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PubMed1993

Alpha 4 beta 7 integrin mediates B cell binding to fibronectin and vascular cell adhesion molecule-1. Expression and function of alpha 4 integrins on human B lymphocytes.

Cell-cell and cell-extracellular matrix interactions are mediated by a wide array of cell surface molecules known as adhesion receptors, including the integrin family that comprises numerous alpha beta heterodimers. A new integrin group, the beta 7 subfamily, has been recently defined. Its two members, alpha 4 beta 7 and alpha H beta 7, are involved in the lymphocyte migration to the Peyer's patches and the intestinal mucosa, respectively. We have analyzed the expression of alpha 4 beta 7 integrin on B cells from different cellular compartments and at different activation states. Resting peripheral blood B lymphocytes constitutively express large amounts of alpha 4 beta 7. By contrast, alpha 4 beta 7 integrin, which is absent on resident B cells from different lymphoid tissues, is induced upon activation. Functional studies indicates that alpha 4 beta 7 is mediating B cell attachment to fibronectin and vascular cell adhesion molecule-1 through distinct epitopes on this integrin. Furthermore, the alpha 4 beta 7 integrin is also implicated in intercellular interactions as deduced by the ability of anti-alpha 4 beta 7 mAb to trigger homotypic B cell aggregation. Finally, alpha 4 beta 7 and alpha 4 beta 1 integrins redistribute at the cell membrane in a similar clustering pattern when B cells attach to fibronectin- and vascular cell adhesion molecule-1-coated surfaces. Our studies demonstrate the differential regulation on the expression and function of alpha 4 beta 7 integrin among different human B cell populations.

Antigens, Neoplasm↗
PubMed1993

A novel cyclic pentapeptide inhibits alpha 4 beta 1 and alpha 5 beta 1 integrin-mediated cell adhesion.

Lymphocytes and monocytes initiate and modulate inflammatory and immune responses for host defense. This process is dependent upon extravasation of leukocytes from the circulation to sites of antigenic challenge and is controlled, in part, by various integrins, including alpha 4 beta 1 and alpha 5 beta 1. A small cyclic pentapeptide that inhibits, in vitro, both alpha 4 beta 1 and alpha 5 beta 1 activity is described. This peptide, Arg-Cys-Asp-Thioproline-Cys (RC*D[ThioP]C*), is cyclized by a disulfide bond through the cysteine residues (the asterisks denote cyclizing residues). RC*D(ThioP)C* inhibits alpha 5 beta 1-mediated leukocyte adhesion to the 120-kDa Arg-Gly-Asp (RGD)-containing binding site of fibronectin. Two different adhesion activities of alpha 4 beta 1 are also inhibited: alpha 4 beta 1-mediated cell adhesion to the alternatively spliced CS-1 site of fibronectin and the alpha 4 beta 1-dependent binding of leukocytes to cytokine-activated endothelial cells. Both alpha 4 beta 1 and alpha 5 beta 1 can be purified by affinity chromatography using the immobilized pentapeptide. The peptide does not inhibit adhesion to other extracellular matrix proteins including laminin and vitronectin. The specificity of the RC*D(ThioP)C* peptide for alpha 4 beta 1 and alpha 5 beta 1 suggests potential therapeutic utility for inhibiting inflammatory disease.

Amino Acid Sequence↗
PubMed1993

Alpha 4 beta 1-integrin expression on sickle reticulocytes: vascular cell adhesion molecule-1-dependent binding to endothelium.

Important complications in sickle cell anemia occur secondary to vascular occlusion, which is postulated to be initiated by interactions of erythrocytes with vascular endothelial cells. In patients with sickle cell anemia, up to 25% of reticulocytes express the alpha 4 beta 1-integrin complex. Furthermore, erythrocytes from patients with sickle cell anemia bind to endothelial cells activated by tumor necrosis factor alpha via (TNF alpha) via interactions between erythrocyte alpha 4 beta 1 and endothelial cell vascular cell adhesion molecule-1 (VCAM-1). Thus, binding of alpha 4 beta 1-expressing reticulocytes to cytokine-activated endothelial cells may initiate vascular complications in sickle cell anemia and perhaps other hemolytic anemias during episodes of infection and inflammation.

Anemia, Sickle Cell↗
PubMed1995

Spreading and focal contact formation of human melanoma cells in response to the stimulation of both melanoma-associated proteoglycan (NG2) and alpha 4 beta 1 integrin.

In this study, we evaluated the potential role for a specific melanoma-associated chondroitin sulfate proteoglycan core protein, termed NG2, to collaborate with alpha 4 beta 1 integrin in focal contact formation in human melanoma cells. Although melanoma cells adhered to substrata coated with either the alpha 4 beta 1 integrin binding fibronectin synthetic peptide CS1-OVA or anti-NG2 mAbs, no spreading or focal contact formation was observed on either substratum. However, melanoma cells spread and formed focal contacts on "chimeric substrata" coated with CS1-OVA and the anti-NG2 mAb, 9.2.27, indicating that engaging both adhesion receptors changes the adhesion phenotype of melanoma cells by reorganizing the cytoskeleton. The collaboration between the two receptors is specific to fibronectin, since cells adherent on substrata coated with low concentrations of either laminin and 9.2.27 or type IV collagen and 9.2.27 failed to spread, while cells adherent on low concentrations of fibronectin and 9.2.27 exhibited a fully spread morphology. Two selective tyrosine kinase inhibitors, genistein and herbimycin A, totally inhibited cell spreading on the substrata coated with CS1-OVA and 9.2.27, indicating that tyrosine kinase(s) is important for cell spreading and focal contact formation. When cells were cultured on substrata coated with CS1-OVA and 9.2.27, two proteins (M(r) 130,000 and 120,000) were tyrosine phosphorylated in a genistein- and herbimycin A-sensitive fashion. These proteins were not immunologically related to pp125FAK or alpha 4 beta 1 integrin. Importantly, when melanoma cells were cultured on substrata coated with CS1 and then stimulated with 9.2.27-conjugated microsphere beads, formation of focal contacts and stress fibers was also observed, indicating that NG2 can collaborate with alpha 4 beta 1 integrin when each receptor is engaged on distinct and separate substrata. These results demonstrate that NG2 acts as a coreceptor for spreading and focal contact formation in association with alpha 4 beta 1 integrin in melanoma cells and suggest a model in which the NG2 core protein communicates to alpha 4 beta 1 integrin by an inside-out signaling mechanism.

Antibodies, Monoclonal↗
PubMed1995

Regulation of lymphocyte pseudopodia formation by triggering the integrin alpha 4/beta 1.

Video microscopy and digital imaging were used to quantitatively analyze lymphocyte adhesion and formation of pseudopodia on the extracellular matrix protein fibronectin (FN). A morphology kinetics assay comparing pseudopodial extension values over a 24-h period showed that HPB-ALL T leukemic cells undergo a wave of morphologic change, returning to a round shape after 8 h. Using anti-alpha 4 and anti-alpha 5 mAbs and a panel of cell types that are single or double positive for expression of the alpha 4/beta 1 and alpha 5/beta 1 FN binding integrins, it was determined that cell adhesion to FN was influenced by both beta 1-integrins, whereas alpha 4/beta 1 was found to be the major FN receptor mediating pseudopodia extension. The protein kinase inhibitor staurosporine, the protein kinase C inhibitors calphostin C and chelerythrine, and the protein tyrosine kinase inhibitor herbimycin A blocked pseudopodial extension in HPB-ALL cells. In contrast, two cAMP-dependent protein kinase inhibitors H8 and H89 did not inhibit. Inhibitors of phospholipase A2, lipoxygenases, and cyclooxygenases could block formation of pseudopodia, yet had little or no effect on cell adhesion to FN. The preincubation of cells with arachidonic acid could prevent the inhibition mediated by the reversible phospholipase A2 inhibitor cibacron blue. We conclude that the formation of lymphocyte pseudopodia in response to FN can utilize the adhesive and signaling activities of the alpha 4/beta 1-integrin and the enzymatic activities of protein kinases and phospholipases.

Antibodies, Monoclonal↗
PubMed1994

Adhesion to fibronectin primes eosinophils via alpha 4 beta 1 (VLA-4).

Human peripheral blood eosinophils adhered specifically to microtitre plates coated with plasma fibronectin (Fn) in a dose- and time-dependent fashion. Adhesion was optimal at 60 min at a concentration of 100 micrograms/ml. Adherence to Fn was up-regulated by platelet-activating factor (PAF; optimum concentration of 10(-6) M) and was significantly inhibited by a polyclonal anti-Fn antibody (P < 0.05). The following evidence suggested that eosinophil adhesion to Fn was mediated by alpha 4 beta 1: (1) eosinophil adherence to Fn was not inhibited by an Arg-Gly-Asp-Ser (RGDS) synthetic peptide; (2) there was a dose-dependent adherence of eosinophils to microtitre plates coated with the 40,000 MW proteolytic fragment of Fn that contains the CS-1 alpha 4 beta 1 binding region, whereas adherence to the 120,000 MW chymotryptic fragment of Fn, which contains the RGD-dependent binding site, was weak and only observed at high concentrations (> 250 micrograms/ml); (3) significant inhibition of eosinophil adherence to Fn was achieved by monoclonal antibodies (mAb) against the alpha chain of VLA-4 but not by a mAb against CD45 or a mouse myeloma antibody as negative controls. After adhesion to Fn, eosinophils were investigated for their capacity to release leukotriene C4 in response to stimulation with a suboptimal concentration of calcium ionophore (2 x 10(-6) M). Significant enhancement of release was detected with Fn-coated plates but not with the control bovine serum albumin (BSA) (P < 0.01). Furthermore, this enhancement was significantly inhibited by the alpha 4 beta 1 mAb HP2/1 (P < 0.05) but not by an anti-CD45 mAb. From these studies we conclude that (1) alpha 4 beta 1 (VLA-4) integrin is a major receptor for Fn on human eosinophils and (2) adhesion to Fn may prime eosinophils for mediator release during allergic inflammation.

Antibodies↗
PubMed1993

Expression of a functional laminin receptor (alpha 6 beta 1, very late activation antigen-6) on human eosinophils.

The mechanisms responsible for the accumulation of eosinophils at sites of allergic and other inflammatory reactions are unknown, but recent studies have implicated both eosinophil and endothelial adhesion molecules in this process. However, less well studied have been the adhesive interactions between eosinophils and the subendothelial basement membrane and interstitial connective tissues. To test the hypothesis that eosinophils might interact with extracellular matrix proteins, we analyzed purified human eosinophils for the expression and function of various beta 1 integrins. Using indirect immunofluorescence and flow cytometry, purified eosinophils from mildly allergic donors were found to consistently express the integrin subunits beta 1 (CD29), alpha 4 (CD49d, very late activation antigen [VLA]-4 alpha), and alpha 6 (CD49f, VLA-6 alpha). No significant expression of the alpha 1, alpha 2, alpha 3, alpha 5, or beta 4 subunits was detected. Platelet contamination of the eosinophil preparations was excluded by light microscopy and by the inability to detect expression of platelet glycoproteins alpha v, CD41b, and CD42b. Immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of eosinophils confirmed the expression of cell-surface beta 1, alpha 4, and alpha 6. Furthermore, eosinophils purified from allergic donors were shown to adhere to plate-bound laminin, but not to type 1 or type 4 collagen. Adhesion to laminin was concentration-dependent, required divalent cations, and was completely and specifically inhibited by the anti-alpha 6 monoclonal antibody (MoAb) GoH3 and by the anti-beta 1 MoAb 33B6. Interestingly, the anti-beta 1 MoAb 18D3 (which like 33B6 blocks eosinophil binding to VCAM-1) did not inhibit eosinophil adhesion to laminin, suggesting that there are functionally distinct epitopes on the beta 1 subunit. Eosinophils purified from 4 healthy, nonallergic donors also showed alpha 6-dependent adhesion to laminin, although these cells adhered less well. These studies establish the expression of alpha 6 beta 1 on human eosinophils and document its function as a laminin receptor. Interaction of eosinophil alpha 6 beta 1 with laminin, eg, in basement membranes, may contribute to the localization of these cells at inflammatory sites in vivo.

Animals↗
PubMed1993

Alpha 4 beta 1 recognition of the Hep II domain of fibronectin is constitutive on some hemopoietic cells but requires activation on others [corrected].

Leukocyte adhesion to the carboxyl-terminal region of fibronectin, a major component of extracellular matrices, involves recognition of the CS-1 site and the Hep II domain. We have previously shown that cultured T and B lymphoid cells constitutively attach via the alpha 4 beta 1 integrin to a 38-kDa fibronectin fragment that contains CS-1 and Hep II, and to a 58-kDa fragment that contains Hep II only. In this report we have studied the adhesion of other hemopoietic cells to the CS-1 and Hep II regions of fibronectin. Cultured monocytic cells and peripheral blood T lymphocytes constitutively bound to the 38-kDa fragment indicating that alpha 4 beta 1 was functional. These cells, however, were unable to bind to the 58-kDa fragment. On lymphoid cells both fragments were shown to bind to very close regions of alpha 4 beta 1 as indicated by the inhibition pattern of mAb to various alpha 4 epitopes, and by the good inhibitory capacity of soluble 38-kDa fragment on cell adhesion to 58-kDa fragment. These results suggested that alpha 4 beta 1 is present on certain cell populations as a partially active form able to recognize the "high affinity" ligand CS-1 but not the "low affinity" ligand Hep II. Binding of monocytic cells and peripheral blood T lymphocytes to the Hep II domain could be induced by several agents: first, long (48-h) and short (20-min) treatment with phorbol esters; second, cell incubation with the divalent cation Mn2+; third, and most effective, cell incubation with the mAb TS2/16, which is directed to the beta 1 integrin subunit. Binding to the 58-kDa fragment in all three cases was completely inhibited by mAb anti-alpha 4, thus confirming the involvement of alpha 4 beta 1 in the recognition of the Hep II domain. No major changes on alpha 4 beta 1 surface expression were observed after these treatments as determined by immunofluorescence analyses. Our results indicate that hemopoietic cells may differentially bind the CS-1 and Hep II ligands in fibronectin depending on the activation state of alpha 4 beta 1, a fact that may be relevant for the migration and function of leukocytes.

Antibodies, Monoclonal↗
PubMed1995

Porcine vascular cell adhesion molecule (VCAM) mediates endothelial cell adhesion to human T cells. Development of blocking antibodies specific for porcine VCAM.

Vascular cell adhesion molecule (VCAM) is expressed on activated endothelial cells and binds to the alpha 4 beta 1 integrin receptor, very late antigen-4 (VLA-4), expressed on human lymphoid cells. Anti-VCAM mAbs have been shown to prolong allograft survival. To explore the role of porcine VCAM (pVCAM) in xenotransplantation, a recombinant secreted form of pVCAM (spVCAM) was expressed in 293-EBNA cells and purified by metal affinity chromatography. A human lymphoid cell line bound to spVCAM in a VLA-4-dependent manner. Using spVCAM as an immunogen, we developed three anti-pVCAM mAbs that reacted with cell surface pVCAM on porcine aortic endothelial cells (PAEC) but not to human VCAM on human umbilical vein endothelial cells. Pairwise interaction analysis indicated that these mAbs recognized distinct epitopes on pVCAM. Two anti-pVCAM mAbs, 2A2 and 3F4, inhibited the binding of Ramos cells to spVCAM, while the third, 5D11, did not. Similarly, mAbs 2A2 and 3F4 inhibited binding of Ramos cells or human peripheral blood T cells to activated PAEC. The extent of inhibition with mAbs 2A2 and 3F4 was comparable to the inhibition obtained with a blocking mAb to human VLA-4. These anti-pVCAM mAbs will provide a means to specifically block pVCAM in a xenograft setting and allow the determination of the role of pVCAM in a primary xenogeneic immune response.

Amino Acid Sequence↗
PubMed1995

Differential expression of L-selectin, VLA-4, and LFA-1 on CD34+ progenitor cells from bone marrow and peripheral blood during G-CSF-enhanced recovery.

To examine mechanisms of mobilization and homing of hematopoietic progenitor cells, coexpression of CD34 and the adhesion molecules L-selectin (CD62L), VLA-4 (alpha 4 beta 1-integrin, CD49d/CD29), and LFA-1 (alpha L beta 2-integrin, CD11a/CD18) was evaluated. Samples from leukapheresis (LP) products and bone marrow (BM) were obtained on the same day from patients who received granulocyte colony-stimulating factor (G-CSF) after cytotoxic chemotherapy. The proportion of CD34+ cells expressing L-selectin tended to be greater in LP products compared with BM. In samples from both sources, the mean fluorescence intensity of CD34 was significantly greater on CD34+/L-selectin-positive cells compared with the CD34+/L-selectin-negative cell subset. Three-color immunofluorescence showed that early CD34+/HLA-DRdim or CD34+/HLA-DR- progenitor cells were strongly positive for L-selectin, whereas L-selectin-negative cells were only found in the CD34+HLA-DRbright subset. The mean fluoresence intensity of VLA-4 and LFA-1 was significantly greater on CD34+ cells from BM compared with LP products. Moreover, a distinct population of CD34dim/VLA-4bright and CD34dim/LFA-1bright cells was found only in samples from BM. This subset may be enriched for myeloid progenitor cells, since the cloning efficiency of CD34+ cells for CFU-GM was significantly greater in BM samples than in LP products. Binding of CD34+ cells to endothelial cells was partially inhibited by a blocking antibody to beta 2-integrin. In conclusion, L-selectin is expressed in significant amounts on more primitive CD34+ cells which circulate in considerable numbers in the peripheral blood. This suggests that L-selectin plays a role in redistribution and homing of hematopoietic progenitor cells to the bone marrow following cytotoxic damage. Conversely, strong expression of VLA-4 and LFA-1 was mainly found on lineage-committed progenitor cells of the bone marrow.

Adult↗
PubMed1996

Induction of experimental bone metastasis in mice by transfection of integrin alpha 4 beta 1 into tumor cells.

Cell adhesion receptors (eg, integrins and CD44) play an important role in invasion and metastasis during tumor progression. The increase in integrin alpha 4 beta 1 expression on primary melanomas has been reported to significantly correlate with the development of metastases. alpha 4 beta 1 is a cell surface heterodimer that mediates cell-cell and cell-extracellular matrix interactions through adhesion to vascular cell adhesion molecule (VCAM)-1 and to the IIICS region of fibronectin. To test the effects of alpha 4 beta 1 expression on tumor cell metastasis, Chinese hamster ovary cells were transfected with human alpha 4 cDNA. Whereas alpha 4-negative Chinese hamster ovary cells developed only pulmonary metastasis, alpha 4-positive Chinese hamster ovary cells developed bone and pulmonary metastasis in 3 to 4 weeks when injected intravenously into nude mice. Bone metastasis was inhibited by antibody against alpha 4 or VCAM-1. Expression of alpha 3 beta 1, alpha 6 beta 1, or alpha V beta 1 did not induce bone metastasis. Expression of alpha 4 beta 1 also induced bone metastasis in K562 human erythroleukemia cells injected into SCID mice. These results demonstrate that alpha 4 beta 1 can induce tumor cell trafficking to bone, probably via interaction with VCAM-1 that is constitutively expressed on bone marrow stromal cells.

Animals↗
PubMed1996

Adhesion receptors on bone marrow stromal cells: in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and gamma-irradiated mice.

Cell adhesion molecules (CAMs) play a key role in interactions between stromal and hematopoietic cells in bone marrow (BM) and in cell traffic through vascular endothelium. To examine the identity of CAMs involved in these processes in mouse BM, we have investigated the in vivo expression of vascular cell adhesion molecule-1 (VCAM-1) and its counter-receptor, very late antigen-4 (VLA-4). Radioiodinated monoclonal antibodies (MoAbs) detecting VLA-4 and VCAM-1 were injected intravenously. Antibody binding was detected in BM by light and electron microscope radioautography. VCAM-1 labeling was restricted to stromal reticular cells and endothelial cells lining BM sinusoids. VCAM-1+ reticular cells formed patchy concentrations, especially in subosteal regions, associated with lymphoid, granulocytic, and erythroid cells. After gamma-irradiation to deplete hematopoietic cells, reticular cells and endothelial cells all showed VCAM-1 labeling in apparently increased intensity. VLA-4 labeling was shown by undifferentiated blast cells and lymphohematopoietic cells both in BM cell suspensions and in vivo, especially at reticular cell contact points. The results demonstrate that VCAM-1 is expressed in vivo by certain BM reticular cells, suggesting that the molecule mediates adhesion to multiple lineages of lymphohematopoietic cells. The finding that VCAM-1 is also expressed constitutively by BM sinusoidal endothelium, unlike its inductive expression by endothelia elsewhere, suggests that VCAM-1 and VLA-4 may be involved in regulating the normal cell traffic between BM and the blood stream.

Anemia, Aplastic↗
PubMed1995

Lymphocyte adhesion and transendothelial migration in the central nervous system: the role of LFA-1, ICAM-1, VLA-4 and VCAM-1. off.

Lymphocyte adhesion to and migration across endothelial cell (EC) monolayers, derived from the rat blood-retinal barrier (BRB), were measured in vitro. The binding of concanavalin A (Con A)-activated peripheral lymph node lymphocytes and the migration of CD4+ T-cell lines could be significantly increased by treating the EC with interleukin-1 beta (IL-1 beta). To determine the role of various adhesion molecules during the processes of lymphocyte binding and transmonolayer migration (diapedesis), lymphocytes were treated with monoclonal antibody (mAb) specific for CD11a (alpha L subunit of leucocyte functional antigen-1; LFA-1), CD18 (beta 2 subunit of leucam family) and CD49d (alpha 4 subunit of very late activation antigen-4; VLA-4) and EC with mAb specific for CD54 (intercellular adhesion molecule-1; ICAM-1) and CD106 (vascular cell adhesion molecule-1; VCAM-1). Binding of the highly adhesive but non-migratory Con A-activated lymphocytes was inhibited by mAb to CD11a (reduced to 73% and 65% of control lymphocyte adhesion) and CD18 (42% and 54%) on non-activated and IL-1 beta-treated EC, respectively, but not by mAb to ICAM-1 or VCAM-1. Diapedesis of the highly migratory T-cell line lymphocytes was also blocked by antibodies to CD11a (reduced to 11% and 10% of control T-cell migration), CD18 (29% and 43%) but in addition was also inhibited by anti-ICAM-1 (17% and 53%) on non-activated and IL-1 beta treated EC, respectively. Both anti-VLA-4 and anti-VCAM-1 were also effective in producing a smaller reduction in migration, but only on IL-1 beta activated EC (66% and 58% of control migration, respectively). These studies indicate that lymphocyte adhesion to central nervous system (CNS) vascular EC is largely dependent on LFA-1 but not through its interaction with ICAM-1. In contrast, lymphocyte diapedesis is mostly supported through the LFA-1/ICAM-1 pairing, with a small proportion being mediated by VLA-4/VCAM-1 on IL-1 beta-activated EC. This latter pathway, however, also appears to be dependent on LFA-1 interacting with the EC.

Animals↗
PubMed1995

[Role of adhesion molecules (VLA-4) in the asthmatic response to allergens].

We evaluated the role of very late antigen-4 (VLA-4) in asthmatic responses. Brown-Norway rats were sensitized with ovalbumin and then challenged with ovalbumin. Respiratory impedance, and the influx of eosinophils and of VLA-4-positive cells were measured. Eosinophils were stained with Giemsa's solution and VLA-4-positive cells were detected by an immunocytochemical method with a monoclonal antibody against rat VLA-4 (MR alpha 4-1). The numbers of eosinophils and of VLA-4-positive cells in sections of lung tissue from the rats were counted. The effect of MR alpha 4-1 and of a new anti-allergic drug, TYB-2285, on late asthmatic responses was also studied. Respiratory impedance had increased in all the rats by 6-7 hours after the challenge, which indicated that these animals had a late asthmatic response. These rats had more eosinophils and more VLA-4-positive cells than did sensitized animals that were not challenged. The rats given MR alpha 4-1 had significantly smaller increases in respiratory impedance and less eosinophil influx than did those given only phosphate-buffered saline. The rats given TYB-2285 had significantly smaller increases in impedance and less influx of eosinophils and of VLA-4-positive cells. These results show that infiltration of eosinophils and of VLA-4-positive cells corresponds closely with the late asthmatic response, and they suggest that the VLA-4/VCAM-1 pathway plays an important role in this response. These data also suggest that the infiltration of VLA-4-positive cells can be used to evaluate the effect of anti-allergic drugs on the late asthmatic response.

Allergens↗
PubMed1996

Very late antigen-4/vascular cell adhesion molecule-1 (VLA-4/VCAM-1) pathway is involved in the transendothelial migration of lymphocytes in bancroftian filariasis.

The role of endothelial vascular cell adhesion molecule-1 (VCAM-1) in the trafficking of lymphocytes from the vascular circulation through endothelium and into sites of filarial inflammation was investigated in asymptomatic microfilaremic (MF; n = 16) and in patients with filaria-associated lymphatic pathology (LP; n = 23). When compared, by human umbilical vein endothelial cell ELISA, with PBMC supernatants generated from MF patients, filarial Ag (Brugia malayi adult Ag (BmA))-stimulated supernatants from LP patients stimulated over 50% more VCAM-1 (lymphatic pathology (LP) = 0.377 relative ELISA units vs MF = 0.246; p = 0.02). No difference was seen between patient groups with nonfilarial Ag (streptolysin O)-stimulated supernatant (LP = 0.160 relative ELISA units vs MF = 0.166). BmA-stimulated supernatants from LP patients stimulated significantly more T cell migration (percentage of relative migration LP = 79.9% vs MF = 25.8%; p = 0.01) through tightly confluent human umbilical vein endothelial cell monolayers cultured on collagen gels. Anti-VCAM-1 inhibited the increased T cell migration induced by BmA-stimulated supernatants by 97.7%, anti-VLA-4 by 74.7%, and blockade of NF-kappa B-dependent VCAM-1 transcription with 50 microM pyrrolidine dithiocarbamate resulted in 87.7% inhibition. Biopsies from 87.5% of the LP patients, but only 38.5% of the MF patients, demonstrated VCAM-1 on vascular endothelium. BmA-stimulated supernatants pretreated with anti-IL-1 alone resulted in VCAM-1 expression that was 23.7% of that with untreated supernatants while anti-IL-4, anti-IFN-gamma, or anti-TNF alone had essentially no effect on VCAM-1 expression.

Adolescent↗
PubMed1996

Specific regulation of VLA-4 and alpha 4 beta 7 integrin expression on human activated T lymphocytes.

Modulation of VLA integrins was studied in several human T cell clones upon specific and nonspecific cellular activation. Human activated T lymphocytes down-regulated both alpha 4 beta 1 and alpha 4 beta 7 integrins upon specific recognition of alloantigens (cytotoxic T cells) or in the presence of Staphylococcus enterotoxin B (superantigen recognizing noncytotoxic T cells). In contrast, the expression of other membrane integrins, such as VLA-1 and VLA-5 integrins, was not modified. Down-regulation of alpha 4 beta 1 and alpha 4 beta 7 integrins was observed as early as 3 h after stimulation, lasted later than 72 h and was partially inhibited by cytochalasin D. Interestingly, neither target cells nor NK cells modulated CD49d expression after interaction with T cells of K562, respectively, suggesting that CD49d expression was linked to specific T cell activation. The down-regulation of the CD49d chain in T cell clones stimulated with immobilized anti-CD3 mAbs confirmed the role of TCR-mediated activation in CD49d regulation. However, the CD3-independent cellular aggregation induced by soluble anti-CD43 mAb was also able to strongly down-regulate alpha 4 beta 1 and alpha 4 beta 7. The present work shows the first evidence that CD49d subunit-bearing integrin expression is distinctly regulated from other integrins after Ag or superantigen recognition by human activated T cells. CD49d modulation may be relevant for the traffic and tissue localization of locally activated T cells during immune responses.

Antigen-Presenting Cells↗
PubMed1996

A critical role of VLA-4 in erythropoiesis in vivo.

Hematopoiesis requires specific interactions with the microenvironments, and VLA-4 has been implicated in these interactions based on in vitro studies. To study the role of VLA-4 in hematopoiesis in vivo, we performed in utero treatment of mice with an anti-VLA-4 monoclonal antibody. Although all hematopoietic cells in fetal liver expressed VLA-4, the treatment specifically induced anemia. It had no effect on the development of nonerythroid lineage cells, including lymphoids and myeloids. In the treated liver almost no erythroblast was detected, whereas the erythroid progenitors, which give rise to erythroid colonies in vitro, were present. These results indicate that VLA-4 plays a critical role in erythropoiesis, while it is not critical in lymphopoiesis in vivo.

Animals↗