The beta 1-integrin (CD29) receptors: mediators of T lymphocyte--extracellular matrix recognition that affect adhesion, activation and lymphokine secretion.
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Cell Adhesion↗
Biomedical subjects
O Lider
Publications and source records attributed to O Lider.
Involvement of a protein kinase C and protein phosphatases in adhesion of CD4+ T cells to and detachment from extracellular matrix proteins.
For immune surveillance and function to be effective, T lymphocytes constantly recirculate via lymph and blood between lymphoid organs and body tissues. To enable efficient cell movement and migration, cell adhesion to components of the basement membrane and the extracellular matrix (ECM) must be a rapid and transitory process. Whether phosphorylation and dephosphorylation of cellular proteins are involved in this phenomena was explored by monitoring the adhesion of T cells to immobilized ECM proteins. A short exposure of 51Cr-labeled human CD4+ T cells to phorbol esters in vitro induced a rapid beta 1-integrin-mediated adhesion to both fibronectin and laminin, as determined by inhibition with anti-integrin antibodies. Adhesion was reversible; detachment from the immobilized ECM ligands occurred between 20 and 120 min without further intervention. This T cell adhesion was regulated by the activation of protein kinase C because (a) staurosporine and H-7 inhibitors of protein kinase C suppressed T cell adhesion, and (b) PMA-induced down-regulation of intracellular levels of protein kinase C was associated with the abrogation of the T cell adhesiveness to fibronectin and laminin. Furthermore, inhibition of protein phosphatases activity by okadaic acid delayed the detachment of the T cells from fibronectin or laminin. Thus, we suggest that T cell-ECM interactions such as adhesion and detachment are regulated, respectively, by protein kinase C and protein phosphatases.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering.
Oral administration of myelin basic protein (MBP) is an effective way of suppressing experimental autoimmune encephalomyelitis (EAE). We have previously shown that such suppression is mediated by CD8+ T cells, which adoptively transfer protection and suppress immune responses in vitro. In the present study we have found that modulator cells from animals orally tolerized to MBP produce a suppressor factor upon stimulation with MBP in vitro that is specifically inhibited by anti-transforming growth factor beta (TGF-beta) neutralizing antibodies. No effect was observed with antibodies to gamma interferon, tumor necrosis factor alpha/beta, or indomethacin. In addition, the active form of the type 1 isoform of TGF-beta 1 (TGF-beta 1) can be directly demonstrated in the supernatants of cells from animals orally tolerized to MBP or ovalbumin after antigen stimulation in vitro. Antiserum specific for TGF-beta 1 administered in vivo abrogated the protective effect of oral tolerization to MBP in EAE. Furthermore, injection of anti-TGF-beta 1 serum to nontolerized EAE animals resulted in an increase in severity and duration of disease. These results suggest that immunomodulation of EAE induced by oral tolerization to MBP and natural recovery mechanisms use a common immunoregulatory pathway that is dependent on TGF-beta 1. Implications of such an association are of therapeutic relevance to human autoimmune diseases and may help to explain one of the mechanisms involved in the mediation of active suppression by T cells.
Administration, Oral↗
T lymphocyte adhesion to the fibronectin and laminin components of the extracellular matrix is regulated by the CD4 molecule.
The adhesion of T cells to components of the extracellular matrix (ECM) is mediated by the beta 1 subfamily of integrin receptors, designated VLA. It has been recently demonstrated that the binding of VLA receptors to protein components of the ECM is rapidly augmented by the activation of the T cells without, however, any actual change in the level of expression of the VLA receptors for fibronectin (FN) or laminin (LN). Thus, it is likely that activation of existing VLA receptors is required for binding. The activation must be regulated by T cell surface molecules capable of transducing signals into the cell. We studied the role of the CD4 molecule in the binding of rat CD4+ T cells to the FN and LN components of the ECM. We now report that the CD4 molecule appears to play a major role in regulating T cell interactions with ECM. This conclusion is based on the following observations: (a) monoclonal antibodies directed against the CD4 molecule inhibited T cell adhesion to both FN and LN; (b) down-regulation of the CD4 molecule resulted in partial loss of the ability of CD4+ T cells to adhere to FN and LN; (c) a CD4+ T cell clone adhered to both FN and LN while a CD4-CD8- clone expressing an identical T cell receptor bound weakly to both proteins and (d) treatment of the CD4+ T cells with an inhibitor of the CD4-associated tyrosine protein kinase activity inhibited T cell adhesion to both ECM proteins.
Animals↗
Anti-inflammatory effects of heparin and its derivatives: inhibition of complement and of lymphocyte migration.
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Animals↗
Activated T lymphocytes and macrophages secrete fibronectin which strongly supports cell adhesion.
Matrix-bound fibronectin (FN) appears to be involved in cell adhesion and motility mediated by integrin receptors. Although lymphoid cells and other cell types are capable of producing and secreting FN, the precise role of this secreted FN-like factor in regulating immune reactions is unclear. In the present study we analyzed the adhesive properties of FN secreted by rat CD4+ T cells and clone cells activated by the T cell mitogen concanavalin A (Con A), antigen, or via the CD2 pathways, or by macrophages (M phi) activated by lipopolysaccharide (LPS). Immobilized culture supernatant (CS) from the activated T cells or M phi supports the adhesion of activated rat or human CD4+ T cell or murine tumor cell. These CS contained FN and were more potent at facilitating cell adhesion then plasma FN. The adhesion activity of CS was attributed to FN because (a) gelatin columns depleted the FN present in the CS and (b) pretreating the cells with peptides of the cell-binding domain of FN abrogated their ability to bind CS. CS-mediated adhesion appears to occur primarily via the recognition of the Arg-Gly-Asp (RGD) by the beta 1-integrin-specific receptors of the adhesive cells. Thus, we postulate that FN secreted by various types of leukocytes is involved in promoting essential cell-matrix interactions, possibly affecting cell-adhesive and migratory processes at inflammatory or extravasation sites.
Amino Acid Sequence↗
T cells in the spinal cord in experimental autoimmune encephalomyelitis are matrix adherent and secrete tumor necrosis factor alpha.
We examined T cells isolated from an autoimmune tissue lesion and from lymphoid organs for their ability to secrete tumor necrosis factor-alpha (TNF-alpha) and to adhere to extracellular matrix (ECM) proteins. CD4+ T cells were obtained from spleens, popliteal lymph nodes, and spinal cords of Lewis rats that had been immunized with myelin basic protein (MBP) to induce experimental autoimmune encephalomyelitis (EAE). We now report that, irrespective of whether or not the T cells were activated with MBP or the T cell mitogen concanavalin A (ConA), the T cells isolated from the spinal cord lesions secreted greater amounts of TNF-alpha and adhered better to ECM than did T cells from the draining lymph node. Thus, the lesions of EAE concentrate a subpopulation of CD4+ T cells with enhanced ability to interact with blood vessel wall components and to secrete TNF-alpha.
Animals↗
Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. V. Hierarchy of suppression by myelin basic protein from different species.
We have been investigating the suppression of experimental autoimmune encephalomyelitis (EAE) by oral tolerization to autoantigens. In the present study the tolerizing effect of orally administered myelin basic protein (MBP) from different species was examined in the Lewis rat, Hartley guinea pig, and SJL/J mouse model of EAE. Animals were fed guinea pig, rat, bovine, human or mouse-MBP and then immunized with the homologous species of MBP or myelin: Lewis rats were immunized with rat MBP, Hartley guinea pigs with guinea pig-MBP, and SJL/J mice with mouse myelin. Clinical expression of EAE and delayed-type hypersensitivity (DTH) responses to MBP were assessed. In each species, suppression of disease and DTH responses were most pronounced by tolerization with the homologous species of MBP. In addition, cross-species tolerization was observed in each species and in general was less suppressive than homologous MBP although in some instances MBP from a heterologous species was as effective as tolerization with the homologous species. We also studied guinea pig-MBP induced EAE in the Lewis rat because it is a widely studied model of EAE and found that oral tolerization with guinea pig MBP was as suppressive as rat MBP. Of note is that oral tolerization with mouse MBP suppressed myelin-induced EAE in the SJL mouse in which autoimmunity to proteolipid protein appears to play a primary role, suggesting that antigen-driven bystander suppression following oral tolerization with autoantigens (Miller et al., 1991b) may be an important contributing mechanism for suppression of EAE following oral tolerization with MBP in this model.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation.
Interaction of T and B lymphocytes, platelets, granulocytes, macrophages and mast cells with the subendothelial extracellular matrix (ECM) is associated with degradation of heparan sulfate (HS) by a specific endoglycosidase (heparanase) activity. The enzyme is released from intracellular compartments (i.e., lysosomes, specific granules) in response to various activation signals (i.e., thrombin, calcium ionophore, immune complexes, antigens, mitogens), suggesting its regulated involvement in inflammation and cellular immunity. In contrast, various tumor cells appear to express and secrete heparanase in a constitutive manner, in correlation with their metastatic potential. Heparanase enzymes produced by different cell types may exhibit different molecular properties and substrate cleavage specificities. The platelet enzyme appears also in a latent form. It can be activated by tumor cells and thereby facilitate their extravasation in the process of metastasis. Degradation of ECM-HS by all cell types was facilitated by a proteolytic activity residing in the ECM and/or expressed by the invading cells. This proteolytic activity produced a more accessible substrate for the heparanase enzymes. Heparanase-inhibiting, nonanticoagulant species of heparin markedly reduced the incidence of lung metastasis in experimental animals. These species of heparin also significantly impaired the traffic of T lymphocytes and suppressed cellular immune reactivity and experimental autoimmune diseases. Heparanase activity expressed by intact cells (i.e., platelets, mast cells, neutrophils, lymphoma cells) was found to release active HS-bound basic fibroblast growth factor from ECM and basement membranes. Heparanase may thus elicit an indirect neovascular response in processes such as wound repair, inflammation and tumor development. The significant anticancerous effect of heparanase-inhibiting molecules may therefore be attributed to their potential inhibition of both tumor invasion and angiogenesis. Both normal leukocytic cells and metastatic tumor cells can enter the bloodstream, travel to distant sites and extravasate to the parenchyma at these sites. We suggest that heparanase is utilized for this purpose by both types of cells. Other functions (i.e., enzyme activities, adhesive interactions, chemotactic and proliferative responses) of metastatic tumor cells seem to mimic the equivalent functions of leukocytes as they migrate across blood vessels to gain access to sites of inflammation.
Animals↗
Antigen-driven peripheral immune tolerance. Suppression of organ-specific autoimmune diseases by oral administration of autoantigens.
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Administration, Oral↗
Antigen-driven bystander suppression after oral administration of antigens.
Suppression of experimental autoimmune encephalomyelitis (EAE) in Lewis rats by the oral administration of myelin basic protein (MBP) is mediated by CD8+ T cells that can be isolated from the spleens of MBP-fed animals. These cells adoptively transfer protection to naive animals subsequently immunized with MBP and complete Freund's adjuvant (CFA) and suppress in vitro MBP proliferative responses. Using a transwell system in which the modulator spleen cells from MBP-fed animals are separated by a semipermeable membrane from responder cells, MBP, or OVA-specific T cell lines, we have found that cell contact is not required for in vitro suppression to occur. In vitro suppression is dependent, however, upon antigen-specific triggering of modulator T cells. Once antigen-specific triggering occurs, suppression across the transwell is mediated by an antigen-nonspecific soluble factor that equally suppresses an MBP line or an ovalbumin (OVA) line. This phenomenon of antigen-driven bystander suppression was also demonstrated in vivo. Specifically, Lewis rats fed OVA which were then immunized with MBP/CFA plus OVA given separately subcutaneously were protected from EAE. Animals fed OVA and then immunized with MBP/CFA without OVA given subcutaneously were not protected. The protective effect of feeding OVA could be adoptively transferred by CD8+ T cells from OVA-fed animals into MBP/CFA plus OVA-injected animals. Feeding bovine serum albumin (BSA) or keyhole limpet hemocyanin did not suppress EAE in animals immunized with MBP/CFA plus OVA. EAE was suppressed, however, if BSA was fed and animals then immunized with MBP/CFA plus BSA given subcutaneously. Antigen-driven bystander suppression appears to be an important mechanism by which antigen-driven peripheral tolerance after oral administration of antigen is mediated, and presumably occurs in the microenvironment accounting for the antigen specificity of suppression generated by oral tolerization to antigens.
Administration, Oral↗
Nonencephalitogenic CD4-CD8- V alpha 2V beta 8.2+ anti-myelin basic protein rat T lymphocytes inhibit disease induction.
Recently there has been a number of reports suggesting that CD4-CD8- T cells participate in the processes of inflammatory reaction. In an attempt to delineate the distinctive functions of double negative (DN) T lymphocytes in an autoimmune-induced disease, we isolated and cloned such T cells, along with control CD4+ cells, from Lewis rats immunized with guinea-pig myelin basic protein in CFA. Both clones proliferated in response to the guinea-pig myelin basic protein and its synthetic encephalitogenic peptide, and expressed the same TCR V genes homologous to the mouse V alpha 2 and V beta 8.2 families that appear to be the defining entity of experimental autoimmune encephalomyeltis (EAE). Moreover, the TCR D and J region gene products of the DN cell were found to be similar to another encephalitogenic rat T cell clone. The two T clones did not differ markedly in their ability to produce TNF and IL-2 and to adhere to vascular wall-derived extracellular matrix- and laminin-coated plates. Surprising, therefore, was the finding that, although the CD4+ T lymphocytes were capable of inducing EAE, the DN cells did not elicit disease but rather inhibited subsequent EAE induction. Thus, TCR V alpha 2V beta 8.2 and its junctional region gene products are not the only prerequisite segment for a T cell to become encephalitogenic. We suggest that the important determinants of the T cell ability to induce disease are features of the T cell, other than or in addition to, the T cell receptor.
Animals↗
Suppression of adjuvant arthritis in Lewis rats by oral administration of type II collagen.
Adjuvant arthritis is induced by intradermal injection of Mycobacterium tuberculosis (MT) in oil. The role of immunity to type II collagen (CII) in adjuvant arthritis (AA) has not been well defined. We found that oral administration of chicken CII given 3 micrograms per feeding on days -7, -5, and -2 before disease induction consistently suppressed the development of AA. A decrease in delayed-type hypersensitivity responses to CII was also observed that correlated with suppression of AA. AA was optimally suppressed by 3 and 30 micrograms of collagen type II variably by 300 micrograms, and not by 0.3 microgram or 1 mg. Oral administration of collagen type I also suppressed AA; only minimal effects were seen with collagen type III. Suppression was Ag specific: feeding CII did not suppress experimental autoimmune encephalomyelitis; feeding myelin basic protein suppressed experimental autoimmune encephalomyelitis, but not AA. Suppression of AA could not be consistently obtained by feeding MT. Suppression of AA could be adoptively transferred by T cells from CII fed animals and could be obtained when CII was fed after disease onset. Our results suggest that autoimmunity to CII has a pathogenic role in AA and raise the possibility that cross-reactive epitopes exist between CII and MT. Alternatively, the pathogenesis of AA may be dependent on developing immunity to CII. These results further demonstrate the effectiveness of oral tolerance as a means to suppress experimental autoimmune diseases.
Administration, Oral↗
Characterization of immunomodulatory properties and accessory cell function of small intestinal epithelial cells.
We have studied the immunomodulatory properties of epithelial cells from the small intestine on T cell immune function in vitro. Proliferation of lymph node cells stimulated either with antigen or with mitogen was inhibited by epithelial cells in a dose-dependent fashion. The epithelial cell-mediated suppression of lymphocyte proliferation was blocked by indomethacin, a cyclooxygenase pathway inhibitor, demonstrating that the suppressive effect of epithelial cells was related to prostaglandin secretion. Furthermore, the action of epithelial cell-secreted prostaglandin on lymphocytes was related to its effect on IL-2 as the suppressive effect of epithelial cells was abrogated by the addition of exogenous IL-2. As previously reported, epithelial cells constitutively express MHC class II and we found them able to present antigen in a class II-restricted fashion when their suppressive effects were blocked by indomethacin. Furthermore, epithelial cells activated by LPS secrete an IL-1 like molecule in a fashion analogous to other antigen-presenting cells. These results demonstrate that epithelial cells can both enhance and suppress in vitro T cell immune responses and further characterize the mechanisms by which intestinal epithelial cells may function in gut-associated immune responses.
Adjuvants, Immunologic↗
Inhibition of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen.
The ability to prevent the expression of retinal SAg induced experimental autoimmune uveitis (EAU) in Lewis rats by oral administration of the SAg and SAg fragments was investigated. Oral administration of the SAg molecule prevented or markedly diminished the clinical appearance of SAg-induced disease as measured by ocular inflammation. Furthermore, oral administration of the SAg also markedly diminished uveitis induced by the uveitogenic M and N fragments of the SAg. M and N fragments were not effective in preventing SAg-induced EAU, although feeding the M fragment prevented disease induced by the M fragment. Oral administration of the SAg did not prevent myelin basic protein induced experimental autoimmune encephalomyelitis, whereas feeding myelin basic protein did. In vitro studies demonstrated a significant decrease in proliferative responses to the SAg in lymph node cells draining the site of immunization from fed vs nonfed animals. Furthermore, the addition of splenocytes from SAg-fed animals to cultures of a CD4+ SAg-specific cell line profoundly suppressed the cell line's response to the SAg, whereas these splenocytes had no effect on a purified protein derivative-specific cell line. The Ag-specific in vitro suppression was blocked by anti-CD8 antibody (OX-8) demonstrating that this suppression is dependent on CD8+ T-cells. These experiments demonstrate that Ag-specific immunomanipulation can be achieved in the EAU model by oral administration of the SAg and raise the possibility that such an approach may have practical clinical implications in uveitis as well as other human autoimmune diseases.
Administration, Oral↗
Inhibition of T lymphocyte heparanase by heparin prevents T cell migration and T cell-mediated immunity.
Previously we reported that activated T lymphocytes express a heparanase enzyme that degrades the heparan sulfate moiety of the proteoglycan of the extracellular matrix (ECM). Expression of the heparanase enzyme was found to be associated with the ability of activated T lymphocytes to penetrate blood vessel walls and accumulate in target organs. We recently found that relatively low doses of heparin administered to mice or rats inhibited T cell-mediated immune reactions. In the present study we investigated the effects in vitro and in vivo of the heparanase inhibitor, heparin, on the expression of T lymphocyte heparanase and on the ability of T lymphocytes to mediate a delayed-type hypersensitivity (DTH) reaction. We found that heparanase was induced by immunizing mice with antigen in vivo or by activating T lymphocytes with concanavalin A in vitro. Relatively low doses of heparin administered once daily in vivo (5 micrograms) or present in vitro (0.1 microgram/ml) inhibited the expression of heparanase induced by immunization or by concanavalin A incubation. Higher or lower doses of heparin did not have these effects. The same doses of heparin that inhibited expression of heparanase also inhibited the ability of the lymph node cells to migrate to a site of antigen and adoptively produce a DTH reaction. These findings suggest that modulation of cell-mediated immune reactions may be achieved by relatively low doses of heparin which inhibit expression of T lymphocyte heparanase.
Animals↗
Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. III. Synergistic effect of lipopolysaccharide.
Oral administration of myelin basic protein (MBP) suppresses experimental autoimmune encephalomyelitis (EAE) in Lewis rats immunized with MBP in Freund's adjuvant. The immunomodulator bacterial lipopolysaccharide (LPS) when given orally in conjunction with MBP enhances the protective effects of MBP feeding in EAE. This synergy was achieved only following oral administration of LPS but not following subcutaneous injection. In contrast, subcutaneous administration of LPS abrogated oral tolerance. A synergism between oral LPS and MBP was also demonstrated for antigen-specific suppression of delayed type hypersensitivity (DTH) responses. Antibody responses to MBP were suppressed by oral administration of MBP but not by MBP plus LPS. The lipid A moeity of LPS mimicked the effects of LPS on disease protection and DTH suppression. These data demonstrate that adjuvants can enhance the induction of antigen-specific oral tolerance for suppression of cell-mediated experimental autoimmune responses.
Administration, Oral↗
Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. II. Suppression of disease and in vitro immune responses is mediated by antigen-specific CD8+ T lymphocytes.
We have previously demonstrated that the oral administration of guinea pig myelin basic protein (MBP) protects Lewis rats against the induction of experimental autoimmune encephalomyelitis (EAE) when subsequently immunized with guinea pig MBP in CFA. In addition, animals made orally tolerant to MBP also have diminished proliferative and antibody responses to MBP, but not to other Ag. Nonetheless, the mechanism of oral tolerance to MBP in the EAE model remains undefined. In the present study, we report that T cells isolated from the spleen and mesenteric lymph nodes of MBP orally tolerized animals can adoptively transfer protection against EAE. Furthermore, these T cells are of the CD8+ subclass. In addition, CD8+ T cells from MBP orally tolerized animals also suppress in vitro proliferative responses and antibody responses to MBP in an Ag-specific fashion. These results demonstrate that active cellular mechanisms are initiated after oral administration of an autoantigen that can down-regulate an experimental autoimmune disease and provide the basis for the isolation and characterization of the cells mediating both in vivo and in vitro suppression.
Administration, Oral↗