most T lymphocytes found in chronically inflamed skin, but not in other tissues, react with the monoclonal antibody HECA-452, which has been designated as reacting with a cutaneous lymphocyte-associated antigen (CL%). These CLA+ T cells are also memory cells and bind to E-selectin. Berg et al [42**] have recently shown that HECA-452 inhibits CLA+ T-cell adhesion to E-selectin and that E-selectin binds CLA, which may be a modified sLeX, possibly sialyl-sLex. As Emselectin is expressed on ECs in many chronic cutaneous inflammatory sites, it is likely that it mediates one of the steps in T-cell *] migration to these tissues [ 41 ??
pathways
Another family of proteins mediating leukocyte EC adhesion are the selectins, which consist of three Ca2+-dependent lectins [ 281: L-selectin found on leukocytes and formerly known as LECAMI, LAM-l, peripheral lymphnode homing receptor, and the Mel-14 or Leu-8 antigen; E-selectin or endothelial leukocyte adhesion molecule (ELAM)-1 found on activated ECs; and P-selectin or GMP-140, CD62, or PADGEM, found on platelets and in ECs. The selectins each consist of an outermost lectin domain followed by an epidermal growth factor domain and a variable number of short consensus repeats found in complement-binding proteins. L-selectin binds to sialylated glycoproteins of which three found on lymph node HEV have been described recently, including Sgpso, Sgp’o [29”] and a protein of 105 kD [30]. L-selectin on lym phocytes was thought to be exclusively a lymph node homing receptor. Recently, however, it was shown that L-selectin contributed to lymphocyte adhesion to activated HUVECs when measured under non-static condi tions, i.e. when the EC monolayer was rotated rather than stationary [31**]. Under rotated conditions a significant component of the adhesion was inhibited by monoclonal antibodies (mAbs) to L-selectin. As previous studies on L-selectin measured lymphocyte adhesion to frozen sections of lymph nodes that were rotated using the Stamper-Woodruff assay, one interpretation of these results is that L-selectin mediates initial lymphocyte adhesion to both HEVs and non-HEV-activated HUVECs under conditions of shear stress. Therefore, in addition to the ligands for L-selectin on HEVs, there is also a carbohydrate-containing ligand molecule for L-selectin on cytokine-activated ECs [31**]. E-selectin was discovered as an adhesion molecule for neutrophils on IL-I-activated HUVECs. It appears to have two carbohydrate ligands, sialyl-Lewisx (sLex) [ 32-341, found on neutrophils, and sialyl-lewisa [35]. Recently, Butcher and colleagues [36=] have shown that L-selectin on neutrophils is glycosylated with sLex, so that neutrophils may adhere to cytokine-activated endothelium by binding to E-selectin on the EC, in part through sLex coupled to L-selectin on the neutrophil. This initial adhesion
Effect of lymphocyte
activation
Three decades ago it was observed that activated lymphocytes homed from the blood preferentially to inflammatory sites. The basis of this migration is beginning to be elucidated. Irz vitro activation of lymphocytes enhances lymphocyte adhesion: anti-CD3 activation of T cells transiently enhances the afhnity of LFA-1 for immobilized ICAM- [43]; and T-lymphocyte activation through CD3 or the IL-2 receptor increases T-cell adhesion to ECs and is mediated by LFA-1 and independent of VLA-4 [44-l. Stimulation of lymphocytes with phorbol esters, calcium ionophores and mitogens such as concanavalin A rapidly increases lymphocyte-EC adhesion, and is inhibitable by anti-VLA4 and anti-LFA-1 [ 10,11,24**,44*]. The enhanced adhesion of these in vitro activated lymphocytes through the VIA4 and LFA-1 pathways is not the result of an increase in the expression of these molecules, but appears to be controlled by an enhanced affinity of these adhesion receptors for EC ligands [44*,45]. Phosphorylation of the cytoplasmic domain of the p chain of LFA-1 is involved in this increased affinity [46*,47*]. Spertini et al. [48*] have also shown that lymphocyte activation transiently increases the alhnity of L-selectin for a carbohydrate ligand, after which L-selectin is rapidly shed from the cell surface. In addition to the increased adhesion after in vitro T-cell activation, it was demonstrated recently that in vivo during an immune response there is an increase in the ability of lymph node T cells to bind to ECs [49]. These adher: ent T cells are large lymphoblasts that have an increased expression of VLA4 and can be inhibited from binding by anti-VI&4, confirming that in viva activation enhances the VLA4 adhesion pathway. Similarly, T cells recovered from rheumatoid synovium have an up-regulated expression of VIA-4 and an enhanced ability to bind to the CS-1 peptide of Iibronectin and to synovial ECs 150,511. After antigen activation a proportion of lymphoblasts may undergo differentiation into ‘memory’ T cells, which have
lymphocyte
an enhanced expression of several adhesion molecules, including CD44, CD58, and VIA-4 (CD49d/CD29). These memory T cells are more adherent to normal and cy tokine stimulated HUVECs than naive T cells [24**,52]. Adhesion of the T-helper memory cells is mediated by VLA-&VCAM-1, LFA-l-ICAh4 and a ligand on the lym phocyte interacting with E-selectin. Naive T cells do not bind to E-se&in, nor do they utilize the VLA4 or VCAM pathways. Their adhesion appears mediated only by LFAI-ICAM [ 24**] Thus, T-cell activation and differentiation involves enhanced expression and affinity of the integrin receptors that mediate binding to ECs. One likely effect of this would be to allow these activated and memory T cells to bind more efficiently to ECs in areas of in&n-mation than naive or unactivated lymphocytes. This may be important, as the memory subset of T cells is responsible for the recall response to antigen and for most of the cytokine production by antigen-stimulated T cells,
Adhesion
molecule expression
in vivo
Lymphocytic infiltrates and adhesion molecule expression in inflammatory sites have been extensively investigated. Chronic inflammatory lesions have usually shown’s predominance of T memory cells. The preferential accu-’ mulation of these cells in inflammatory sites, such as delayed type hypersensitivity (DTH) reactions and rheumatoid synovium, is thought to be the result of their selective migration out of the blood into these tissues. This conclusion is supported by recent studies showing the early arrival of these cells in a cutaneous blister model [53]. Histological studies have demonstrated the presence of ICAMl, VCAMl, and E-selectin in many inflammatory lesions, of which DTH is a good example. E-selectin is rapidly up-regulated on ECs in DTH reactions, probably as a result of TNF release by tissue mast cells [54=,55]. Its expression is restricted to ECs and is present on the endothelium for up to 1 week after initiation of the DTH reaction [56,57*]. VCAM1, which is found minimally on normal ECs, increases more slowly during DTH and also appears on a variety of non-endothelial cells [57*]. Expression of ICAMl on ECs occurs at low levels in normal skin but increases, especially in keratinocytes, in DTH [57*,58]. All three of these adhesion molecules, ICAM-1, VCAM-1 and E-selectin have been observed on the syn ovium in rheumatoid arthritis [59,60*], and ICAM- is present in kidney allografts [61,62] and on brain ECs in encephalomyelitis 163,641, as well as other inflammatory sites.
Measurement
of lymphocyte
migration
In vitro
The cytokines IFN-)I and TNF-ol, and to a lesser extent IFN-a and TNI-j3, not only enhance lymphocyte adhe-
homing to sites of inflammation
lssekutz
sion to ECs in vitro, but also recruit lymphocytes into the skin after intradermal injection [65,66]. Several recent studies have presented models for examining the chemotaxis of T cells across ECs in vitro in order to evaluate the effects of adhesion molecules and cytokines. May and Ager [67*], using rat ECs from lymph node HEVs, found IFN-y and TNI-ol to be potent stimulators of T-cell transendothelial migration but
In vivo Another approach to investigating the role of adhesion molecules on lymphocyte homing to sites of inflammation has been the use of neutralizing antibodies, soluble receptors and soluble peptide ligands to block or compete with the adhesion molecules. Antibody to L-selectin inhibits lymphocyte homing to peripheral lymph nodes and a,soluble form of L-selectin blocks neutrophil accumulation in the inllamed peritoneum in mice [70**]. Anti-LFA-1 in the mouse inhibits part of the lymphocyte homing to lymph nodes and in recent studies in the rat was found to be a very potent inhibitor of lymphocyte migration to cutaneous inflammatory sites and sites of cytokine injection (TB Issekutz, abstract 1144, FASEB J 1992). Anti-LFA-1 and anti-RAM-1 treatment was also effective at inhibiting lymphocyte infiltration of kidney and cardiac allografts and prolonged’graft survival [ 61,7I**]. .! , Recent reports have also demonstrated that VU-4 is important for lymphocyte extravasation in inflammation. Anti-VLA-4 treatment of rats inhibited the migration of T lymphocytes and lymphoblasts from the blood to cutaneous DTH, LPS-induced inflammation, and to intradermal sites injected with the cytokines IFN-y, IFN-a, and TNF-cl [72**]. The inhibition was greatest for lym phoblasts which, as noted earlier, have an enhanced expression of VLA-4. Anti-VIA-4 also strongly inhibited migration to gut-associated lymphoid tissues, which are chronically exposed to intestinal antigens and are likely to be stimulated by cytokines. Furthermore, peptides derived from fibronectin that also bind to CL& can inhibit the transfer of contact hypersensitivity by sensitized T cells in the mouse [73**]. Anti-VIA4 also partially inhibits the migration of lymphocytes to the inflamed joints of rats with adjuvant arthritis [74*].
Conclusion This brief review presents some of the new information on lymphocyte migration to sites of inflammation. Although our understanding has improved considerably
289
BO
lymphocyte --_ _-_
activation and effector functions
i:: rhc past few years it is apparent that this migranon :s a complex and highly regulated process. There is .,till little known about many of its aspects, including the transendothelial movement of the lymphocyte following adhesion, the tissue specificity of migration, and the response of the endothelium in different tisjlles to cytokines and extravascular cells. Nevertheless, Improvements in cloning technology, transgenic models, ;~r?d in vitro culture systems will continue to insure rapid progress, and it is clear that intervention in this area has great +hera.peutic potential.
References and recommended ._._
10.
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12.
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RICE
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3.
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4.
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GIMBRONE
17. ..
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19.
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20.
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21.
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22. .
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NORTAMO P,
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8. .
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lymphocyte
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31. ..
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PHILLIPSML, NUDEIMAN E, GAETA FCA. PEREZ M, SINGHAI. AK HAKOMOR~ B, PAULSONJC: ELAM-1 Mediates Cell Adhesion by Recognition of a Carbohydrate Ligand, Sialyl-LeX. Science 1990, 250:113&1132.
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35.
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-_
Issekutz ._-..
PICKER LJ, WARN~CK RA, BURNS AR, D~ERSZHUK CM, BERG EL, EC: The Neutrophil Selectin LECAM-1 Presents Carbohydrate Ligands to the Vascular Selectins ELAM-I and GMP-140. Cell 1991, 66:921-933. This elegant study demonstrates the somewhat unexpected finding that L-selectin on neutrophils is decorated with sialyl~L@, which is tf+e Lgand for F-selectin and plays an important role in neutrophil adhesion tc both E-selectin and P-selectin, possibly because of its location on thr microvilli of these cells. 36. .
BUTCHER
37.
Lo SK, IEE S, RAMOS RA, UIHB R, ROSA M, CHI-ROSSC G, WRIGHT SD: Endothelial-Leukocyte Adhesion Molecule 1 Stimulates the Adhesive Activity of Leukocyte Integrm CR3 (CDllb/CDl& Mac-l, CL,,,&) on Human Neutrophils. J EqD Med 1991, 173:1493-1500.
38.
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L~BB RR, CHI-RUSSOG, LEONEDR, ROSAMD, BIXLERS, NEWMAI~ BM, LUHOWSKYJS, BENJAMIN CD, Douc~s IG, GOE!Z SE. HESSION C, CHOW EP: Expression and Functional Chat acterization of a Soluble Form of Endothelial-Leukoc- L.. Adhesion Molecule 1. .J Immunol 1991, 147:124--129. Production of a soluble form of E-selectin is described and it is dem 1; strated that lymphocytes and especially CD4+ T memon; cells adh+to immobilized E-selectin.
39. .
40.
LA:
29. ..
to sites of inflammation
and Sialyl LeX is Recognized by the Endothelial CeU Leukocyte Adhesion Molecule ELAM-1. .J Biol Cbem 1991. 266:14 869-14 872.
This paper shows that VLA-4 mediates much of the lymphocyte adherence to cytokine stimulated rat ECs, that lymphocytes from an inflammatoty site express increased levels of m-4, and that rat VLA-4 binds to human VCAMI on HUV?Xs. 23. ..
homing
LJ, MICHIE SA, Roar IS, BUTCHER EC: A Unique P11i notype of Skin-associated Lymphocytes in Humans: Preferential Expression of the HECA-452 Epitope by Benign and Malignant T Cells at Cutaneous Sites. Am J Putbol lY90. 136:1053-1068.
,%CKER
PICKER LJ, KISHIMOTOTK, SMITH CW, WARNOCKRA, BUTCHER EC: ELAM-1 is an Adhesion Molecule for Skin-homing T Cells. Nature 1991, 349~796799. This interesting report demonstrates that the lymphocytes that bmd 11; E-selectin react with monoclonal antibodyHECAz452, which recogruscs an antigen expressed by T cells found in’inflamed skin. Furthermore, high levels of E~selectih are expressed in chronically inflamed cutaneous sites in preference to other intlammatory tissues. It is suggested that these T cells may selectively migrate to inflamed skin. because of this E-selectin-positive endothelium. 41. ..
42. ..
BERC; EL, YO~HINO T, Ro’rr IS, ROBINSON MK, WARN~CK RA, KISHIMOTOTK, PICKERLJ, BIJTCHEREC: The Cutaneous Lymphocyte Antigen is a Skin Lymphocyte Homing Receptor for the Vascular Lectin EndotheIiaI Cell-Leukocyte Adhesion Molecule 1. J E$J Med 1991, 174:1461-1466. An elegant demonstration that the carbohydrate antigen recognized by the HECA~452 mAb that reacts with T cells found in inflamed skin binds to E-selectin. It is suggested that CL4 may be a modified form of sL@ This report helps explain why CIA+ cells infiltrate inflamed skin displaying E-selectin expressing endothelium. 43.
DUSTIN
ML,
SPRINGER
Transiently Stimulates 1989, 341:61-24.
TA: T Cell Adhesiveness
Receptor Through
Cross-linking LFA-1. Nature
Effect of T CeU Activation on Lymphocyte Endothelial Cell Adherence and the Role of WA-4 in the Rat. Cell Immunol 1992, 140:420-431. T~ceUactivation by mitogens rapidly induces lymphocyte adhesion to rat ECs through VLA-4 and LFA~l, while activation through the CD3 or IL-2 receptors seems to stimulate increased adhesion through LFA-1 independent of U-4. Furthermore, increased VLA4-mediated adhesion occurs in the absence of increased VL&4 expression. 44. .
WYSOCKI J, ISSEKI!TZ TB:
45.
SHIMIZI
Y, VAN &ENTER GA, HORGAN KJ, !%AW S: Regulated Expression and Binding of Three VLA (BI) Integrin Receptors on T Cells. Nature 1990, 345:25&254.
291
292
LvmDhocvte activation and effector functions 46. .
HIBBS ML, JAKES S, STACKER SA, WAUACE RW, SPRINGER TA: The Cytoplasmic Domain of the Integrin Lymphocyte Function-associated Antigen 1 p Subunit: Sites Required for Binding to Intercellular Adhesion Molecule 1 and the Phorbol Ester-stimulated Phosphorylation Site. J Eap Med 1991, 1741227-1238. This paper identifies the sites in the p chain of LFA-1 that are phosphorylated and describes how this influences receptor binding to ICAMI. 47. .
VALMUL, AUTEROM, SILJANDER P, PATARROYOM, GAHMBERGCG: Phosphorylation of the P-subunit of CDll/CD18 Integrins by Protein Kinase C Correlates with Leukocyte Adhesion. Eur J Immunol 1991, 21:2857-2862. Phosphorylation of the p chain of LFA~l is associated with enhanced adhesion through LFA-I. This may contribute to the increased adhesion of activated leukocytes. 48. .
SPERTINI0, KANSASGS, MUNROJM, GIFFINJD, TEDDERTF: Regulation of Leukocyte Migration by Activation of the Leukocyte Adhesion Molecule-l (LAM-l) Selectin. Nature 1991, 349691494. The affinity of L-selectin (LAM-1 ) for a carbohydrate-based ligand can be rapidly upregulated on both lymphocytes and neutrophils, but requires leukocyte lineage-specific stimuli. This lineage specific enhancement of L-selectin affinity may contribute to the differences in migration to inflammatory sites by these cells.
with particular emphasis and cell distribution. 58.
on the differences
in kinetics of expression
LEWISRE, BUCHSBAUMM, WHITAKERD, MUWHY GF: Intercellular Adhesion Molecule Expression in the Evolving Human Cutaneous Delayed Hypersensitivity Reaction. J Invest Dermat01 1989, 93672477.
KOCH AE, BURROWSJC, HAINES GK, CARLOSTM, HARLANJM, LEIBOVICHSJ: hnmunolocalization of Endothelial and Leukocyte Adhesion Molecules in Human Rheumatoid and Osteoarthritic Synovial Tissues. Lab Invest 1991, 64313320. The expression of the principle endothelial adhesion molecules for leukocytes, namely E-selectin, ICAM- and VCAM-1, is described in two common types of arthritis. 59. .
RICE GE, MUNRO JM, CORLESS C, BEV~IACQUAMP: Vascular and Nonvascular Expression of INCAM-110: a Target for Mononuclear Leukocyte Adhesion in Normal and Inflamed Human Tissues. Am J Pathl 1991, 138~385-292. One of the first descriptions of the tissue expression of VCAMl, also known as INCAM110. 60. .
61.
COSIMI AB, CONTI D, DELMONICO FL, PREFFER Fl, WEE S, ROTHLEXN R, FAANESR, COL~IN RB: In Vivo Effects of Monoclonal Antibody of ICAM- (CD54) in Nonhuman Primates with Renal Allografts. J Immunol 1990, 144:4604-4612.
62.
KANAGAWAK, ISHIKURAH, T AKAHASHIC, TAMATANIT, MNASAKA M, TOGASHI M, KOYANAGI T, YOSHIKI T: Identification of ICAM-l-positive Cells in the Nongrafted and Transplanted Rat Kidney - an Immunohistochemical and Ultrastructural Study. Transplantation 1991, 52:1057-1062.
49.
ISSEKUTZTB: Effect of Antigen Challenge on Lymph Node Lymphocyte Adhesion to Vascular Endothelial Cells and the Role of VLA-4 in the Rat. Cell Immunol 1991, 138:30@312.
50.
IAFF~N A, GARCIAVICUNAR, HIJMEXL~A, POSTIGO AA, CORBI AL, DE LWD&XIRI MO, SANCHEZ-MADRID F: Upregulated Expression and Function of VLA-4 Fibronectin Receptors on Human Activated T Cells in Rheumatoid Arthritis. J Clin Invest 1991, 88:546552.
63.
VAN DINTHER-JANSSEN ACHM, HORST E, KOOPMANG, NEWMANN W, SCHEPER RJ, MEIJER CJLM, PAIS ST: The VIA-4NCAM-1 Pathway is Involved in Lymphocyte Adhesion to EnJ Immunol 1991, dothelium in Rheumatoid Synovium. 147:4207-4210.
O’NEIL JK, BUTIXR C, BAKER D, GSCHMEISSNERSE, KRAALG, B~JTCHEREC, TURK JL: Expression of Vascular Addressins and ICAM- by Endothelial Cells in the Spinal Cord During Chronic Relapsing Experimental Allergic Encephalomyelitis in the Biozzi AB/H Mouse. Immunolog), 1991, 72:52&525.
64.
PITZALISC, KINGSLEY G, HASKARDD, PANAYIG: The Preferential Accumulation of Helper-inducer T Lymphocytes in Inflammatory Lesions: Evidence for Regulation by Selective Endothelial and Homotypic Adhesion. Eur J Immunol 1988, 18:1397-1402.
FABRY2, WALDSCHMIDTMM, HENDRICKSOND, KEINERJ, LOVEHOMAN L, TAKEI F, HAR’~ MN: Adhesion Molecules on Murine Brain Microvascular Endothelial Cells: Expression and Regulation of ICAMand Lgp 55. J Neuroimmunol 1992, 36:1-11.
65.
ISSEKUTZTB, STOLTZ JM, V.D. MEIDE P: Lymphocyte Recruitment in Delayed-type Hypersensitivity. The Role of Gammainterferon. J Immunol 1988, 140:298+2993.
66.
ISSEKUTZTB, STOLTZ JM: Stimulation tion by Endotoxin Tumor Necrosis Cell Immunol 1989, 120:16%173.
51.
52.
53.
PITZALISC, KINGSLEYGH, COVELLIM, !dELICONI R, MARKEY A, PANAYI GS: Selective Migration of the Human Helper-inducer Memory T Cell Subset: Confirmation by In Vivo Cellular Kinetic Studies. Eur J Immunol 1991, 21~369376.
WALDORFHA, WALSHLJ, SCHECHTERNM, MURXY GF: Early Cellular Events in Evolving Cutaneous Delayed Hypersensitivity in Humans. Am J Path01 1991, 138:477-486. This report describes the histological changes in E-selectin and ICAW 1 expression in evolving DTH and the relationship of these adhesion molecules to mast cells and T memory cells in the reactions. 54. .
55.
56.
WAISH LJ, TR~NCHIERIG, WALIXRF HA, WHITAKERD, MURPHY GF: Human Dermal Mast Cells Contain and Release Tumor Necrosis Factor a, which Induces Endothelial Leukocyte Adhesion Molecule 1. Proc Nat1 Acad Sci USA 1991, 88:422W224. COTRAN RS, GI~RONE MA JR, BEV~LACQUA MP, MENDRICKDL, POBER JS: Induction and Detection of a Human Endothelial Activation Antigen In Vivo. J Eap Med 1986, 164661-666.
NORIUS P, POSTON RN, THOMAS DS, THORNHILL M, HAWK J, HAXARD Do: The Expression of Endothelial Leukocyte Adhesion Molecule- 1 (ELAM- l), Intercellular Adhesion Molecule-l (ICAM-l), and Vascular Cell Adhesion Molecule1 (VCAM-1) in Experimental Cutaneous Inflammation: a Comparison of Ultraviolet B Erythema and Delayed Hypersensitivity. J Invest Dermatol 1991, 96~763-770. A systematic description of the changes in E-selectin, ICAMI, and VCAM1 expression in two types of cutaneous inflammatory reactions 57. .
of Lymphocyte MigraFactor, and Interferon.
MAY MJ, AGER A: ICAM- 1-independent Lymphocyte Transmigration Across High Endothellum: Differential Up-regulation by Interferon-y, Tumor Necrosis FActor-a and Interleukin lp. Eur J Immunol 1992, 22:21?226. This report shows that IFN-I and TFN-a, but not IL~F,stimulate lymphocyte transendothelial migration across rat cultured HEV cells and that the lymphocyte adhesion was independent of ICAM- but inhibitable by anti-p, integrin and VLA-4.binding peptldes.
67. .
68.
KAVANALJGH AF, LIGHTFOOT E, LIPSKYPE, OPPENHEIMER~MARKS
N: Role of CDll/CD18 in Adhesion and Transendothelial Migration of T Cells: Analysis Utilizing CDlS-deficient . Cell Clones. J Immunol 1991, 146:41494156.
T
OPPENHEIMER-MARKS N, DAVISLS, BOGLJEDT, RAMBERG J, LIPSK~ PE: Differential Utilization of ICAM- and VCAM-1 During the Adhesion and Transendothelial Migration of Human T Lymphocytes. J Immunol 1991, 147:2913-2921. An interesting study showing that the VLA-&VCAM adhesion pathway, and to a lesser extent the LFA-l-ICAM pathway, mediated T~cell adhesion to IL-l-stimulated HUVEC. The former did not function in transendothellal migration but ICAM- played a major role and was strategically located to function in this migration. 69. ..
70. ..
WATSON SR, FENNIE C, LANKYLA: Neutrophll Influx into an Inflammatory Site Inhibited by a Soluble Homing Receptor-IgG Chimaera. Nature 1991, 349:164-167.
Lymphocyte
This report shows that recombinant soluble L~selectin in ziivo inhibits the migration of neutrophils into the inflamed peritoneal cavity in mice. This novel approach suggexs that soluble receptors can, under some circumstances, inhibit in tli~o leukocyte migration to inflammation. ISOBEM, YAGITAH, OKUMURAK, IHARAA: Specific Acceptance of Cardiac Allograft After Treatment with Antibodies to ICAM- and LFA-1. Scbnce 1992, 255:1125-1127. Anti-LFA-1 and anti-ICAM- each prolong cardiac allograft sutival in mice and decrease lymphocyte infiltration into the graft. Treatment with these mAbs in combination produces complete tolerance to these allografts.
71. ..
72. ..
ISSEKIITZ TB:
Inhibition of In Vito Lymphocyte Migration to Inflammation and Homing to Lymphoid Tissues by the TA2 MonoclonaI Antibody: a Likely Role for W-4 In Vito. .I lmmllnol 1991. 147:417E++184. This paper demonstrates that in t~ivo U-4 does mediate the traffic of lymphocytes out of the blood, and that blocking VIA 4 with an antis ad mAb strongly inhibits the migration of lymphocytes to cutaneous infiammato~ sites and to skin injected with cytokine. Furthermore, cq integrins appear to mediate most of the lymphocyte migration to gutassociated lymphoid tissues.
homing
to sites of inflammation
lssekutz
MEUTANIH, KLJPPER TS: Two Integrin-binding Peptides Abrogate T Cell-mediate Immune Responses In Viva Proc Natl Acad Sci (JSA 1991, 88BO72-8076. Two peptides that bind to VLA4 and VIA-5, both of which can mediate binding to fibronectin, can inhibit the transfer of contact hypersensitivity, possibly by altering T~cell migration through binding to these two integrins.
73. ..
FERGLJSON TA,
ISSiKtrIW ‘ITS, ISSEKLIT% AC: T Lymphocyte Migration to Arthritic Joints and DermaI Inflammation in the Rat: Differing Migration Patterns and the Involvement of VLA-4. Clin Immunol Immunopathol 1991, 61:436447. Anti~VLA-4 inhibits the migration of lymphocytes to arthritic joints in rat adjuvant arthritis. The importance of tissue specificity in the migration of Iymphoqws to intlammato~ sites is demonstrated.
74. .
TEi Issekutz, Department of Pediatrics, Izaak Walton Killam Children’s tlospitai, 5850 l’niversity Avenue, Ifdlifax, Nova Scotia, Canada B3J 3G9.
293
homing
to sites of inflammation
Thomas lzaak Walton
Killam Children’s
The identification receptors, involved
the in
understanding endothelial receptors of
by monoclonal integrins,
cells
Halifax, Nova Scotia, Canada
antibodies
and gene cloning of the major
molecular
in the
molecules,
past
Opinion
few
antigen-l
These
our
lymphocytes
and
antibodies
and
soluble
the in vivo expression
of which
in Immunology
in various
types
of
1992, 4:287-293
ducible on a wide variety of cells with cytokines. ICAMis constitutively expressed on ECs and hematopoietic is cells, but not on other cells [6,7-l. Its expression not altered by cytokines [i’**,8* 1. Studies have suggested but there is a third ligand for LFA-1, and a glycoprotein of 124 kD, ICAM3, has been identified recently on leukocytes, although it is not found on ECs [9]. Thus, LFA-1 on lymphijqtes binds to ICAM- and possibly low levels of ICAM- on unstimulated ECs and, after cytokine stimulation, to the increased ICAM- on activated ECs. Anti-LFA-I inhibits a portion (4&60%) of the adhesion of lymphocytes to normal unstimulated EC and, to a smaller degree, their adhesion to activated ECs [ lO,ll].
,. Very
late activ&n
antigen-4
’
pattiway
Treatment of HUVECs with TNF-a, IL-l, or IL-4 induces the production of the vascular cell adhesion molecule (VCAM)-1 on the surface of the HUVECs [2,12-141. VCAMI is a 110 kD glycoprotein that also belongs to the Ig superfamily [15,16*-,I?]. The major form on both TNFcland IL1 stimulated HUVECs has seven domains, but there is an additional shorter form with six domains generated by alternative splicing to exclude exon 5 [16**,18-1. The role of this short VCAM is unknown. The & integrin qpl (CD49d/CD29), also known as the very late activation antigen (VLA)-4, mediates lymphocyte adhesion to VCAM-1 [ 13,191. m-4 is expressed on virtually all lymphocytes, monocytes, and eosinophils. It has been shown to bind to immobilized soluble recombinant VCAM-1 [ 201 and to the CS-1 peptide of fibronectin [ 211. Anti-VLA4 antibody inhibits adhesion of human and rat lymphocytes and lymphoblasts to cytokine activated ECs [13,19,22*,23*“]. VLA4 does not mediate resting lym
cell adhesion
activation
between
molecules,
advanced
is being recognized.
pathways function
has
for studying
importance
One of the first steps in the migration of lymphocytes out of the blood is their adhesion to endothelial cells (ECs) in the post-capillary venule. The adhesion of lymphocytes to cultured human umbilical vein endothelial cells (HUVECs) or ECs from other species has been used to model this process in vitro. Some blood lymphocytes adhere B, unstimulated ECs. This adhesion may be similar to the. binding of lymphocytes to normal ECs that is thought to precede migration of lymphocytes through normal blood vessels in the skin and other tissues. Gram-negative bacterial lipopolysaccharide (LPS) and the cytokines, tumor necrosis factor (TNF), interleukin (IL)-1, interferon (IFN)-y and IL-4 activate ECs and enhance lymphocyte adhesion [l-4]. The adhesion molecules and how they pertain to lymphocyte migration in inflammation will be the focus of this review.
The lymphocyte
adhesion
migration
years.
Introduction
Lymphocyte-endothelial
and
as reagents
the
endothelial
interactions
inflammation
Current
and
adhesion
are being applied
adhesion
Hospital,
selectins
lymphocyte of the
B. lssekutz
pathway
Lymphocytes have integrin molecules on their surface that mediate much of their adhesion to ECs. The p2 integrin, CDlla/CDlS, or lymphocyte function-activation antigen (LFA)-1, can bind to the amino-terminal domain of the intercellular adhesion molecules (ICAM)- 1 (CD54), an 85-l 10 kD glycoprotein with five tandem Ig-like domains [5]. LFA-1 can also bind to ICAM-1, a 60kD glycoprotein with two Ig domains that have homology with the two amino-terminal domains of ICAM-1. ICAM- is expressed at low levels on unstimulated ECs and is in-
Abbreviations CM-cutaneous lymphocyte-associated antigen; DTH-delayed type hypersensitivity; EC-endothelial cell; ELAM--endothelial leukocyte adhesion molecule; HW-high endothelial venule; HUVEC-human umbilical vein endothelial ICAM-intercellular
adhesion
LP!-lipopolysaccharide;
molecule;
IFN-interferon;
sle -sialyl-LewiP;
IL-interleukin;
TNF-tumor W-very
@ Current
necrosis factor;
late activation
Biology
LFA-lymphocytic VCAM-vascular
function-associated cell adhesion
cell;
antigen;
molecule;
antigen.
Ltd ISSN 0952-7915
287
288
lymphocyte
activation
and effector
functions
phocyte adhesion to unstimulated ECs, but 5&60’% of the increased adhesion observed after stimulation of ECs with IL-2, TNI-a, IFN-y, and LPS is mediated by VLA4. IL-4 stimulated adhesion occurs entirely through VCAMI [3,4]. VIA4 in combination with LFA-1 appears to account for most of the integrin-mediated lymphocyte adhesion to ECs observed in vitro [ 23**,24**]. Another integrin closely related to VLA-4 (c1,&) is CL&~, also known as lymphocyte Peyer’s patch adhe(LPAM1) [ 251. This integrin mediates sion molecule-l lymphocyte adhesion to Peyer’s patch high endothelial venules (HEVS) in the mouse. Recently, a human integrin p7 was cloned and it is likely that it is the homologue of BP in the mouse and can associate with a4 [ 26,271. a& may mediate adhesive interactions with activated ECs in some tissues.
The selectin
then appears to be stabilized and enhanced by the p2 integrins of the neutrophil [37]. With regard to lymphocytes, it was shown that resting, unstimulated T lymphocytes also bind to E-selectin on cytokine-activated HUVECs [23**,38] and immobilized soluble E-selectin, and that the adherent T cells are mainly CD4+ memory cells [ 230*,39*]. Elegant studies by Picker et al. [40,41*0] have shown that most T lymphocytes found in chronically inflamed skin, but not in other tissues, react with the monoclonal antibody HECA-452, which has been designated as reacting with a cutaneous lymphocyte-associated antigen (CL%). These CLA+ T cells are also memory cells and bind to E-selectin. Berg et al [42**] have recently shown that HECA-452 inhibits CLA+ T-cell adhesion to E-selectin and that E-selectin binds CLA, which may be a modified sLeX, possibly sialyl-sLex. As Emselectin is expressed on ECs in many chronic cutaneous inflammatory sites, it is likely that it mediates one of the steps in T-cell *] migration to these tissues [ 41 ??
pathways
Another family of proteins mediating leukocyte EC adhesion are the selectins, which consist of three Ca2+-dependent lectins [ 281: L-selectin found on leukocytes and formerly known as LECAMI, LAM-l, peripheral lymphnode homing receptor, and the Mel-14 or Leu-8 antigen; E-selectin or endothelial leukocyte adhesion molecule (ELAM)-1 found on activated ECs; and P-selectin or GMP-140, CD62, or PADGEM, found on platelets and in ECs. The selectins each consist of an outermost lectin domain followed by an epidermal growth factor domain and a variable number of short consensus repeats found in complement-binding proteins. L-selectin binds to sialylated glycoproteins of which three found on lymph node HEV have been described recently, including Sgpso, Sgp’o [29”] and a protein of 105 kD [30]. L-selectin on lym phocytes was thought to be exclusively a lymph node homing receptor. Recently, however, it was shown that L-selectin contributed to lymphocyte adhesion to activated HUVECs when measured under non-static condi tions, i.e. when the EC monolayer was rotated rather than stationary [31**]. Under rotated conditions a significant component of the adhesion was inhibited by monoclonal antibodies (mAbs) to L-selectin. As previous studies on L-selectin measured lymphocyte adhesion to frozen sections of lymph nodes that were rotated using the Stamper-Woodruff assay, one interpretation of these results is that L-selectin mediates initial lymphocyte adhesion to both HEVs and non-HEV-activated HUVECs under conditions of shear stress. Therefore, in addition to the ligands for L-selectin on HEVs, there is also a carbohydrate-containing ligand molecule for L-selectin on cytokine-activated ECs [31**]. E-selectin was discovered as an adhesion molecule for neutrophils on IL-I-activated HUVECs. It appears to have two carbohydrate ligands, sialyl-Lewisx (sLex) [ 32-341, found on neutrophils, and sialyl-lewisa [35]. Recently, Butcher and colleagues [36=] have shown that L-selectin on neutrophils is glycosylated with sLex, so that neutrophils may adhere to cytokine-activated endothelium by binding to E-selectin on the EC, in part through sLex coupled to L-selectin on the neutrophil. This initial adhesion
Effect of lymphocyte
activation
Three decades ago it was observed that activated lymphocytes homed from the blood preferentially to inflammatory sites. The basis of this migration is beginning to be elucidated. Irz vitro activation of lymphocytes enhances lymphocyte adhesion: anti-CD3 activation of T cells transiently enhances the afhnity of LFA-1 for immobilized ICAM- [43]; and T-lymphocyte activation through CD3 or the IL-2 receptor increases T-cell adhesion to ECs and is mediated by LFA-1 and independent of VLA-4 [44-l. Stimulation of lymphocytes with phorbol esters, calcium ionophores and mitogens such as concanavalin A rapidly increases lymphocyte-EC adhesion, and is inhibitable by anti-VLA4 and anti-LFA-1 [ 10,11,24**,44*]. The enhanced adhesion of these in vitro activated lymphocytes through the VIA4 and LFA-1 pathways is not the result of an increase in the expression of these molecules, but appears to be controlled by an enhanced affinity of these adhesion receptors for EC ligands [44*,45]. Phosphorylation of the cytoplasmic domain of the p chain of LFA-1 is involved in this increased affinity [46*,47*]. Spertini et al. [48*] have also shown that lymphocyte activation transiently increases the alhnity of L-selectin for a carbohydrate ligand, after which L-selectin is rapidly shed from the cell surface. In addition to the increased adhesion after in vitro T-cell activation, it was demonstrated recently that in vivo during an immune response there is an increase in the ability of lymph node T cells to bind to ECs [49]. These adher: ent T cells are large lymphoblasts that have an increased expression of VLA4 and can be inhibited from binding by anti-VI&4, confirming that in viva activation enhances the VLA4 adhesion pathway. Similarly, T cells recovered from rheumatoid synovium have an up-regulated expression of VIA-4 and an enhanced ability to bind to the CS-1 peptide of Iibronectin and to synovial ECs 150,511. After antigen activation a proportion of lymphoblasts may undergo differentiation into ‘memory’ T cells, which have
lymphocyte
an enhanced expression of several adhesion molecules, including CD44, CD58, and VIA-4 (CD49d/CD29). These memory T cells are more adherent to normal and cy tokine stimulated HUVECs than naive T cells [24**,52]. Adhesion of the T-helper memory cells is mediated by VLA-&VCAM-1, LFA-l-ICAh4 and a ligand on the lym phocyte interacting with E-selectin. Naive T cells do not bind to E-se&in, nor do they utilize the VLA4 or VCAM pathways. Their adhesion appears mediated only by LFAI-ICAM [ 24**] Thus, T-cell activation and differentiation involves enhanced expression and affinity of the integrin receptors that mediate binding to ECs. One likely effect of this would be to allow these activated and memory T cells to bind more efficiently to ECs in areas of in&n-mation than naive or unactivated lymphocytes. This may be important, as the memory subset of T cells is responsible for the recall response to antigen and for most of the cytokine production by antigen-stimulated T cells,
Adhesion
molecule expression
in vivo
Lymphocytic infiltrates and adhesion molecule expression in inflammatory sites have been extensively investigated. Chronic inflammatory lesions have usually shown’s predominance of T memory cells. The preferential accu-’ mulation of these cells in inflammatory sites, such as delayed type hypersensitivity (DTH) reactions and rheumatoid synovium, is thought to be the result of their selective migration out of the blood into these tissues. This conclusion is supported by recent studies showing the early arrival of these cells in a cutaneous blister model [53]. Histological studies have demonstrated the presence of ICAMl, VCAMl, and E-selectin in many inflammatory lesions, of which DTH is a good example. E-selectin is rapidly up-regulated on ECs in DTH reactions, probably as a result of TNF release by tissue mast cells [54=,55]. Its expression is restricted to ECs and is present on the endothelium for up to 1 week after initiation of the DTH reaction [56,57*]. VCAM1, which is found minimally on normal ECs, increases more slowly during DTH and also appears on a variety of non-endothelial cells [57*]. Expression of ICAMl on ECs occurs at low levels in normal skin but increases, especially in keratinocytes, in DTH [57*,58]. All three of these adhesion molecules, ICAM-1, VCAM-1 and E-selectin have been observed on the syn ovium in rheumatoid arthritis [59,60*], and ICAM- is present in kidney allografts [61,62] and on brain ECs in encephalomyelitis 163,641, as well as other inflammatory sites.
Measurement
of lymphocyte
migration
In vitro
The cytokines IFN-)I and TNF-ol, and to a lesser extent IFN-a and TNI-j3, not only enhance lymphocyte adhe-
homing to sites of inflammation
lssekutz
sion to ECs in vitro, but also recruit lymphocytes into the skin after intradermal injection [65,66]. Several recent studies have presented models for examining the chemotaxis of T cells across ECs in vitro in order to evaluate the effects of adhesion molecules and cytokines. May and Ager [67*], using rat ECs from lymph node HEVs, found IFN-y and TNI-ol to be potent stimulators of T-cell transendothelial migration but
In vivo Another approach to investigating the role of adhesion molecules on lymphocyte homing to sites of inflammation has been the use of neutralizing antibodies, soluble receptors and soluble peptide ligands to block or compete with the adhesion molecules. Antibody to L-selectin inhibits lymphocyte homing to peripheral lymph nodes and a,soluble form of L-selectin blocks neutrophil accumulation in the inllamed peritoneum in mice [70**]. Anti-LFA-1 in the mouse inhibits part of the lymphocyte homing to lymph nodes and in recent studies in the rat was found to be a very potent inhibitor of lymphocyte migration to cutaneous inflammatory sites and sites of cytokine injection (TB Issekutz, abstract 1144, FASEB J 1992). Anti-LFA-1 and anti-RAM-1 treatment was also effective at inhibiting lymphocyte infiltration of kidney and cardiac allografts and prolonged’graft survival [ 61,7I**]. .! , Recent reports have also demonstrated that VU-4 is important for lymphocyte extravasation in inflammation. Anti-VLA-4 treatment of rats inhibited the migration of T lymphocytes and lymphoblasts from the blood to cutaneous DTH, LPS-induced inflammation, and to intradermal sites injected with the cytokines IFN-y, IFN-a, and TNF-cl [72**]. The inhibition was greatest for lym phoblasts which, as noted earlier, have an enhanced expression of VLA-4. Anti-VIA-4 also strongly inhibited migration to gut-associated lymphoid tissues, which are chronically exposed to intestinal antigens and are likely to be stimulated by cytokines. Furthermore, peptides derived from fibronectin that also bind to CL& can inhibit the transfer of contact hypersensitivity by sensitized T cells in the mouse [73**]. Anti-VIA4 also partially inhibits the migration of lymphocytes to the inflamed joints of rats with adjuvant arthritis [74*].
Conclusion This brief review presents some of the new information on lymphocyte migration to sites of inflammation. Although our understanding has improved considerably
289
BO
lymphocyte --_ _-_
activation and effector functions
i:: rhc past few years it is apparent that this migranon :s a complex and highly regulated process. There is .,till little known about many of its aspects, including the transendothelial movement of the lymphocyte following adhesion, the tissue specificity of migration, and the response of the endothelium in different tisjlles to cytokines and extravascular cells. Nevertheless, Improvements in cloning technology, transgenic models, ;~r?d in vitro culture systems will continue to insure rapid progress, and it is clear that intervention in this area has great +hera.peutic potential.
References and recommended ._._
10.
HA.%ARD D, CAVENDERD, BEATN P, SPRINGERT, ZIFF M: T Lymphocyte Adhesion to EndotheIial CeUs: Mechanisms Demonstrated by Anti-LFA-1 MonocIonaI Antibodies. J Immunol 1986, 137:2901-2906.
11.
OPPENHEIMER-MARKS N, DAMS IS, LIPSKYPE: Human T Lymphocyte Adhesion to Endothelial Cells and TransendotheIiaI Migration. J Immunol 1990, 145:14c148.
12.
CARLOS TM, SCHWARTZBR, KOVACH NL. YEE E, Ross0 M, OSBORN L, CHI~ROSSO G, NEU~MANB, LOBB R, HARLANJM: Vascular CeU Adhesion Molecule- 1 Mediates Lymphocyte Adherence to Cytokine-Activated Cultured Human Endothelial Cells. Blood 1990, 7696%970.
13.
SCHWAR~L BR, WAYNER EA, CAIUOS TM, OCHS HD, HARlAN JM: Identification of Surface Proteins Mediating Adherence of CD1 l/CDlB-Deficient Lymphoblastoid CeUs to Cultured Human Endothelium. / Clin Inwst 1990, 85:201%2022.
14.
RICE
15.
OSBORN
reading
Yqa~ 3r particular interest, published within the annual period of re I~CW,hdve been highlighted as: . of speciai interest I. of outstanding interest ~SSEKIJTZTB: Effects of Six Different Cytokines on Lymphocyte Adherence to Microvascular EndotheUum and In Viva Lymphocyte Migration in the Rat. / Immunol 1990, 144:2140-2146. 3*.
THORNHILLMH, KYANAUNG U, HASKARDDo: IL-4 Increases Human EndotheIial Cell Adhesiveness for T CeUs but not for NeutrophUs. J fmmunol 1990, 144:306&3065.
3.
M.4SINOvsKYB, URDAL D, GALlAnN W&l: IL-4 Acts Synergistically with IL-1B to Promote Lymphocyte Adhesion to Microvascular EndotheUum by Induction of Vascular CelI Adhesion Molecule-l. J Immunol 1990, 145:288&2895.
4.
THORNHILL MH, WELUCOME SM, MAHIOUZ DL, LA~WXISJRY JSS,
KYAN-ALJNGU, HASKARD DO: Tumor Necrosis Factor Combines with IL-4 or IFN-gamma to Selectively Enhance EndotheUal CeU Adhesiveness for T CelIs: the Contribution of VascuIar CeU Adhesion Molecule-l-dependent and -independent Binding Mechanisms. J Immunol 1991, 146:592-598. 5.
6.
STAUNTONDE, DUSTIN ML, ERICKSONHP, SPRINGER TA The Arrangement of the ImmunogIobuIin-like Domains of ICAM1 and the Binding Sites for LFA-1 and Rhinovirus. Cell l$@O, 61:243-251. NORTAMOP, SALCEDOR, TIMONENT, PATARROYOM, GAHMBERG
CG: A MonoclonaI Antibody to the Human Leukocyte Adhesion Intercellular Adhesion Molecule-2: Cellular Distribution and Molecular Characterization of the Antigen. J Immunol 1991, 146:253G2535. DE FOUGEROUES AR, STACKER SA, SCHwARnNG R, SPRINGER TA: Characterization of ICAM- and Evidence for a Third Counter-receptor for LFA-1. J Exp Med 1991, 174:253_257. Describes the distribution of ICAM2, which mainly includes lymphocytes, monocytes and endothelial cells,, and demonstrates that ICAM2 expression is not upregulated by TNF or LPS, and that all of the LFA~l dependent lymphocyte adhesion can be accounted for by ICAM- 1 and KXV-2. 7. ..
9.
DE FOUGEROLLESAR, SPRINGER TA: Intercellular Adhesion Molecule 3, a Third Adhesion Counter-receptor for Lymphocyte Function-associated Molecule 1 on Resting Lymphocytes. J Exp Med 1992, 175:185-190.
L, HESSION C, TIZARD R, VASSALLOC, L~JNOWSKYJS, %I-Rosso G, LOSB R: Direct Expression Cloning of Vascular CeU Adhesion Molecule 1, a Cytokine-induced EndotheUaI Protein that Binds to Lymphocytes. Cell 1989, 59:1203-1211.
CYBULSKY MI, FRIES JWU, WILUAMSAJ, SULTANP, DAVIS VM, Splicing of Human MA JR, COLLINS T: Alternative VCAM-1 in Activated Vascular Endothelium. Am J Path01 1991, 138:815420. This paper reports on the cloning of the larger seven domain form of VCAM-1 and demonstrates that the two forms of the molecule are likely to be the result of alternative splicing. The authors show that this larger VCAM1 is the only form detectable by immunoprecipitation from IL-l-treated HLJVECs. 16. ..
GIMBRONE
17. ..
HESSION C, TVXKD R, V~SSALLOC, SCHIFFERSB, GOFF D, MOY P, CHI-ROSSO G, LUHO~XYJ S, LOHB R, OSBORN L: Cloning of an Alternative Form of Vascular CeU Adhesion Molecule-l (VCAMl). J Biol Chem 1991, 2666682685. The cloning of the larger seven domain form of VCAM1 is described. The authors show that both forms of VCAM1 mRNA are produced, that the larger form is the major form on HUVECs, and that both forms can support cell adhesion. C~ULSKY MI, FRIES JWE, WILLIAMSAJ, SULTAN P, EDDY R, BYES M, SHOWS T, GIMBRONE MA JR, COUINS T: Gene Structure, Chromosomal Location, and Basis for Altemative mRNA Splicing of the Human VCAMl Gene. Proc Nat1 Acad Sci IJSA 1991, 88:785’+7863. The organization of the human VCAM~l gene is described and localized to a region of chromosome 1. RegUhOly elements for the gene are presented. 18. ..
19.
ELICES MJ, OSBORN L, TAKADA Y, CROUSE C, LUHOWSKYJS, HEMLER ME, IOBB RR: VCAM-1 on Activated EndotheUum Interacts with the Leukocyte Integrin VLA-4 at a Site Distinct from the VLA-4/Fibronectin Binding Site. Cell 1990, 60:577-584.
20.
IQBB R, CHI-ROSSOG, LEONED, ROSAM, NEWMANB, LUHOWS~ S, OSBORN L, SCHIFFER S, BENJAMINC, DOUGAS I, HESSION C, CHOW P: Expression and Functional Characterization of a Soluble Form of Vascular Cell Adhesion Molecule 1. Biccbem Biophys Res Commun 1991, 178:149&1504.
21.
WAYNERFA, GARCIA-PARDOA, HUMPHIUESMJ, MCDONAI~ JA, CARTERWG: Identification and Characterization of the T Lymphocyte Adhesion Receptor for an Alternative CeU Attachment Domain (CS-1) in Plasma Fibronectin. J Cell Biol 1989, 109~1321-1330.
22. .
ISSEKUTZTB, WXRETOU;IICZA: Effect of a New MonocIonaI Antibody, TA-2, that Inhibits Lymphocyte Adherence to Cytokine Stimulated Endothelium in the Rat. J Immunol 1991, 147:109-116.
NORTAMO P,
15 R, RENKONEN R, TIMONEN T, PRIETO J, PATARROYOM, GAHMBERGCG: The Expression of Human Intercellular Adhesion Molecule-2 is Refractory to Intlammatory Cytokines. Eur J Immunol 1991, 21:262%2632. Reports the ceU distribution of ICAM- and shows that this molecule is not upregulated by cytokine treatment of ECs suggesting that there is a third unidentified ICAM involved in LFA-1 mediated adhesion.
8. .
GE, MUNROJM, BE~ILACQIIAMP: Inducible CeU Adhesion Molecule 110 (INCAM-110) is an Endothelial Receptor for Lymphocytes. A CDll/CDl%independent Adhesion Mechanism. J Eq Med 1990, 171:136+1374.
lymphocyte
SHIMIZUY, SHAW S, GRABER N, GOPAL VT, HORGAN KJ, VAN &VENTER GA, NEWMANW: Activation-independent Binding of Human Memory T Cells to Adhesion Molecule ELAM-1. Nature 1991, 349:79%302. CD4+ T cells of the memory phenotype but not naive T cells bind to IL-1 activated HUVECs using E-se&tin (Em-l). This adhesion is not affected by T-cell activation, unlike integrin-mediated adhesion.
SHIMVUY, NEWMANW, GOPAL TV, HORGANKJ, GRABERN, BEALL LD, VANSE~NTER GA, SHAWS: Four Molecular Pathways of TceU Adhesion to Endothelial Cells: Roles of LFA-1, VCAM-1. and EL.061 and Changes in Pathway Hierarchy Under Different Activation Conditions. J Celf Bioll991, 113:1203-1212. A careful exploration of the known pathways involved in CD4 + T~cell adhesion to HUVECs and the changes that accompany EC and T-cell activation. This study also demonstrates the multiple pathways used by memov T cells versus naive T cells. 24. ..
25.
H~LZMANNB, WEISSMANIL: Peyer’s Patch-specific Lymphocyte Homing Receptors Consist of a VLA-4-l&e Alpha Chain Associated with Either of Two Integrin Beta Chains, One of Which is Novel. &WE0 J 1989, 8:1735%1741.
26.
ERLE DJ, RUEG(; C, SHEPPARDD, PYIELA R: Complete Amino Acid Sequence of an Integrin !3 Subunit (8,) Identified in Leukocytes. J Rio1 Chem 1991, 266:ll 00%11016.
27.
KIISHAW PJ, MURANT SJ: Expression and Regulation of p7 (BP) Integrins on Mouse Lymphocytes: Relevance to the MucosaI Immune System. Eurj Immunol 1991, 21:2591-2597.
28.
Lectin Ceil Adhesion Molecules (LEC-CAMS)! i. New Family of Cell Adhesion Proteins Involved with !6flammation. / CeN Biocbem 1991, 45:13%146. &KY
IMAIY, SINGER MS, FENNIEC, L%.SKY LA, ROSEN SD: Identilication of a Carbohydrate-based Endothelial Ligand for a Lymphocyte Homing Receptor. J Cell Riol 1’991, 113:1213_1221. The authors employed a novel reagent, a soluble form of L-selectin, to immunoprecipitate and characterize the ligands for L-selectin on lymph node HEVs, and identify a major 50 kD sulfated, fucosylated, sialylated glycoprotein. 30.
BERG EL, ROBINSONMK, WARNOCKRA, BUTCHEREC: The Human Peripheral Lymph Node Vascular Addressin is a Ligand for LECAM-1, the Peripheral Lymph Node Homing Receptor. J Cell Biol 1991, 114:343-349.
31. ..
SPERTINI0, L~ISCINSK~~ FW, KANSASGS, MIJNROJM, GRIFFINJD, GIMBRONEMA JR, TEIIDERTF: Leukocyte Adhesion Molecule1 (LAM-l, L-selectin) Interacts with an Inducible EndotheIiaI CeU Ligand to Support Leukocyte Adhesion. J Immunol 1991, 147:2565-2573. An elegant series of studies is presented, showing that L-selectin mediates the binding of lymphocytes and neutrophils to cytokine-stimulated HUVECs when adhesion is measured under non static conditions. It is shown for the first time that a carbohydrate-containing ligand molecule for L-selectin is also present on non~HEV endothelium after cytokine activation. 32.
PHILLIPSML, NUDEIMAN E, GAETA FCA. PEREZ M, SINGHAI. AK HAKOMOR~ B, PAULSONJC: ELAM-1 Mediates Cell Adhesion by Recognition of a Carbohydrate Ligand, Sialyl-LeX. Science 1990, 250:113&1132.
33.
WAIZ G, ARUFFOA, KOLANUSW, BEVILACQUA M, SEED B: Recognition by ELAM-1 of the Sialyl-Le Determinant of Myeloid and Tumor Cells. Science 1990, 250:1132-1135.
34.
LOWE JB, STOOLMAN LM, NAIR RP, IARSEN RD, BERHEND TL, MARKSRM: ELAM-l-Dependent Cell Adhesion to Vascular Endothelium Determined by a Transfected Human Fucosyltransferase cDNA. Cell 1990, 63475-484.
35.
BERG EL, ROBINSON MK, MANSSON0, BUTCHER EC, MAGNANI JL: A Carbohydrate Domain Common to Both Sialyl Lea
-_
Issekutz ._-..
PICKER LJ, WARN~CK RA, BURNS AR, D~ERSZHUK CM, BERG EL, EC: The Neutrophil Selectin LECAM-1 Presents Carbohydrate Ligands to the Vascular Selectins ELAM-I and GMP-140. Cell 1991, 66:921-933. This elegant study demonstrates the somewhat unexpected finding that L-selectin on neutrophils is decorated with sialyl~L@, which is tf+e Lgand for F-selectin and plays an important role in neutrophil adhesion tc both E-selectin and P-selectin, possibly because of its location on thr microvilli of these cells. 36. .
BUTCHER
37.
Lo SK, IEE S, RAMOS RA, UIHB R, ROSA M, CHI-ROSSC G, WRIGHT SD: Endothelial-Leukocyte Adhesion Molecule 1 Stimulates the Adhesive Activity of Leukocyte Integrm CR3 (CDllb/CDl& Mac-l, CL,,,&) on Human Neutrophils. J EqD Med 1991, 173:1493-1500.
38.
GKABERN, GOPAL TV, WUON D, BEALL ID, POLTE T, NEWMAN W: T Cells Bind to Cytokine-activated Endothelial Cells Via a Novel, Inducible Sialoglycoprotein and Endothelial Leukocyte Adhesion Molecule-l. J Immunol 1990, 145:819E3,?
L~BB RR, CHI-RUSSOG, LEONEDR, ROSAMD, BIXLERS, NEWMAI~ BM, LUHOWSKYJS, BENJAMIN CD, Douc~s IG, GOE!Z SE. HESSION C, CHOW EP: Expression and Functional Chat acterization of a Soluble Form of Endothelial-Leukoc- L.. Adhesion Molecule 1. .J Immunol 1991, 147:124--129. Production of a soluble form of E-selectin is described and it is dem 1; strated that lymphocytes and especially CD4+ T memon; cells adh+to immobilized E-selectin.
39. .
40.
LA:
29. ..
to sites of inflammation
and Sialyl LeX is Recognized by the Endothelial CeU Leukocyte Adhesion Molecule ELAM-1. .J Biol Cbem 1991. 266:14 869-14 872.
This paper shows that VLA-4 mediates much of the lymphocyte adherence to cytokine stimulated rat ECs, that lymphocytes from an inflammatoty site express increased levels of m-4, and that rat VLA-4 binds to human VCAMI on HUV?Xs. 23. ..
homing
LJ, MICHIE SA, Roar IS, BUTCHER EC: A Unique P11i notype of Skin-associated Lymphocytes in Humans: Preferential Expression of the HECA-452 Epitope by Benign and Malignant T Cells at Cutaneous Sites. Am J Putbol lY90. 136:1053-1068.
,%CKER
PICKER LJ, KISHIMOTOTK, SMITH CW, WARNOCKRA, BUTCHER EC: ELAM-1 is an Adhesion Molecule for Skin-homing T Cells. Nature 1991, 349~796799. This interesting report demonstrates that the lymphocytes that bmd 11; E-selectin react with monoclonal antibodyHECAz452, which recogruscs an antigen expressed by T cells found in’inflamed skin. Furthermore, high levels of E~selectih are expressed in chronically inflamed cutaneous sites in preference to other intlammatory tissues. It is suggested that these T cells may selectively migrate to inflamed skin. because of this E-selectin-positive endothelium. 41. ..
42. ..
BERC; EL, YO~HINO T, Ro’rr IS, ROBINSON MK, WARN~CK RA, KISHIMOTOTK, PICKERLJ, BIJTCHEREC: The Cutaneous Lymphocyte Antigen is a Skin Lymphocyte Homing Receptor for the Vascular Lectin EndotheIiaI Cell-Leukocyte Adhesion Molecule 1. J E$J Med 1991, 174:1461-1466. An elegant demonstration that the carbohydrate antigen recognized by the HECA~452 mAb that reacts with T cells found in inflamed skin binds to E-selectin. It is suggested that CL4 may be a modified form of sL@ This report helps explain why CIA+ cells infiltrate inflamed skin displaying E-selectin expressing endothelium. 43.
DUSTIN
ML,
SPRINGER
Transiently Stimulates 1989, 341:61-24.
TA: T Cell Adhesiveness
Receptor Through
Cross-linking LFA-1. Nature
Effect of T CeU Activation on Lymphocyte Endothelial Cell Adherence and the Role of WA-4 in the Rat. Cell Immunol 1992, 140:420-431. T~ceUactivation by mitogens rapidly induces lymphocyte adhesion to rat ECs through VLA-4 and LFA~l, while activation through the CD3 or IL-2 receptors seems to stimulate increased adhesion through LFA-1 independent of U-4. Furthermore, increased VLA4-mediated adhesion occurs in the absence of increased VL&4 expression. 44. .
WYSOCKI J, ISSEKI!TZ TB:
45.
SHIMIZI
Y, VAN &ENTER GA, HORGAN KJ, !%AW S: Regulated Expression and Binding of Three VLA (BI) Integrin Receptors on T Cells. Nature 1990, 345:25&254.
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292
LvmDhocvte activation and effector functions 46. .
HIBBS ML, JAKES S, STACKER SA, WAUACE RW, SPRINGER TA: The Cytoplasmic Domain of the Integrin Lymphocyte Function-associated Antigen 1 p Subunit: Sites Required for Binding to Intercellular Adhesion Molecule 1 and the Phorbol Ester-stimulated Phosphorylation Site. J Eap Med 1991, 1741227-1238. This paper identifies the sites in the p chain of LFA-1 that are phosphorylated and describes how this influences receptor binding to ICAMI. 47. .
VALMUL, AUTEROM, SILJANDER P, PATARROYOM, GAHMBERGCG: Phosphorylation of the P-subunit of CDll/CD18 Integrins by Protein Kinase C Correlates with Leukocyte Adhesion. Eur J Immunol 1991, 21:2857-2862. Phosphorylation of the p chain of LFA~l is associated with enhanced adhesion through LFA-I. This may contribute to the increased adhesion of activated leukocytes. 48. .
SPERTINI0, KANSASGS, MUNROJM, GIFFINJD, TEDDERTF: Regulation of Leukocyte Migration by Activation of the Leukocyte Adhesion Molecule-l (LAM-l) Selectin. Nature 1991, 349691494. The affinity of L-selectin (LAM-1 ) for a carbohydrate-based ligand can be rapidly upregulated on both lymphocytes and neutrophils, but requires leukocyte lineage-specific stimuli. This lineage specific enhancement of L-selectin affinity may contribute to the differences in migration to inflammatory sites by these cells.
with particular emphasis and cell distribution. 58.
on the differences
in kinetics of expression
LEWISRE, BUCHSBAUMM, WHITAKERD, MUWHY GF: Intercellular Adhesion Molecule Expression in the Evolving Human Cutaneous Delayed Hypersensitivity Reaction. J Invest Dermat01 1989, 93672477.
KOCH AE, BURROWSJC, HAINES GK, CARLOSTM, HARLANJM, LEIBOVICHSJ: hnmunolocalization of Endothelial and Leukocyte Adhesion Molecules in Human Rheumatoid and Osteoarthritic Synovial Tissues. Lab Invest 1991, 64313320. The expression of the principle endothelial adhesion molecules for leukocytes, namely E-selectin, ICAM- and VCAM-1, is described in two common types of arthritis. 59. .
RICE GE, MUNRO JM, CORLESS C, BEV~IACQUAMP: Vascular and Nonvascular Expression of INCAM-110: a Target for Mononuclear Leukocyte Adhesion in Normal and Inflamed Human Tissues. Am J Pathl 1991, 138~385-292. One of the first descriptions of the tissue expression of VCAMl, also known as INCAM110. 60. .
61.
COSIMI AB, CONTI D, DELMONICO FL, PREFFER Fl, WEE S, ROTHLEXN R, FAANESR, COL~IN RB: In Vivo Effects of Monoclonal Antibody of ICAM- (CD54) in Nonhuman Primates with Renal Allografts. J Immunol 1990, 144:4604-4612.
62.
KANAGAWAK, ISHIKURAH, T AKAHASHIC, TAMATANIT, MNASAKA M, TOGASHI M, KOYANAGI T, YOSHIKI T: Identification of ICAM-l-positive Cells in the Nongrafted and Transplanted Rat Kidney - an Immunohistochemical and Ultrastructural Study. Transplantation 1991, 52:1057-1062.
49.
ISSEKUTZTB: Effect of Antigen Challenge on Lymph Node Lymphocyte Adhesion to Vascular Endothelial Cells and the Role of VLA-4 in the Rat. Cell Immunol 1991, 138:30@312.
50.
IAFF~N A, GARCIAVICUNAR, HIJMEXL~A, POSTIGO AA, CORBI AL, DE LWD&XIRI MO, SANCHEZ-MADRID F: Upregulated Expression and Function of VLA-4 Fibronectin Receptors on Human Activated T Cells in Rheumatoid Arthritis. J Clin Invest 1991, 88:546552.
63.
VAN DINTHER-JANSSEN ACHM, HORST E, KOOPMANG, NEWMANN W, SCHEPER RJ, MEIJER CJLM, PAIS ST: The VIA-4NCAM-1 Pathway is Involved in Lymphocyte Adhesion to EnJ Immunol 1991, dothelium in Rheumatoid Synovium. 147:4207-4210.
O’NEIL JK, BUTIXR C, BAKER D, GSCHMEISSNERSE, KRAALG, B~JTCHEREC, TURK JL: Expression of Vascular Addressins and ICAM- by Endothelial Cells in the Spinal Cord During Chronic Relapsing Experimental Allergic Encephalomyelitis in the Biozzi AB/H Mouse. Immunolog), 1991, 72:52&525.
64.
PITZALISC, KINGSLEY G, HASKARDD, PANAYIG: The Preferential Accumulation of Helper-inducer T Lymphocytes in Inflammatory Lesions: Evidence for Regulation by Selective Endothelial and Homotypic Adhesion. Eur J Immunol 1988, 18:1397-1402.
FABRY2, WALDSCHMIDTMM, HENDRICKSOND, KEINERJ, LOVEHOMAN L, TAKEI F, HAR’~ MN: Adhesion Molecules on Murine Brain Microvascular Endothelial Cells: Expression and Regulation of ICAMand Lgp 55. J Neuroimmunol 1992, 36:1-11.
65.
ISSEKUTZTB, STOLTZ JM, V.D. MEIDE P: Lymphocyte Recruitment in Delayed-type Hypersensitivity. The Role of Gammainterferon. J Immunol 1988, 140:298+2993.
66.
ISSEKUTZTB, STOLTZ JM: Stimulation tion by Endotoxin Tumor Necrosis Cell Immunol 1989, 120:16%173.
51.
52.
53.
PITZALISC, KINGSLEYGH, COVELLIM, !dELICONI R, MARKEY A, PANAYI GS: Selective Migration of the Human Helper-inducer Memory T Cell Subset: Confirmation by In Vivo Cellular Kinetic Studies. Eur J Immunol 1991, 21~369376.
WALDORFHA, WALSHLJ, SCHECHTERNM, MURXY GF: Early Cellular Events in Evolving Cutaneous Delayed Hypersensitivity in Humans. Am J Path01 1991, 138:477-486. This report describes the histological changes in E-selectin and ICAW 1 expression in evolving DTH and the relationship of these adhesion molecules to mast cells and T memory cells in the reactions. 54. .
55.
56.
WAISH LJ, TR~NCHIERIG, WALIXRF HA, WHITAKERD, MURPHY GF: Human Dermal Mast Cells Contain and Release Tumor Necrosis Factor a, which Induces Endothelial Leukocyte Adhesion Molecule 1. Proc Nat1 Acad Sci USA 1991, 88:422W224. COTRAN RS, GI~RONE MA JR, BEV~LACQUA MP, MENDRICKDL, POBER JS: Induction and Detection of a Human Endothelial Activation Antigen In Vivo. J Eap Med 1986, 164661-666.
NORIUS P, POSTON RN, THOMAS DS, THORNHILL M, HAWK J, HAXARD Do: The Expression of Endothelial Leukocyte Adhesion Molecule- 1 (ELAM- l), Intercellular Adhesion Molecule-l (ICAM-l), and Vascular Cell Adhesion Molecule1 (VCAM-1) in Experimental Cutaneous Inflammation: a Comparison of Ultraviolet B Erythema and Delayed Hypersensitivity. J Invest Dermatol 1991, 96~763-770. A systematic description of the changes in E-selectin, ICAMI, and VCAM1 expression in two types of cutaneous inflammatory reactions 57. .
of Lymphocyte MigraFactor, and Interferon.
MAY MJ, AGER A: ICAM- 1-independent Lymphocyte Transmigration Across High Endothellum: Differential Up-regulation by Interferon-y, Tumor Necrosis FActor-a and Interleukin lp. Eur J Immunol 1992, 22:21?226. This report shows that IFN-I and TFN-a, but not IL~F,stimulate lymphocyte transendothelial migration across rat cultured HEV cells and that the lymphocyte adhesion was independent of ICAM- but inhibitable by anti-p, integrin and VLA-4.binding peptldes.
67. .
68.
KAVANALJGH AF, LIGHTFOOT E, LIPSKYPE, OPPENHEIMER~MARKS
N: Role of CDll/CD18 in Adhesion and Transendothelial Migration of T Cells: Analysis Utilizing CDlS-deficient . Cell Clones. J Immunol 1991, 146:41494156.
T
OPPENHEIMER-MARKS N, DAVISLS, BOGLJEDT, RAMBERG J, LIPSK~ PE: Differential Utilization of ICAM- and VCAM-1 During the Adhesion and Transendothelial Migration of Human T Lymphocytes. J Immunol 1991, 147:2913-2921. An interesting study showing that the VLA-&VCAM adhesion pathway, and to a lesser extent the LFA-l-ICAM pathway, mediated T~cell adhesion to IL-l-stimulated HUVEC. The former did not function in transendothellal migration but ICAM- played a major role and was strategically located to function in this migration. 69. ..
70. ..
WATSON SR, FENNIE C, LANKYLA: Neutrophll Influx into an Inflammatory Site Inhibited by a Soluble Homing Receptor-IgG Chimaera. Nature 1991, 349:164-167.
Lymphocyte
This report shows that recombinant soluble L~selectin in ziivo inhibits the migration of neutrophils into the inflamed peritoneal cavity in mice. This novel approach suggexs that soluble receptors can, under some circumstances, inhibit in tli~o leukocyte migration to inflammation. ISOBEM, YAGITAH, OKUMURAK, IHARAA: Specific Acceptance of Cardiac Allograft After Treatment with Antibodies to ICAM- and LFA-1. Scbnce 1992, 255:1125-1127. Anti-LFA-1 and anti-ICAM- each prolong cardiac allograft sutival in mice and decrease lymphocyte infiltration into the graft. Treatment with these mAbs in combination produces complete tolerance to these allografts.
71. ..
72. ..
ISSEKIITZ TB:
Inhibition of In Vito Lymphocyte Migration to Inflammation and Homing to Lymphoid Tissues by the TA2 MonoclonaI Antibody: a Likely Role for W-4 In Vito. .I lmmllnol 1991. 147:417E++184. This paper demonstrates that in t~ivo U-4 does mediate the traffic of lymphocytes out of the blood, and that blocking VIA 4 with an antis ad mAb strongly inhibits the migration of lymphocytes to cutaneous infiammato~ sites and to skin injected with cytokine. Furthermore, cq integrins appear to mediate most of the lymphocyte migration to gutassociated lymphoid tissues.
homing
to sites of inflammation
lssekutz
MEUTANIH, KLJPPER TS: Two Integrin-binding Peptides Abrogate T Cell-mediate Immune Responses In Viva Proc Natl Acad Sci (JSA 1991, 88BO72-8076. Two peptides that bind to VLA4 and VIA-5, both of which can mediate binding to fibronectin, can inhibit the transfer of contact hypersensitivity, possibly by altering T~cell migration through binding to these two integrins.
73. ..
FERGLJSON TA,
ISSiKtrIW ‘ITS, ISSEKLIT% AC: T Lymphocyte Migration to Arthritic Joints and DermaI Inflammation in the Rat: Differing Migration Patterns and the Involvement of VLA-4. Clin Immunol Immunopathol 1991, 61:436447. Anti~VLA-4 inhibits the migration of lymphocytes to arthritic joints in rat adjuvant arthritis. The importance of tissue specificity in the migration of Iymphoqws to intlammato~ sites is demonstrated.
74. .
TEi Issekutz, Department of Pediatrics, Izaak Walton Killam Children’s tlospitai, 5850 l’niversity Avenue, Ifdlifax, Nova Scotia, Canada B3J 3G9.
293