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PubMed1996

Adhesion mechanisms involved in C5a-induced eosinophil homotypic aggregation.

During the process of migration into tissues, leukocytes interact primarily with vascular endothelial cells but they have also been shown to interact with each other. In this study we investigated the adhesion mechanisms involved in guinea pig eosinophil homotypic aggregation as assessed by changes in light transmission. The anti-CD18 monoclonal antibody (mAb) 6.5E, at concentrations in excess of those previously shown to abrogate CD18-dependent eosinophil adherence to serum-coated plastic, inhibited C5a-induced eosinophil aggregation to a maximum of 49-68%. In contrast, the anti-intercellular adhesion molecule-1 (ICAM-1) mAb RR1/1, which binds to guinea pig eosinophils and has been shown to block guinea pig ICAM-1 function, had no effect on C5a-induced responses. Similarly, two functionally active anti-very late antigen-4 (VLA-4) mAbs has no effect on eosinophil aggregation and did not affect the CD18-independent component of the aggregation response. The role of L-selectin in eosinophil aggregation was investigated by using heparin, the selectin-binding polysaccharide fucoidin, and the anti-L-selectin mAb MEL-14. Heparin concentration dependently inhibited C5a- and platelet- activating factor- (PAF) induced aggregation but C5a-induced responses were inhibited more potently. Fucoidin, but not the carbohydrate dermatan sulphate, effectively inhibited C5a-induced eosinophil aggregation. PMA- and PAF- induced responses were also inhibited by fucoidin. Moreover, fucoidin and 6.5E were additive in their ability to inhibit C5a-induced aggregation. Similarly, MEL-14 effectively inhibited C5a-induced eosinophil aggregation. In conclusion, we have demonstrated that guinea pig eosinophil homotypic aggregation is mostly dependent on CD11/CD18 and L-selectin present on the eosinophil surface. In addition, VLA-4 plays no role in mediating this aggregation response.

Animals↗
PubMed1998

Interleukin-18/interferon-gamma-inducing factor, a novel cytokine, up-regulates ICAM-1 (CD54) expression in KG-1 cells.

Intercellular adhesion molecule-1 (ICAM-1, CD54) is a membrane glycoprotein and a member of the immunoglobulin superfamily. It plays a central role in cell to cell-mediated immune responses and is a ligand for leukocyte function-associated antigen-1 (LFA-1). We report here that a newly discovered cytokine, interferon-gamma-inducing factor (IGIF) [H. Okamura et al. (1995) Nature 378, 88] recently proposed to be designated as IL-18, selectively up-regulates ICAM-1 expression in KG-1 cells, a human myelomonocytic cell line, in which IL-18 also enhances interferon-gamma production. IL-18 induced heterotypic aggregation between KG-1 and Peer T cells, which was blocked by anti-ICAM-1 and/or LFA-1 antibodies. Anti-interferon-gamma antibody did not block the IL-18-induced up-regulation of ICAM-1 on KG-1 cells. These results thus show that IGIF/IL-18, enhances ICAM-1 expression in KG-1 cells in an interferon-gamma-independent pathway, up-regulates ICAM-1 functions, and that IL-18 might play a potential role in immunoregulation by mediating immune cell infiltration into the tissues.

Cell Line↗
PubMed1999

alpha9beta1 integrin is expressed on human neutrophils and contributes to neutrophil migration through human lung and synovial fibroblast barriers.

Accumulation of leukocytes in inflamed tissue involves their migration through vascular endothelium and then in the connective tissue. Recently we utilized a barrier of human synovial, dermal, and lung fibroblasts (HSF, HDF, and HLF) grown on polycarbonate filters as a model of human polymorphonuclear leukocyte (PMN) migration through connective tissue. The beta2 integrins (CD 11/ CD18) and alpha4, alpha5, and alpha6beta1 (VLA-4, -5, and -6) integrins each contributed to this PMN migration. Here we report that on human blood leukocytes, alpha9beta1 (VLA-9) is expressed only on PMNs and that it is up-regulated after PMN activation. Based on monoclonal antibody (mAb) blocking studies, alpha9beta1 integrin contributed to C5a-induced PMN migration through fibroblast (HLF and HSF) barriers. This role was apparent only when alternate mechanisms such as CD18, alpha4, alpha5, and alpha6beta1 integrins were blocked and then mAb to alpha9beta1 integrin inhibited the residual PMN migration (by 40-50%) through the HLF or HSF barrier, resulting in > or = 75% inhibition overall. In contrast, PMN migration across interleukin-1-activated endothelium (HUVEC) in response to a C5a gradient, which is partly (30-40%) via CD11/CD18-independent mechanisms, was not inhibited by adhesion blocking by mAbs to alpha4, alpha5, alpha6, and alpha9beta1 even in combination. These results indicate that alpha9beta1 integrin on PMN may have a special role, in conjunction with other beta1 integrins, in mediating PMN migration in the extravascular space, and may contribute to differential neutrophil function within tissues.

Animals↗
PubMed2004

Alpha lipoic acid inhibits human T-cell migration: implications for multiple sclerosis.

We have demonstrated previously the ability of the antioxidant alpha lipoic acid (ALA) to suppress and treat a model of multiple sclerosis (MS), relapsing experimental autoimmune encephalomyelitis (EAE). We describe the effects of ALA and its reduced form, dihydrolipoic acid (DHLA), on the transmigration of human Jurkat T cells across a fibronectin barrier in a transwell system. ALA and DHLA inhibited migration of Jurkat cells in a dose-dependent fashion by 16-75%. ALA and DHLA reduced matrix metalloproteinase-9 (MMP-9) activity by 18-90% in Jurkat cell supernatants. GM6001, a synthetic inhibitor of MMP, reduced Jurkat cell migration, but not as effectively as ALA and DHLA did. Both ALA and DHLA downmodulated the surface expression of the alpha4beta1 integrin (very late activation-4 antigen; VLA-4), which binds fibronectin and its endothelial cell ligand vascular cell adhesion molecule-1 (VCAM-1). Moreover, ALA, but not DHLA, reduced MMP-9-specific mRNA and extracellular MMP-9 from Jurkat cells and their culture supernatants as detected by relative reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. ALA and DHLA inhibited Jurkat cell migration and have different mechanisms for inhibiting MMP-9 activity. These data, coupled with its ability to treat relapsing EAE, suggest that ALA warrants investigation as a therapy for MS.

Antioxidants↗
PubMed2002

Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases.

This review focuses on providing insights into the structural basis and clinical relevance of LFA-1 and VLA-4 inhibition by peptides and small molecules as adhesion-based therapeutic strategies for inflammation and autoimmune diseases. Interactions of cell adhesion molecules (CAM) play central roles in mediating immune and inflammatory responses. Leukocyte function-associated antigen (LFA-1, alpha(L)beta(2), and CD11a/CD18) and very late antigen (VLA-4, alpha(4)beta(1), and CD49d/CD29) are members of integrin-type CAM that are predominantly involved in leukocyte trafficking and extravasation. LFA-1 is exclusively expressed on leukocytes and interacts with its ligands ICAM-1, -2, and -3 to promote a variety of homotypic and heterotypic cell adhesion events required for normal and pathologic functions of the immune systems. VLA-4 is expressed mainly on lymphocyte, monocytes, and eosinophils, but is not found on neutrophils. VLA-4 interacts with its ligands VCAM-1 and fibronectin (FN) CS1 during chronic inflammatory diseases, such as rheumatoid arthritis, asthma, psoriasis, transplant-rejection, and allergy. Blockade of LFA-1 and VLA-4 interactions with their ligands is a potential target for immunosuppression. LFA-1 and VLA-4 antagonists (antibodies, peptides, and small molecules) are being developed for controlling inflammation and autoimmune diseases. The therapeutic intervention of mostly mAb-based has been extensively studied. However, due to the challenging relative efficacy/safety ratio of mAb-based therapy application, especially in terms of systemic administration and immunogenic potential, strategic alternatives in the forms of peptide, peptide mimetic inhibitors, and small molecule non-peptide antagonists are being sought. Linear and cyclic peptides derived from the sequences of LFA-1, ICAM-1, ICAM-2, VCAM-1, and FN C1 have been shown to have inhibitory effects in vitro and in vivo. Finally, understanding the mechanism of LFA-1 and VLA-4 binding to their ligands has become a fundamental basis in developing therapeutic agents for inflammation and autoimmune diseases.

Autoimmune Diseases↗
PubMed1996

Changes in markers, receptors and adhesion molecules expressed on murine hemopoietic stem cells after a single injection of 5-fluorouracil.

Cytokines play a crucial role in the differentiation and proliferation of hemopoietic cells, and it has recently been found that adhesion molecules play crucial roles not only in differentiation and proliferation, but also in the homing and other functions of hemopoietic cells. We have very recently established a new method for purifying pluripotent hemopoietic stem cells (P-HSC) in mice by injecting 5-fluorouracil (5-FU). The P-HSC were found to be low-density, lineage marker-negative (Lin-), CD71- and major histocompatibility complex class I(high). In the present study, we analyze changes in the expression of various HSC markers (Sca-1 and CD34), receptors (c-kit and interleukin-6 receptor [IL-6R]) and adhesion molecules (very late activation antigen-4 [VLA-4], lymphocyte function-associated antigen-1 [LFA-1], and CD44) after 5-FU injection. The percentage of Sca-1+ cells increases after 5-FU treatment, reaching a maximum on day 3, whereas the percentage of IL-6R+ cells decreases, reaching a minimum on day 3. The percentage of CD34+ cells does not change after 5-FU treatment. The percentages of both c-kit(low) and c-kit(high) cells decrease, reaching a minimum on day 3 after 5-FU treatment, whereas the percentage of c-kit- cells reciprocally increases, reaching a maximum on day 3. However, there is no change in the expression of adhesion molecules (VLA-4, LFA-1 and CD44) on the P-HSC.

Animals↗
PubMed2002

Effects of VLA-4 antagonists in rat whole embryo culture.

BACKGROUND: Pharmacological antagonism of VLA-4 (Very Late Antigen 4, alpha(4)beta(1) integrin) has become an attractive target for the treatment of predominantly eosinophil mediated disease states such as asthma, allergic rhinitis, multiple sclerosis, rheumatoid arthritis, diabetes, and inflammatory bowel disease. Gene knockouts of the alpha(4)-integrin subunit of VLA-4 or its cell surface ligand, VCAM-1, however, have been shown to result in embryo-lethality in homozygous null mice due to defects in chorio-allantoic or epi-myocardial fusion. Although gene knockout phenotypes are not always manifested by pharmacological antagonism, those studies suggested that VLA-4 antagonists might cause embryo-lethality or drug-induced malformations. METHODS: To test these concepts, early neurulating rat embryos were cultured by the methods of New ('78) after intra-coelomic microinjection of a VLA-4 blocking antibody or in the presence of small molecule VLA-4 antagonists. RESULTS: Defects in chorio-allantoic fusion were induced after microinjection of VLA4 blocking antibody and after continuous exposure to small molecule antagonists. In a minority of affected embryos chorio-allantoic fusion was completely blocked whereas the majority of affected embryos had only superficial chorio-allantoic fusion and the allantois was enlarged and edematous. Although the allantoic mesoderm covered the trophoblasts of the chorionic plate and contained blood vessels there was only minimal invasion of the trophoblasts by the allantoic mesoderm. The lowest observed effect level generally correlated with the IC(approximately 95), as determined in 90% plasma. DISCUSSION: Based on these data, VLA-4 antagonism might represent a significant risk to the developing embryo/fetus. In vitro exposure, however, is "constant" and does not take into account the elimination phase of these xenobiotics in vivo. Given the high concentrations required to elicit an effect, therapeutic blood levels in vivo may be several fold lower than those that affect the conceptus, depending on the tissue penetration of the compound and the route of administration. VLA-4 also exists in a range of conformations and activation states in vivo and the gene KOs and present studies do not define whether these developmental processes are dependent upon a particular activation state of VLA-4. Therefore, state-selective antagonists may have an improved embryonic safety profile. Additional studies will be required to determine potential effects of VLA-4 antagonists on embryo/fetal development in vivo.

Allantois↗
PubMed2001

A homogeneous fluorometric assay for measuring cell adhesion to immobilized ligand using V-well microtiter plates.

We have developed a homogeneous high-capacity assay format for measuring integrin- and selectin-dependent cell binding to immobilized ligand using V-well microtiter plates. 2',7'-Bis(2-carboxyethyl)-5-(and-6)-carboxylfluorescence, acetoxymethylester-labeled cells are added to ligand-coated V-shaped microtiter wells. Bound cells are separated from free cells using centrifugal force to produce shear stress. Nonadherent cells accumulate in the nadir of the well and are measured using a fluorescence plate reader. Antibody or low-molecular-weight inhibitors of either the ligand or the cell surface receptor result in less cell binding, more cells in the pellet, and increased signal. The optimization and validation of the very late antigen-4/vascular cell adhesion molecule-1 assay is described in detail. We demonstrate that this assay can be rapidly adapted to measure other integrin- and selectin-mediated interactions. This assay format has several advantages over conventional assays. The centrifugal process is biologically relevant and eliminates the washing steps to remove nonadherent cells that can cause well-to-well and plate-to-plate variation. Because the assay is robust with a high signal-to-noise ratio and low variability, it is ideally suited for studying multiple parameters of cell adhesion and for high capacity screening.

Anti-Allergic Agents↗
PubMed1995

Integrin stimulation decreases tyrosine phosphorylation and activity of focal adhesion kinase in thymocytes.

FAK, focal adhesion kinase, is expressed in a variety of cell types and has been suggested to transduce signals brought about by integrin-extracellular matrix (ECM) interactions. Integrin stimulation increases tyrosine phosphorylation and activity of FAK in all the cells examined to date. In contrast, in thymocytes stimulation of VLA-4 (alpha 4 beta 1) and LFA-1 (alpha L beta 2) resulted in a marked decrease in tyrosine phosphorylation and activity of FAK.

Animals↗
PubMed1996

Eotaxin stimulates eosinophil adhesion to human lung microvascular endothelial cells.

Effects of the human C-C chemokines eotaxin, MIP-1 alpha, and RANTES on human eosinophil or neutrophil adhesion to human lung microvascular endothelial cells (LMVEC) were investigated. Basal adhesion of unstimulated eosinophils to LMVEC was increased following pretreatment of LMVEC with TNF alpha (10ng/ml) for 6h. Stimulation of eosinophils with eotaxin (30 and 100ng/ml) resulted in increased adhesion to LMVEC pretreated with TNF alpha but not culture medium. Neutrophil adhesion was not increased by eotaxin under similar conditions. Neither MIP-1 alpha (3-100 ng/ml) nor RANTES (3-100 ng/ml) increased eosinophil or neutrophil adhesion to LMVEC pretreated for 6 h with either TNF alpha (10 ng/ml) or culture medium. Monoclonal antibodies (mAb) against eosinophil adhesion molecule VLA-4 (2B4; 30 micrograms/ml) but not CD18 (6.5E; 10 micrograms/ml) inhibited eotaxin-induced eosinophil adhesion to TNF alpha-activated LMVEC. 2B4 in combination with 6.5E reduced adhesion to basal levels. These data show that eotaxin, but not MIP-1 alpha or RANTES, stimulates eosinophil adhesion to LMVEC and that this effect can be abolished by anti-VLA-4 and CD18 mAb in combination. These results suggest that eotaxin may facilitate eosinophil migration from blood vessels in the lung by increasing eosinophil adhesion to endothelial cells.

Antibodies, Monoclonal↗
PubMed1997

A synthetic peptide, FN-C/H-V, from the C-terminal heparin-binding domain of fibronectin promotes adhesion of PMA stimulated U937 cells.

Hematopoietic cells differentially bind to the C-terminal heparin-binding domain of fibronectin depending on the activation state of integrin alpha 4 beta 1. In this study, we have identified a synthetic peptide derived from the C-terminal heparin-binding domain of fibronectin that promotes adhesion of PMA-treated U937 cells (a monocytic cell line) in a dose-dependent manner. A peptide (FN-C/H-V; residues Gln1892 to Gly1910) was active to inhibit adhesion of PMA-treated U937 cells to the 29-kDa fragment comprising the C-terminal heparin-binding domain of fibronectin. A peptide with scrambled version of FN-C/H-V lost the inhibitory activity on the adhesion. Furthermore, the IgG-conjugated FN-C/H-V promoted the adhesion of PMA-treated U937 cells to an extent comparable to that of the 29-kDa fragment. The adhesion of PMA-treated U937 cells on IgG-conjugated FN-C/H-V was inhibited both by anti-alpha 4 beta 1 antibody and by glycosaminoglycans including chondroitin sulfate and heparan sulfate. The other peptide, FN-C/H-II, was also a weak adhesion-promoting domain. These results suggest that the amino acid sequence defined by peptide FN-C/H-V contributes to the main adhesion-promoting activity of the 29-kDa fragment of fibronectin to stimulated U937 cells. The regulation of interactions of alpha 4 beta 1 integrin and glycosaminoglycans with ligands in fibronectin may have important implications for the migration and function of U937 cells.

Amino Acid Sequence↗
PubMed1998

Fibronectin binding promotes a PKC-dependent modulation of NF-kappa B in human T cells.

NF-kappa B was identified as one of the transcription factors leading to antigen-independent stimulation through activation of integrin receptors. This effect was dependent upon stimulation of alpha 4 beta 1 and alpha 5 beta 1 integrins, the major fibronectin-binding integrins of Jurkat T cells, since either RGD or CS-1 peptides at 10(-4) M could prevent NF-kappa B activation. At variance with fibroblasts and smooth muscle cells, in which only p50 and p65 components of the NF-kappa B complex are induced, adhesion of T cells to fibronectin resulted in a strong upregulation of p50 and c-Rel and in a partial increase in p65 activity. The upregulation of NF-kappa B activity was abrogated by calphostin C, an inhibitor of protein kinase C. Cell adhesion determined a strong reduction in the cytoplasmic levels of the NF-kappa B inhibitor I kappa B alpha, reduction that was prevented after treatment with calphostin C, suggesting that PKC-dependent I kappa B alpha phosphorylation might be involved in the upregulation of NF-kappa B.

Binding, Competitive↗
PubMed1999

1,25-Dihydroxyvitamin D3 suppresses the expression of the VCAM-1 receptor, VLA-4 in human leukemic HL-60 cells.

Very late antigen-4 (VLA-4) is the complex with alpha4 and beta1 integrins, which is the receptors to fibronectin and VCAM-1. We evaluate the effect of 1,25(OH)2D3 on the expression of VLA-4 in human leukemic HL-60, U937 cells and human melanoma A375 cells. Flow cytometric analysis demonstrate that the expression of alpha4 integrin is negatively regulated in the cell lines we studied. The expression of beta1 integrin is also decreased in HL-60 and U937 cells. The mRNA expression of alpha4 integrin is significantly decreased by the treatment with 1,25(OH)2D3, whereas 1,25(OH)2D3 does not alter the expression of beta1 mRNA. The adhesion assay demonstrate that the number of adherent cells treated with 1, 25(OH)2D3 is significantly lower than that untreated on VCAM-1-coated wells. Because VCAM-1 is highly expressed in the endothelial cells, it is possible that 1,25(OH)2D3 prevents the attachment of the cells from the endothelial cells in vivo.

Antigens, CD↗
PubMed2000

Blockade of JAK2 by tyrphostin AG-490 inhibits antigen-induced eosinophil recruitment into the mouse airways.

We studied the effect of tyrphostin AG-490, a specific Janus kinase 2 (JAK2) inhibitor, on antigen-induced eosinophil recruitment into the airways of sensitized mice and on IL-5-induced chemokinesis and adhesiveness of eosinophils. The in vivo administration of AG-490 prevented antigen-induced eosinophil infiltration in the airways of sensitized mice in a dose-dependent manner. However, the administration of AG-490 did not affect antigen-induced IL-5 production in the airways nor in vitro antigen-induced IL-5 production and T cell proliferation of spleen cells. Furthermore, AG-490 inhibited IL-5-induced chemokinesis and beta1-integrin adhesiveness of eosinophils in vitro. Because antigen-induced eosinophil recruitment into the airways is mediated by IL-5, these results indicate that JAK2 activation is critical for antigen-induced, IL-5-dependent mobilization of eosinophils into the tissue.

Animals↗
PubMed2002

Phytochemical inhibition of interleukin-4-activated Stat6 and expression of VCAM-1.

Cellular functions induced by cytokine interleukin (IL)-4 and IL-4 signaling through signal transducer and activator of transcription (Stat)6 typify a Th2-type immune response. We investigated the inhibitor effect of the NFkappaB blocker parthenolide in the late-phase, Th2-type immune response. Parthenolide blocked by 90.6 +/- 7.4% the IL-4-induced expression of the endothelial vascular cell adhesion molecule (VCAM)-1, a hallmark of extravasation of very late antigen-4-positive leukocytes. The noncytotoxic concentrations of 10 microM parthenolide left a section of the IL-4 receptor signal transduction intact. Parthenolide did not interfere with the immediate IL-4-induced phosphorylation of endothelial Stat6 on its tyrosine residue Y641 and with tyrosine phosphorylation of the adapter molecule, Jak2-both processes are obligatory for dimerization and nuclear translocation of Stat6. But parthenolide inhibited the Stat6 DNA-binding activity in IL-4-stimulated endothelial cells and inhibited the IL-4-driven activation of a luciferase reporter gene under the control of Stat6-responsive elements (IC(50) 5.11 +/- 0.67 microM). Together, these data suggest an anti-chronic disease profile for the sesquiterpene lactone parthenolide.

Animals↗
PubMed1995

Focal adhesion kinase (pp125FAK) is tyrosine phosphorylated after engagement of alpha 4 beta 1 and alpha 5 beta 1 integrins on human T-lymphoblastic cells.

pp125FAK is a novel protein tyrosine kinase associated with focal adhesions. It has been shown that ligation of VLA beta 1 integrins on a number of cell types enhanced tyrosine phosphorylation and kinase activity of pp125FAK. Cellular transformation by retroviral oncogene products or mitogenic neuropeptides also result in the activation of this kinase. On the basis of these observations, pp125FAK has been proposed to be a key regulatory molecule connecting cell adhesion, transformation, and growth. We have previously shown that ligation of VLA beta 1 integrins induced CD3-dependent T cell proliferation and stimulated tyrosine phosphorylation of a molecular mass with a 105-kDa protein (pp105). Here we report that engagement of alpha 4 beta 1 and alpha 5 beta 1 integrins by adherence to their respective ligands stimulated tyrosine phosphorylation of 105- to 120-kDa proteins (pp105 and pp120, respectively) in human H9 T-lymphoblastic cells. At least one component of the 105- to 120-kDa proteins was found to be tyrosine-phosphorylated pp125FAK. While kinetics of adherence-dependent tyrosine phosphorylation of pp120/pp125FAK and pp105 are closely similar, pp105 appeared to be distinct from pp125FAK. Given T cell costimulation induced by VLA beta 1 integrins and the putative functional role of pp125FAK in cell growth, tyrosine phosphorylation of these two distinct proteins may be involved in T cell activation and proliferation.

Cell Adhesion↗
PubMed1995

Administration of monoclonal antibodies against vascular cell adhesion molecule-1/very late antigen-4 abrogates predisposing autoimmune diabetes in NOD mice.

The interaction of vascular cell adhesion molecule-1 and very late antigen-4 (alpha 4 beta 1-integrin) has been recently known to be profoundly involved in the trafficking of lymphocytes from the circulation into the inflammatory tissues. To elucidate the role of these molecules in the development of autoimmune diabetes, the expression of these adhesion molecules on inflamed islets and the effects of administration of monoclonal antibodies to these molecules on insulitis and overt diabetes were evaluated in nonobese diabetic (NOD) mice. Immunohistochemical study revealed the overexpression of vascular cell adhesion molecule-1 on vascular endothelium near or within inflamed islets and alpha 4-integrin on islet-infiltrating mononuclear cells. Either anti-vascular cell adhesion molecule-1 or anti-alpha 4-integrin monoclonal antibody prevented the transfer of diabetes in irradiated NOD mice which received spleen cells from acutely diabetic NOD mice. When both monoclonal antibodies were administrated to NOD mice during 2-30 weeks of age, neither lymphocytic infiltration to islets nor overt diabetes was observed. Furthermore, administration of these antibodies even from 10 weeks of age could inhibit the development of insulitis and diabetes, whereas administration during 2-5 weeks of age could not. Splenocytes obtained from these treated mice showed no significant change of cytokine production and preserved the ability to transfer diabetes into NOD scid/scid mice. This suggests that treatment with antibodies against these adhesion molecules can inhibit insulitis and diabetes without affecting the Th1/Th2 balance or effector T cells. The blockade of vascular cell adhesion molecule-1/very late antigen-4 interaction would be suitable for therapeutical treatment of the predisposing and latent type I (insulin-dependent) diabetic subjects.

Animals↗
PubMed1996

Human intestinal intraepithelial lymphocytes bind to mucosal mesenchymal cells through VLA4 and CD11A.

Human intestinal intraepithelial lymphocytes (IEL), predominantly CD8+ T lymphocytes, are uniquely situated at the basolateral surfaces of epithelial cells in contact with the myofibroblasts that comprise the basement membrane. Since mesenchymal cells may anchor IEL in this location and may also serve as antigen-presenting cells, the mechanism of binding to IEL was investigated. Lymphocytes were radiolabeled with [51Cr] sodium chromate, cocultured with mesenchymal cell monolayers, and the nonadherent lymphocytes removed by washes. Those adherent to the monolayers were counted by measuring the amount of radiolabel retained in the well. A large fraction of IL-2-activated IEL bound to KD (lip fibroblast), HISM (jejunal smooth muscle), and JF (jejunal fibroblast) cell lines after a 2-hr incubation: 33 +/- 11, 37 +/-14, and 48 +/- 15%, respectively. When monoclonal antibodies directed at the alpha chains of the very late activation antigens (CD49) were added alone or combined with anti CD11a to assays measuring IEL binding to KD or JF monolayers, the greatest inhibition (33 to 38%) occurred with anti-alpha 4 combined with anti-CD11a. The majority of IEL expressed alpha 1 and alpha 4 before and after a 3-day culture with IL-2, with no change in surface density. VCAM-1, a binding partner to alpha 4, was not expressed on KD or JF cells, and anti-VCAM antibody had no effect on binding. In summary, alpha 4 and CD11a on IEL mediate binding to mesenchymal cells.

Cell Adhesion↗