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Biomedical subjects

O Lider

Publications and source records attributed to O Lider.

At least 73 records · Page 4Linked to original sources
PubMed1994

Inhibition of cell adhesion to glycoproteins of the extracellular matrix by peptides corresponding to serum amyloid A. Toward understanding the physiological role of an enigmatic protein.

Synthetic peptides related to amino acid residues 29-42 of human serum amyloid A (SAA), Tyr-Ile-Gly-Ser-Asp-Lys-Tyr-Phe-His-Ala-Arg-Gly-Asn-Tyr, were found to inhibit the adhesion of human T-lymphocytes and of mouse M4 melanoma cells to surfaces coated with the major cell adhesive glycoproteins of the extracellular matrix, laminin or fibronectin. Correspondingly inhibitory activity was manifested by the entire 14-residue peptide, by its YIGSD laminin-related domain, and by RGN, the fibronectin-related domain. Intact recombinant SAA (rSAA) and its 1-76 fragment, an amyloid A (AA) protein, also inhibited cell adhesion. The peptides did not inhibit collagen and ADP-induced aggregation of human platelets. Proteolysis of SAA by lysosomal enzymes originating from human neutrophils led to generation of specific peptide segments some of which pertain to the 29-42 domain. It is suggested that the acute-phase protein SAA might be involved, either directly or via its peptide fragments, in inhibition of inflammatory reactions or metastatic processes which depend on integrin and possibly other extracellular-matrix-specific receptors mediated specific recognition and interactions with immobilized components of blood-vessel walls.

Amino Acid Sequence↗
PubMed1994

TNF-alpha binds to the N-terminal domain of fibronectin and augments the beta 1-integrin-mediated adhesion of CD4+ T lymphocytes to the glycoprotein.

Certain inflammatory cytokines and growth factors have been previously shown to interact with glycosaminoglycan moieties of the extracellular matrix (ECM). We have examined the association of the pleiotropic cytokine TNF-alpha with glycoprotein constituents of ECM. TNF-alpha interacted with fibronectin (FN) and laminin, and to a lesser degree with collagen. The major binding site for TNF-alpha on FN was localized to its 30-kDa N-terminal fragment (FN-N') with a Ki in the sub-nM range. The binding of 125I-labeled TNF-alpha to immobilized FN or FN-N' persisted for at least 24 h, and was specifically inhibited by antibodies to FN, mAb directed against the FN-N' domain, unlabeled TNF-alpha, and by the truncated forms of TNF-alpha receptors. Once bound to immobilized FN or FN-N', the cytokine could not be released by the soluble TNF-alpha-receptors, although it could be released by anti-TNF-alpha Ab. TNF-alpha was also found to interact with soluble FN, although with a lower affinity. Similar to the soluble cytokine, the FN-bound TNF-alpha appears to be functional; it augmented the beta 1-integrin-mediated adhesiveness of activated CD4+ human T cells to the glycoprotein. Hence, binding of TNF-alpha to immobilized FN, which modifies its functional accessibility to soluble TNF-alpha receptors, does not abolish but rather may locally restrict its activity. This study suggests that a major ECM glycoprotein can present, in a restricted manner, a functional adhesion-modulating cytokine to immune cells, and that ECM glycoproteins may regulate their intrinsic cell-adhesive properties by associating with cytokines.

Amino Acid Sequence↗
PubMed1994

Orally administered myelin basic protein in neonates primes for immune responses and enhances experimental autoimmune encephalomyelitis in adult animals.

Antigen-driven tolerance is an effective method for suppression of autoimmune diseases. Adult animals can be tolerized against the induction of experimental autoimmune encephalomyelitis (EAE) by both oral and parenteral administration of myelin basic protein (MBP). We have found that in contrast to previous studies of neonatal tolerance in which parenterally administered autoantigens induced tolerance, the oral administration of MBP in neonatal rats did not result in tolerization to MBP, but instead, primed for immunologic responses. Proliferative responses to MBP and its encephalitogenic epitope were present in animals fed with MBP as neonates and co-culture of encephalitogenic T cells with cells from neonatal rats fed with MBP were associated with enhanced MBP responses rather than the suppression observed with cells from adult rats fed with MBP. Furthermore, neonates fed with MBP and immunized 6-8 weeks later with MBP in adjuvant to induce EAE revealed enhancement of disease severity, and were not protected from a second attack upon active reinduction of EAE. Subcutaneous injection of soluble MBP into neonates had no effect on EAE induction as adults, whereas intraperitoneal injection of MBP in neonates was associated with marked suppression of disease in adults. Suppression of EAE began to appear in animals fed with MBP at 4 weeks of age, and was similar to oral tolerance in adult animals when animals were fed at 6 weeks of age. These results suggest that immaturity of the immunoregulatory network associated with oral tolerance and sensitization to autoantigens via the gut in the neonatal period may contribute to the pathogenesis of autoimmune diseases.

Administration, Oral↗
PubMed1994

Inhibition of T cell adhesion to extracellular matrix glycoproteins by histamine: a role for mast cell degranulation products.

Mast cells, which are capable of releasing a multitude of preformed and newly generated biological mediators and cytokines, are involved in various inflammatory processes. We studied whether histamine, a mast cell degranulation product, influences the adhesive interactions of T cells with extracellular matrix (ECM) glycoproteins, an event that occurs at sites of inflammation and is mediated primarily by virtue of cell-surface receptors of the beta 1-integrin subfamily. A prerequisite of lymphocyte-ECM interactions is activation of the cells, which modulates the affinity of the otherwise inactive integrins. Isolated rat CD4+ T cells were preincubated with histamine and activated with phorbol myristate acetate (PMA), and their ability to adhere to immobilized ECM components (fibronectin and laminin) was determined. Preincubation with histamine resulted in a 40-50% decrease in the adhesion of the CD4+ cells to both fibronectin or laminin. The notion that inhibition of T cell adhesion to ECM proteins by histamine-induced increase of the cells' intracellular levels of cAMP, thus interfering with calcium influx-associated events that occur during T cell activation, is supported by the finding that T cell adhesion was also abrogated by pharmacological inducers of cAMP. When the T cells were preincubated with supernatants of immunologically activated mast cells and then activated with PMA, a 40-50% inhibition of their adhesion to fibronectin or laminin was also observed. The inhibitory moiety present in the mast cell degranulation supernatants was resistant to heat (80 degrees C). Histamine exerted its suppressive effect on adhesion of T cells via their H2 receptors, as pretreatment with H2 antagonists abrogated the inhibitory effect. Thus, both purified histamine and mast cell-secreted histamine appear to be capable of affecting T cell interactions with ECM.

Animals↗
PubMed1994

Inhibition of CD4+ T lymphocyte binding to fibronectin and immune-cell accumulation in inflammatory sites by non-peptidic mimetics of Arg-Gly-Asp.

The Arg-Gly-Asp (RGD) cell adhesion motif has been demonstrated in various studies to play a pivotal role in leucocyte and platelet interactions with plasma and extracellular matrix (ECM) glycoproteins. The recognition of the RGD sequence is mediated by heterodimeric receptors designated integrins of the beta 1 subfamily, expressed on distinct cell types, including T lymphocytes. We have recently shown that flexible non-peptidic mimetics of RGD, in which the two ionic side groups were separated by a linear spacer of 11 atoms, bound specifically to the platelet integrin alpha 11b beta 3, and inhibited T cell-mediated immune responses. The present study was designed to (i) further characterize the structural requirements for RGD interactions with CD4+ T cells, and (ii) examine the mechanisms by which the RGD mimetics interfere with immune cell reactivity in vivo. We now report that freezing the conformational degrees of freedom in the spacer chain, which fixes the relative orientation of the guanidinium and carboxylate side groups in a favourable manner, results in a higher level of inhibition of T cell binding to immobilized fibronectin, an RGD-containing ECM glycoprotein. In vivo, treatment of mice with relatively low doses of the RGD mimetics, but not the RGD peptide, inhibited the elicitation of an adoptively transferred DTH reaction. This inhibition was achieved by direct impairment of the ability of antigen-primed lymph node cells to migrate and accumulate in inflammatory sites. Hence, we suggest that the design and production of non-peptidic mimetics of RGD offers a novel approach to study defined parameters related to the structure-function requirements of small adhesion epitopes. Furthermore, this approach could be used therapeutically to inhibit pathological processes which depend on RGD recognition.

Amino Acid Sequence↗
PubMed1994

Novel psi-S-CH2 peptide-bond replacement and its utilization in the synthesis of nonpeptidic surrogates of the Leu-Asp-Val sequence that exhibit specific inhibitory activities on CD4+ T cell binding to fibronectin.

The Leu-Asp-Val-(LDV)-containing amino acid sequence, derived from the alternatively spliced first connecting segment region of fibronectin (FN), was shown to be recognized primarily by the alpha 4 beta 1-integrin receptor expressed on the surface of various cell types. This adhesion epitope may therefore inhibit integrin-mediated cell interactions with the extracellular matrix glycoprotein, including adhesion, migration, activation and differentiation. To probe the structural requirements for LDV recognition by integrins and examine the feasibility of inhibition of LDV-dependent cell-FN interactions, we have designed and constructed a novel psi-S-CH2 peptide bond surrogate that was employed in the formation of LDV surrogates. The synthesis of the psi-S-CH2 surrogates reported herein is based on Michael addition of 4-methylpentane thiol to an itaconic acid diester to form an S-CH2 bond. We have found that the LDV surrogates comprises of 4-methylpentanoate-Asp-i-butyl amide and 8-methyl-3-(2-methylpropylaminocarbonyl)-5-thianonanoic acid interfered with CD4+ human T-cell adhesion to FN in vitro, with an ED50 of 280 micrograms/mL. A control structural mimetic of the Leu-Glu-Val (LEV) peptide did not interfere with the T-cell-FN interaction. The specificity of the reaction was substantiated by the finding that the LDV mimetics did not interfere with T-cell adhesion to laminin, another major cell-adhesive glycoprotein of the extracellular matrix.(ABSTRACT TRUNCATED AT 250 WORDS)

Amides↗
PubMed1994

Intravenous gammaglobulin treatment in multiple sclerosis and experimental autoimmune encephalomyelitis: delineation of usage and mode of action.

Multiple sclerosis (MS) is a central nervous system demyelinating disease of implicated autoimmune aetiology. The effect was evaluated of intravenous gammaglobulin (IVIg), a successful therapy in various autoimmune diseases, in relapsing-remitting MS patients treated for three years. IVIg treatment significantly reduced the number and severity of acute exacerbations and resulted in a lesser neurological disability. There were no significant short or long-term adverse effects to IVIg treatment. To clarify the putative therapeutic effects of IVIg, this treatment was examined in the animal model of experimental autoimmune encephalomyelitis (EAE) in the rat. IVIg suppressed active EAE in relation to disease severity and duration, despite the presence of T-cell reactivity to specific antigens, while the treatment had no effect on passive EAE induced by adoptive transfer of myelin basic protein specific CD4 + T-cells. It is concluded that IVIg treatment may be a promising treatment in relapsing-remitting MS as it can alter the natural course of the disease.

Adult↗
PubMed1994

Intravenous immunoglobulin treatment of experimental T cell-mediated autoimmune disease. Upregulation of T cell proliferation and downregulation of tumor necrosis factor alpha secretion.

It has been reported previously that intravenous administration of normal human immunoglobulins (IVIg) to human patients can suppress the clinical signs of certain autoimmune diseases. However, the mechanism(s) by which normal Ig interferes with the various disorders and the scheduling of treatment have been poorly delineated. To study these questions, we examined IVIg treatment of two experimentally induced T cell autoimmune diseases in rats: experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA). We now report that IVIg treatment (0.4 g/kg) inhibited the active induction of both EAE and AA, and that this treatment did not affect the acquisition of resistance to reinduction of EAE. The importance of the site of administration and schedule of treatment were studied in the AA model. Ig was effective when given intravenously, but not when administrated subcutaneously or intraperitoneally. IVIg treatment was effective when given daily from immunization to outbreak of disease; but it was also effective when given once at the time of immunization or once 2 wk after induction of AA, just at the clinical outbreak of disease. Administration of IVIg between immunization and outbreak of AA was less effective. Prevention of disease by IVIg occurred despite the presence of T cell reactivity to the specific antigens in the disease. In fact, IVIg administrated to naive rats activated T cell reactivity to some self-antigens. Nevertheless, IVIg treatment led to decreased production of the inflammatory cytokine TNF alpha. Thus, IVIg treatment may exert its therapeutic power not by inhibiting T cell recognition of self-antigens, but by inhibiting the biological consequences of T cell recognition.

Animals↗
PubMed1994

Nonpeptidic analogues of the Arg-Gly-Asp (RGD) sequence specifically inhibit the adhesion of human tenon's capsule fibroblasts to fibronectin.

PURPOSE: Scar formation from the process of wound healing is mediated primarily by fibroblasts and is a major problem in ophthalmology in general and in glaucoma therapy in particular. Interactions between fibroblasts and glycoprotein components of the extracellular matrix (ECM) are among the major causes of scar formation. Recognition of ECM glycoproteins occurs via cell surface integrins that are specific for adhesion epitopes, such as the Arg-Gly-Asp (RGD-) containing amino acid sequence. The RGD sequence, which is present in several matrix and plasma proteins, including fibronectin (FN) and vitronectin, is involved in cell-ECM interactions that occur during inflammatory and homeostatic reactions. The present study was designed to examine the possibility of using RGD-mimetics as inhibitors of fibroblasts-FN interactions. METHODS: Two nonpeptidic mimetics of RGD were designed and constructed, and their inhibitory effect on the adhesion of human tenon's capsule fibroblasts to FN was examined. SF-6,5 consisting of the carboxylate group of Asp and the guanidinium group of Arg divided by a linear atom spacer and a newly designed mimetic, designated NS-11, were examined herein. RESULTS: The RGD mimetics, SF-6,5 and NS-11, but not an Arg-Gly-Glu (RGE) mimetic inhibited the adhesion of ocular fibroblasts to immobilized FN. SF-6,5 and NS-11 did not inhibit adhesion of the fibroblasts to laminin or spontaneous proliferation of fibroblasts. Trypsin pretreatment of the nonpeptidic RGD mimetics did not affect their ability to inhibit adhesion of the ocular fibroblasts to FN, whereas that of the RGD-containing peptide was abolished by the pretreatment. CONCLUSION: Nonpeptidic mimetics of RGD are attractive candidates for therapeutic agents to prevent the formation of scar tissue and related RGD-dependent pathologic events.

Antibodies, Monoclonal↗
PubMed1993

Inhibition of integrin-mediated platelet aggregation, fibrinogen-binding, and interactions with extracellular matrix by nonpeptidic mimetics of Arg-Gly-Asp.

The interaction of the activated platelet integrin, glycoprotein IIb-IIIa (GPIIb-IIIa) with fibrinogen and von-Willebrand factor (vWF) is essential for platelet aggregation. The minimal structure required for this integrin's binding to fibrinogen is the Arg-Gly-Asp (RGD) sequence. Inasmuch as normal level of GPIIb-IIIa-RGD interactions are required for maintaining hemostasis, elevated platelet aggregation can cause adverse pathological effects. We have previously reported that nonpeptidic mimetics of RGD, consisting of carboxylate and guanidinium groups of Asp and Arg divided by a linear 11-atom spacer, acquired a significant affinity for the GPIIb-IIIa integrin and inhibited platelet aggregation. The structural requirements for the interactions of the RGD sequence with GPIIb-IIIa and the inhibitory potential of a newly designed series of mimetics on platelet aggregation and interactions with extracellular matrix (ECM) were assayed herein. Adenosine-diphosphate (ADP)-induced platelet aggregation was inhibited in a dose-dependent manner by various RGD mimetics, with a maximal inhibition of 80-100% with an IC50 of 3 microM for the most potent inhibitor, NS-11, in which a six-membered ring was introduced into the spacer chain, which exceeded the IC50 attained with the original RGDS peptide. The inhibitory effect of the RGD mimetics was attributed to their specific interaction with the GPIIb-IIIa integrin, since these mimetics inhibited the binding of the PAC-1 mAb to GPIIb-IIIA. Furthermore, the binding of 125I-labeled fibrinogen to platelets was inhibited by the RGD surrogates in a dose-dependent and saturable manner. The RGD-mimetics also inhibited up to 70% the adhesion, aggregation, and deposition of platelets onto ECM.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Inhibition of metastatic cell colonization in murine lungs and tumor-induced morbidity by non-peptidic Arg-Gly-Asp mimetics.

The spreading and colonization of tumor cells require their migration to metastatic sites via blood vessels. To penetrate blood-vessel walls, cells, including malignant ones, must recognize and associate with the sub-endothelium extracellular matrix (ECM) and its glycoproteins. Recognition of ECM-glycoproteins, such as fibronectin (FN) and vitronectin (VN), is mediated by integrin receptors expressed on various cell types, including platelets, leukocytes and tumor cells. The Arg-Gly-Asp (RGD)-containing peptide, a major adhesive ligand of ECM, is present in various plasma and matrix glycoproteins, such as FN and VN. Non-peptidic mimetics of RGD, consisting of carboxylate and guanidinium groups of Asp and Arg divided by a linear atom spacer, express a high affinity for the alpha IIb-beta 3 integrin and inhibit platelet aggregation. Herein, the ability of RGD mimetics to inhibit adhesive interactions between tumor cells and RGD, and tumor progression in vivo, was examined. RGD-containing peptides and the RGD mimetic, compound SF-6,5, but not the Arg-Gly-Glu (RGE) peptide or the corresponding mimetic, specifically inhibited B16-F10 melanoma cell adhesion to immobilized VN and FN. Daily administration in vivo of SF-6,5 to mice inhibited the formation of B16-F10 colonies in experimental and spontaneous models of metastases. Moreover, SF-6,5 could prevent mouse death caused by massive colonization of tumor cells in the lungs. The therapeutic effect of RGD-containing peptides on tumor metastasis formation was marginal, probably due to the small amounts used, and its susceptibility to proteolysis in situ. Thus, non-peptidic mimetics of small adhesive epitopes may provide a novel therapeutic tool to prevent an adverse pathological event involving integrin-dependent cell-cell and cell-ECM interactions.

Animals↗
PubMed1993

Structural analysis of integrin recognition and the inhibition of integrin-mediated cell functions by novel nonpeptidic surrogates of the Arg-Gly-Asp sequence.

The pivotal role of the Arg-Gly-Asp (RGD) peptide motif in integrin-mediated cell adhesive interactions with extracellular matrix and plasma proteins stimulated the present design of nonpeptidic mimetics of this sequence. To probe the structural requirements for RGD recognition by integrins, we designed various structural mimetics of the tripeptide sequence, which consist of differentially spaced guanidinium and carboxylic groups. We now report that structures which contain guanidinium and carboxylic groups separated by an 11-carbon atom backbone mimic the distal configuration of functional RGD sequence. These compounds acquire a considerable affinity for the RGD-dependent platelet alpha IIb beta 3 integrin. As a result, these mimetics specifically inhibited platelet aggregation with an IC50 at the submillimolar range and interfered with RGD-dependent adhesion of CD4+ T-lymphocytes and metastatic tumor cells to immobilized fibronectin and vitronectin. A structural mimetic of the Arg-Gly-Glu (RGE) sequence, and structures with incorrect spacing between the functional groups, failed to inhibit these adhesive interactions. Furthermore, substitution of the guanidinium group by a primary amine abrogated the RGD-mediated biological effects. In vivo, an RGD surrogate effectively inhibited the elicitation of a delayed-type hypersensitivity reaction mediated by CD4+ T-cells, while the RGE mimetic did not. This interference suggests for a central role for RGD recognition in the regulation of immune responses. These proteolytically stable RGD mimetics may thus serve as useful therapeutic agents in versatile pathologic processes which depend on RGD recognition.

Amino Acid Sequence↗
PubMed1993

Streptavidin blocks immune reactions mediated by fibronectin-VLA-5 recognition through an Arg-Gly-Asp mimicking site.

Streptavidin is a biotin-binding analogue of egg-white avidin which is secreted by the bacterium Streptomyces avidinii. We have recently reported that streptavidin contains an Arg-Tyr-Asp-Ser (RYDS) sequence which exhibits structural homology to the Arg-Gly-Asp-Ser (RGDS) cell adhesion domain of fibronectin and other matrix-associated glycoproteins. Competition studies with RGD peptides indicated that streptavidin binds to cells via this site and that the binding is independent of biotin recognition. Since the RGD-containing peptide has been shown to play a key role in integrin-mediated cell adhesion, we assumed that streptavidin may utilize the RYDS site to bind to immune cells and thereby abrogate their adhesion-dependent functions. We now report that streptavidin modulates several matrix-dependent interactions of immune cells. In this context, immobilized streptavidin was found to support activated human CD4+ T cell adhesion in an RGD-specific, alpha 5 beta 1-dependent manner. In addition, soluble streptavidin (the commercially available or biotin-blocked forms) inhibited T cell adhesion to fibronectin and interfered with its co-stimulatory effect on tumor necrosis factor-alpha secretion by co-cultures of CD4+ T cells and macrophages. These results suggest that streptavidin is a novel example of a bacterial protein which utilizes RGD mimicry to interfere with integrin-mediated immune responses.

Amino Acid Sequence↗
PubMed1993

Physically damaged extracellular matrix induces TNF-alpha secretion by interacting resting CD4+ T cells and macrophages.

T lymphocytes and macrophages (Mø) are seen to accumulate at sites of lesions in blood vessel walls, suggesting that these cells may contribute to the initiation of the local inflammatory reaction. Tumour necrosis factor-alpha (TNF-alpha), a cytokine produced by both cell types, plays a major role in inflammatory reactions, in blood vessel formation, in thrombosis and in atherosclerosis. We now report that secretion of TNF-alpha by CD4+ T cells and Mø can be induced in vitro in the absence of antigen, in an MHC-II-independent manner by immobilized extracellular matrix (ECM). Moreover, the level of TNF secretion is greatly enhanced in the presence of physically damaged ECM (dECM). This mode of TNF secretion is regulated primarily by the fibronectin or laminin glycoprotein components of ECM. Thus, a multicellular interaction with ECM proteins exposed as a consequence of vascular wall injury can serve to signal the secretion of TNF-alpha by both cell types which induces the recruitment of additional immune cells to the developing lesion.

Animals↗
PubMed1993

Extracellular matrix induces tumour necrosis factor-alpha secretion by an interaction between resting rat CD4+ T cells and macrophages.

T lymphocytes and macrophages (M phi) have been seen to accumulate at sites of lesions in blood vessel walls, suggesting that these cells may contribute to the pathogenesis of inflammatory reactions. Tumour necrosis factor-alpha (TNF-alpha), a cytokine produced by both M phi and T lymphocytes, plays a major role in inflammatory reactions, blood vessel formation, thrombosis and atherosclerosis. We now report that secretion of TNF-alpha by cloned CD4+ rat T cells, and to a lesser degree by peripheral T cells, and M phi can be induced in vitro in the absence of antigen, in a major histocompatibility complex (MHC) class II-independent manner by integrin-mediated recognition of immobilized components of extracellular matrix such as fibronectin and laminin; the secretion of TNF-alpha by the interacting resting cells on fibronectin was partially abrogated by the presence of the Arg-Gly-Asp (RGD)-containing amino acid sequence. This T cell-M phi interaction involves CD2 and CD4 molecules and requires a signal transduced in the T cells by a protein tyrosine kinase. Thus, a multicellular interaction with extracellular matrix protein exposed as a consequence of vascular wall injury can serve to signal the secretion of TNF-alpha which induces the recruitment of additional immune cells to the developing lesion.

Animals↗
PubMed1993

Heat-stressed CD4+ T lymphocytes: differential modulations of adhesiveness to extracellular matrix glycoproteins, proliferative responses and tumour necrosis factor-alpha secretion.

Although cells of the immune system often function under feverish conditions, the effects of elevated temperatures on T cells have not been fully elucidated. Herein, the effects of a 1-hr exposure to 41 degrees of CD4+ human T cell were studied. Heat-shock treatment of activated CD4+ T cells reduced their adhesion to fibronectin and laminin, the major adhesive glycoproteins of the extracellular matrix (ECM) by 25-40%. This decrease was partially due to a minor decrease in the surface expression of beta 1 integrins, which specifically interact with fibronectin and laminin. In contrast, the capacities of heat-stressed T cells to proliferate and to secrete tumour necrosis factor-alpha (TNF-alpha) were increased upon cell activation. In vivo, heat-treated antigen-primed murine T cells, injected directly into the antigen challenging site, induced a more severe delayed-type hypersensitivity (DTH) response than those not exposed to elevated temperatures. In contrast, the same heat-treated cells inoculated intravenously did not induce DTH, suggesting that these cells were impaired with respect to penetration of blood vessel walls. Thus, the effects of heat shock on key cellular functions are expressed in different manners: T-cell-ECM adhesiveness and subsequent extravasation are impaired, whereas their abilities to proliferate and to secrete TNF-alpha are augmented.

CD4-Positive T-Lymphocytes↗