PubMed Health⌕ Search

Biomedical subjects

I R Cohen

Publications and source records attributed to I R Cohen.

At least 19 recordsLinked to original sources
PubMed1992

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↗
PubMed1992

Induction of experimental autoimmune encephalomyelitis by native myelin basic protein-activated T lymphocyte lines.

Self antigens bind to MHC class II molecules in vivo. The capacity of class II molecules to bind native self antigen, namely antigen that has not been processed through an endososomal pathway, could increase susceptibility to autoimmune diseases if recognized by autoreactive T lymphocytes. To confirm this prediction we designed experiments to show that: (a) native myelin basic protein (BP) activates encephalitogenic T lymphocyte lines, and (b) these activated lines cause experimental autoimmune encephalomyelitis (EAE) in naive rats. We show that two encephalitogenic T lymphocytes lines, LEW and BN, are activated by native BP in the presence of paraformaldehyde pre-fixed antigen-presenting cells (APC). The degree of activation, as measured by T lymphocyte proliferation, was equal to that obtained in response to BP processed by APC prior to paraformaldehyde fixing. The response to native BP was confirmed by demonstrating insensitivity to the presence of the lysosomotropic agent chloroquine or protease inhibitors. Activation of T lymphocytes by BP required the presence of syngeneic APC. The activated T lymphocyte lines were injected into naive recipient rats that developed EAE within 5 days. Both disease incidence and severity were equal to that observed in rats that were treated with T lymphocytes activated by processed BP. Hence, at least in EAE, the risk of an autoimmune event could be precipitated by a complex of native antigen and class II molecules on cells that do not possess an endososomal pathway for antigen processing and presentation.

Animals↗
PubMed1992

Juvenile rheumatoid arthritis patients manifest immune reactivity to the mycobacterial 65-kDa heat shock protein, to its 180-188 peptide, and to a partially homologous peptide of the proteoglycan link protein.

Immune reactivity to the 65-kDa mycobacterial heat shock protein (hsp65) has been associated with arthritis in rats and humans. In this report we evaluated patients with juvenile rheumatoid arthritis for such immunity. A high proportion of affected children showed both antibody and T lymphocyte responses to hsp65 and to two related peptides: the nonapeptide 180-188 sequence of hsp65 and a partially homologous peptide of the cartilage proteoglycan link protein. The titer of circulating antibodies was generally higher in patients with clinically active disease. In contrast to the juvenile rheumatoid arthritis patients, patients with adult rheumatoid arthritis tended to have lower responses of their peripheral blood T lymphocytes to the whole hsp65 molecule. Moreover, the adult rheumatoid arthritis patients did not respond to the peptides. Thus, there appear to be immunological differences between juvenile and adult forms of rheumatoid arthritis related to hsp65 reactivity.

Adolescent↗
PubMed1992

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↗
PubMed1992

The cognitive paradigm and the immunological homunculus.

In last month's issue of Immunology Today, Irun Cohen discussed the inadequacies of the clonal selection paradigm and proposed a cognitive paradigm in which preformed internal images guide and restrict the process of clonal activation. Here he clarifies the nature of these internal images, during on concrete examples from the image of infection and the image of self, the immunological homunculus.

Animals↗
PubMed1992

The cognitive principle challenges clonal selection.

Here, Irun Cohen argues that the clonal selection paradigm is no longer a convenient paradigm for organizing thinking about the immune system. He contends that most immunologists now investigate questions for which the clonal selection paradigm makes no provision and that one of its major tenets is contradicted by the prevalence of natural autoimmunity. Instead, he proposes a cognitive paradigm.

Adaptation, Physiological↗
PubMed1992

Antibodies to mycobacterial 65 kDa heat shock protein in systemic sclerosis (scleroderma).

It has been reported that immunity to the 65 kDa heat shock protein of Mycobacterium tuberculosis (MT-hsp65) not only accompanies rheumatoid arthritis (RA), but may also be characteristic of chronic inflammation. We now report serum antibodies to MT-hsp65 in 47% of systemic sclerosis (SSc), 38% of primary Raynaud's phenomenon (PRP) and 5% of systemic lupus erythematosus (SLE). Antibody levels were higher in patients with active or progressive SSc and correlated with the degree of skin fibrosis. Thus, immunity to MT-hsp65 appears in SSc and is not limited to RA. However, it does show some degree of specificity beyond chronic inflammation: PRP patients have a higher reactivity than do SLE patients.

Adolescent↗
PubMed1992

Autoimmune thyroiditis (EAT) in genetically resistant mice mediated by a T cell line.

Experimental autoimmune thyroiditis (EAT) can be induced in genetically susceptible strains of mice by immunization to mouse thyroglobulin (Tg). EAT also can be produced by administration of anti-mouse Tg T cell lines and clones. Previously we were able to raise virulent anti-Tg T cell lines from mice genetically susceptible to EAT. These virulent lines, upon attenuation, were able to vaccinate the susceptible mice against EAT. We now report the isolation of a virulent T cell line from C57BL/6 mice genetically resistant to EAT. The T cell line and its clones recognize a Tg epitope cross-reactive between mouse and bovine Tg. Unexpectedly, the virulent anti-Tg line attenuated in various ways failed to vaccinate C57BL/6 mice against EAT mediated by the line itself. These results shed some light on the regulation of autoimmunity.

Animals↗
PubMed1992

Wound dressing activity mimicking infection on labeled leukocyte imaging.

Although labeled leukocyte imaging is an extremely useful technique for the localization of infection, false-positive results in inflammatory conditions where no infection exists have been described. False-positive results secondary to bleeding have also been reported. The authors recently observed intense uptake of labeled cells in the wound dressings of two patients undergoing leukocyte imaging. Repeat imaging after the removal of these dressings confirmed that the activity seen was in the dressings and did not represent focal infection, as originally thought. Based on these observations, the authors think it prudent to remove such dressings before performing leukocyte imaging.

Adult↗
PubMed1992

T cells in the lesion of experimental autoimmune encephalomyelitis. Enrichment for reactivities to myelin basic protein and to heat shock proteins.

To characterize the cellular immune response in an autoimmune lesion, we investigated the accumulation of specific T cells in the central nervous system in actively induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats, using a limiting dilution analysis (LDA) assay for T cells that proliferate in response to antigens. Lymphocytes isolated from the spinal cord infiltrate were compared with cells from the popliteal lymph nodes with respect to frequency of cells responding to basic protein (BP), mycobacterium tuberculosis (MT), the 65-kD heat shock protein (hsp65), allogeneic brown norway spleen cells, and concanavalin A. Additionally, we compared the BP frequency in acute EAE of cells from the spinal cord, peripheral blood, spleen and lymph nodes, and the spinal cord and lymph node after recovery from EAE. We found that acute EAE was associated with marked enrichment of BP-reactive T cells in the spinal cord relative to their frequency in the lymphoid organs and peripheral blood. The infiltrate was also enriched for T cells responding to hsp65; alloreactive T cells, in contrast, were not enriched. The frequency of BP reactive T cells in the spinal cord was highest at the peak of paralysis; however, BP-reactive T cells could still be detected at moderate frequencies after clinical recovery. We established BP- and Mycobacteria-reactive T cell lines from the spinal infiltrates that were CD4+ and TcR alpha beta +. Most of the BP lines were found to react to the major encephalitogenic epitope of guinea pig BP for rats (amino acids 71-90); these lines were found to mediate EAE in naive recipients. T cell lines recognizing other epitopes of BP were not encephalitogenic. All of the lines responsive to Mycobacteria recognized hsp65 or hsp70. These results indicating that the immune infiltrate in active EAE is enriched with cells responding to the autoantigen and to hsp65 were confirmed in EAE adoptively transferred by anti-BP T cell clone.

Animals↗
PubMed1992

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↗
PubMed1991

Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein.

Insulin-dependent diabetes mellitus is caused by autoimmune destruction of the insulin-producing beta cells resident in the pancreatic islets. We recently discovered that the pathogenesis of diabetes in NOD strain mice was associated with T-cell reactivity to an antigen cross-reactive with a mycobacterial 65-kDa heat shock protein. To identify peptide epitopes critical to the insulin-dependent diabetes mellitus of NOD mice, we studied the specificities of helper T-cell clones capable of causing hyperglycemia and diabetes. We now report the identification of a functionally important peptide within the sequence of the human variant of the 65-kDa heat shock protein molecule. T-cell clones recognizing this peptide mediate insulitis and hyperglycemia. Alternatively, the T cells can be attenuated and used as therapeutic T-cell vaccines to abort the diabetogenic process. Moreover, administration of the peptide itself to NOD mice can also down-regulate immunity to the 65-kDa heat shock protein and prevent the development of diabetes. Thus, T-cell vaccination and specific peptide therapy are feasible in spontaneous autoimmune diabetes.

Animals↗
PubMed1991

Autoimmunity, microbial immunity and the immunological homunculus.

Clonal deletion and anergy are believed by many immunologists to be the fundamental mechanisms responsible for self tolerance. Nevertheless, as Irun Cohen and Douglas Young point out, such notions of nonreactivity cannot explain certain key features of immune behaviour: the immunological dominance of microbial antigens that mimic self, the uniformity of autoimmune diseases and the prevalence of natural autoimmunity among the healthy. The theory of the immunological homunculus is presented here as a unifying principle.

Animals↗