Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effect of FK506 on the activation, proliferation and differentiation of human B lymphocytes in vitro. FK506 inhibited the proliferative response of resting B cells induced by Staphylococcus aureus Cowan strain I (SAC) and phorbol myristate acetate (PMA) in a dose-dependent manner. Inhibition of cell proliferation by FK506 was caused by a selective block of G0 to G1 phase transition leading to cell arrest. In addition, the proliferative response of in vivo-activated B cells and lymphokine-driven B cell proliferation were also found to be sensitive to FK506. Interestingly, FK506 did not affect the expression of activation antigens such as CD23, IL-2 receptor (CD25), and transferrin receptor (CD71). Finally, FK506 had little effect on B cell antibody generation in a T cell-independent system. Conversely, FK506 suppressed neither proliferation nor immunoglobulin secretion in a human B lymphoblastoid cell line. These results indicate that FK506 has discrete effects on the different stages of the B cell maturation.
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PMID:The distinct effects of FK506 on the activation, proliferation, and differentiation of human B lymphocytes. 128 61

Herpes virus saimiri (HVS) immortalizes T lymphocytes from a variety of primates and causes acute T cell lymphomas and leukemias in nonnatural primate hosts. Here we have analyzed the requirements for growth of three HVS-transformed human T cell lines. The cells expressed the phenotype of activated T cells: two were CD4+, and one was CD8+. All three cells responded to all allogeneic human cell lines tested with enhanced proliferation, production of interleukin 2 (IL-2), and increased expression of the IL-2 receptor. Binding of CD2 to its ligand CD58 was the critical event mediating stimulation because: (a) monoclonal antibodies (mAbs) to CD2 and to CD58, but not to a variety of other surface structures, blocked induced and spontaneous proliferation and IL-2 production; (b) only anti-CD2 mAbs were stimulatory if crosslinked; (c) a nonstimulatory cell was rendered stimulatory by CD58 transfection; and (d) the cells responded specifically to CD58 on sheep red blood cells. Growth of the cells required activation because cyclosporin A and FK506 blocked stimulator cell-induced IL-2 production and proliferation as well as the spontaneous growth of the lines. Antibodies to the IL-2 receptor reduced proliferation of the cells and blocked IL-2 utilization. Taken together, these results show that HVS-transformed T cells proliferate in response to CD2-mediated contact with stimulator cells or with each other in an IL-2-dependent fashion. They suggest that HVS transforms human T cells to an activation-dependent autocrine growth.
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PMID:CD2-mediated autocrine growth of herpes virus saimiri-transformed human T lymphocytes. 135 5

The immunosuppressive effects of prodigiosin 25-C were studied in comparison with FK506. Both prodigiosin 25-C and FK506 suppressed T cell proliferation in response to concanavalin A (con A) or phytohemagglutinin (PHA) more significantly than that to lipopolysaccharide. However, prodigiosin 25-C inhibited con A-mediated mitogenic response more strongly than PHA-mediated one. FK506 showed no selectivity among those responses. In addition, when higher concentration of con A was used an inhibitory effect of prodigiosin 25-C became more evident whereas that of FK506 became less evident. Furthermore, prodigiosin 25-C affected neither interleukin-2 (IL-2) production nor IL-2 receptor (IL-2R) and transferrin receptor (TF-R) expression in vitro, though FK506 extensively inhibited IL-2 production and significantly suppressed IL-2R and TF-R expression. When comparing the effects of prodigiosin 25-C and FK506 in vivo by injecting antigens of different nature to a mouse, prodigiosin 25-C selectively inhibited cytotoxic T lymphocyte (CTL) activity induced by an allogenic mastocytoma, P815, without affecting production of antibody against a thymus dependent (TD) antigen, sheep red blood cell (SRBC). On the contrary, FK506 significantly inhibited both CTL induction and the antibody production. When Brucella abortus, a thymus independent (TI) antigen, and SRBC were simultaneously challenged to a mouse, neither prodigiosin 25-C nor FK506 affected antibody production against the TI antigen while the effect on the TD antigen were the same as described above. The present results revealed the unique immunosuppressive property of prodigiosin 25-C which was different from that of FK506.
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PMID:Selective immunosuppression of prodigiosin 25-C and FK506 in the murine immune system. 170 65

FK506 is a recently introduced immunosuppressive agent synthesised by the microorganism Streptomyces tskubaensis. It has been found to be more potent than Cyclosporin A in inhibiting T cell activation. We investigated its effects on the expression of membrane bound as well as soluble interleukin-2 receptors on human lymphocytes. The membrane-bound IL-2 receptor expression was inhibited by FK506 in resting lymphocytes at a concentration of 1 pmol/l. At 10 nmol/l no further inhibition was seen. In activated lymphocytes FK506 exerted no inhibitory effect on the IL-2 receptor expression. The release of soluble IL-2 receptor showed a pronounced decline in the concentration interval between 10 pmol/l and 0.1 nmol/l. Above a concentration of 10 nmol/l, no further decrease was seen. In activated lymphocytes the expression of soluble IL-2 receptors was unaffected by FK506 incubated up to 72 h. Pretreatment of the lymphocytes with the compound did not further depress the expression of the membrane-bound or the soluble receptor. Our results also indicate that the expression of the membrane-bound receptor is more sensitive to the drug than the soluble form of the receptor.
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PMID:The immunosuppressive agent FK506 inhibits in vitro expression of membrane-bound and soluble interleukin-2 receptors on resting but not on activated human lymphocytes. 172 Apr 17

The present study shows the in vitro effects of a novel immunosuppressive agent, FK506, in comparison with cyclosporin A (CsA). FK506 inhibited concanavalin A response and allo-mixed lymphocyte reaction of murine splenic lymphocytes in a dose-dependent manner, and at 40- to 200-fold lower concentrations than CsA. Allo-cytolytic T lymphocyte induction from murine thymocytes was also inhibited by FK506, whereas the ability of cytolytic T lymphocyte to lyse targets was not affected by the agent. Immunosuppressive effects of FK506 were further characterized by using antigen specific-proliferative T lymphocyte clones, BC.21 and KO.6. FK506 inhibited the proliferation of T cell clones stimulated with specific antigens in a dose-dependent manner, and at about 100-fold lower concentrations than CsA. However, cloned T cells, once activated, were scarcely affected by the agent; interleukin-2 (IL-2) driven proliferation of cloned T cells was not inhibited. On the other hand, it was found that FK506 inhibited both IL-2 secretion and IL-2 receptor expression of BC.21 after stimulation with the specific antigen. FK506 also inhibited the proliferation of BC.21 stimulated with phorbol 12-myristate 13-acetate plus calcium ionophore, indicating that it directly affected the signaling pathway downward from the perturbation of the Ti/T3 complex. Finally, it was suggested that FK506 and CsA synergistically inhibited the antigen-driven proliferation of cloned T cells. These results indicate that the novel immunosuppressive agent, FK506, affects T cell activation with mechanisms similar to those of CsA but at considerably lower concentrations.
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PMID:Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation. 244 55

The effect of FK506 on in vitro human lymphocyte responses was assessed in comparison with cyclosporine. FK506 suppressed, in a dose-dependent fashion, the lymphocyte response to stimulation with PHA and with alloantigens in primary mixed lymphocyte reactions at a 70-100-fold lower concentration than CsA--namely, 50% inhibition (IC50) was obtained with 8.6 nM FK506 and with 750 nM CsA in the PHA response, and with 0.21 nM FK506 and with 20 nM CsA in MLR. Allocytolytic T lymphocyte induction was also inhibited by FK506, whereas the ability of CTL to lyse targets was not affected by the agent, indicating that FK506 did not affect the recognition and binding of alloantigen by CTL. FK506 inhibited, in a dose-dependent fashion, both IL-2 receptor and transferrin receptor expression on the alloactivated lymphocytes--whereas this agent inhibited only incompletely both expression of both receptors on lymphocytes stimulated with PHA. Lymphocytes from primary MLR cultured in the presence of FK506 were tested for suppressor cell activity on day 8 of culture. FK506 did not allow for the expression of alloantigen-activated suppressor cells when used in a dose sufficient to inhibit CTL generation.
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PMID:Effect of a new immunosuppressive agent, FK506, on human lymphocyte responses in vitro. I. Inhibition of expression of alloantigen-activated suppressor cells, as well as induction of alloreactivity. 246 92

Recent investigations have shown that some antibiotics also work as immunomodulators. We have recently reported that fosfomycin (FOM) has an immunomodulatory effect on human B-cell activation. FOM is a unique antibiotic which is chemically unrelated to any other known antibacterial agent. In the present study, we examined the effect of FOM on human T-cell function. FOM inhibited the proliferation of human lymphocytes induced by polyclonal T-cell mitogens in a dose-dependent manner. FOM also strongly suppressed mixed lymphocyte reaction and interleukin-2 (IL-2) production by T cells. Moreover, FOM inhibited the expressions of IL-2 receptor (CD25) and transferrin receptor (CD71) on the activated T-cell surfaces. These data suggest that FOM may block the T-cell division during the transition from G1 to S phase of the cell cycle. Combined treatment with FOM and low-dose cyclosporin A or FK506 caused additive or synergistic suppression of T-cell proliferation, but not on IL-2 receptor expression. It seems that the mode of action of FOM on T-cell function involves a specific suppression of IL-2 production.
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PMID:Immunosuppressive activity of fosfomycin on human T-lymphocyte function in vitro. 750 46

The effect of three macrolide antibiotics, midecamycin acetate, josamycin, and clarithromycin, on human T-cell function was investigated in vitro. Midecamycin acetate and josamycin suppressed the proliferative response of peripheral blood mononuclear cells stimulated by polyclonal T-cell mitogens at concentrations between 1.6 and 8 micrograms/ml. At higher concentrations (40 to 200 micrograms/ml), all these drugs showed a marked inhibitory effect. At concentrations of 1.6 to 40 micrograms/ml, these drugs suppressed interleukin-2 (IL-2) production induced by mitogen-stimulated T cells, but not the expression of IL-2 receptor (CD25), in a dose-dependent manner. Therefore, the suppressive action on T-lymphocyte proliferation seems to be based on the ability of these drugs to inhibit IL-2 production by T cells. The drug also inhibited mixed lymphocyte reaction at the same concentrations. Combined treatment with these macrolides and the known immunosuppressants such as FK506 and cyclosporin A resulted in an increased inhibition of T-cell proliferation. The immunomodulatory properties of the antibiotics may have clinical relevance for modulation of the immune response in transplant patients and in patients with inflammatory diseases.
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PMID:Immunomodulatory effects of three macrolides, midecamycin acetate, josamycin, and clarithromycin, on human T-lymphocyte function in vitro. 753 33

The PLSTIRE protein (cyclin-dependent kinase 6 (cdk6)), which shares extensive sequence homology (approximately 70%) with cdk4, was identified as the earliest inducible member of the cdk family of proteins in human T lymphocytes induced to proliferate in vitro by stimulation either with phorbol 12,13-dibutyrate and ionomycin (PDB/I) or PHA. The p40cdk6 protein was present in resting cells and increased amounts were detected 6 h after stimulation. It increased in amount throughout the first cell cycle but was present in reduced amounts at later times. Activity of the kinase, determined by in vitro phosphorylation of recombinant truncated retinoblastoma tumor suppressor gene (Rb) protein (p60Rb), paralleled p40cdk6 protein amounts. Cyclins D2 and D3 were the major cyclins associated with p40cdk6, with D2 predominating in early G1 phase. Both PDB and ionomycin were required for maximal accumulation of p40cdk6, but either agent alone stimulated some increase in amount and activity of the protein. p40cdk6 also increased in amount in cells activated in the presence of cyclosporin A or FK506, drugs that inhibit production of IL-2 and cell proliferation, suggesting that initial induction occurred independently of IL-2-mediated cell cycle progression. Furthermore, increased accumulation of p40cdk6 protein and activity occurred in cells rendered "competent" (responsive to IL-2) by a brief treatment with PDB/I. Thus, increased accumulation of the protein and its activity begin before IL-2/IL-2 receptor interaction, suggesting that the cdk6-cyclin D2 complex might be involved in acquisition of the competent state in human T lymphocytes.
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PMID:Regulation of synthesis and activity of the PLSTIRE protein (cyclin-dependent kinase 6 (cdk6)), a major cyclin D-associated cdk4 homologue in normal human T lymphocytes. 775 65

Currently, the standard immunosuppressive regimen in organ transplantation is centred around cyclosporin. However, despite the use of this drug, rejection is not uncommon and it is associated with significant side-effects. Novel drugs and regimens have been developed to combat allograft rejection. Although FK506 has a similar mode of action and toxicity profile to cyclosporin, results, particularly in the rescue situation, have been encouraging. Sodium brequinar and rapamycin inhibit lymphocyte proliferation and may be most effective when used in combination with cyclosporin. Mycophenolate mofetil has been used in the treatment of psoriasis for many years; it is safe and will perhaps be useful in second-line therapy in patients unable to tolerate cyclosporin. The specific drugs highlighted in this chapter, although successful to differing degrees in preventing immunological rejection of allografts, have wide-ranging toxic effects on other organs in the body. Future use of these drugs is likely to utilize lower doses, supplemented by specific monoclonal antibody therapy, which can target diverse arms of the immune response. Large clinical trials using monoclonal antibodies against the T-cell receptor, the IL-2 receptor, CD4 T cells and specific adhesion molecules such as ICAM-1 are eagerly awaited. The number of new drugs and their mechanism of action, together with the widening spectrum of monoclonal antibodies available, will ensure that the next decade will be an exciting and hopefully profitable period in transplantation medicine. It is hoped that the introduction and assessment of these new agents will be rather more systematic and objective than that of their antecedents.
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PMID:New immunosuppressive treatment in transplantation medicine. 800 93


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