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)

The dependence of T cell proliferation on the production, binding and utilization of the lymphokine growth factor IL-2 has fostered the development and testing of new classes of drugs which act to either inhibit IL-2 production or the interaction of IL-2 with its cellular receptor. We have reviewed evidence which documents the potent immunosuppressive effects of inhibitors of IL-2 synthesis and secretion, such as Ciclosporin A, and of anti-IL-2 receptor MAb. The similarities of the potency and specificity of these agents and their effectiveness in a wide range of clinical settings encourage further studies on their mechanism of action. Perhaps the most dramatic similarity is the induction of long-term nonresponsiveness after drug removal to antigens present at the time of drug therapy. This observation has profound importance both on clinical manipulation with these agents and n the origins and maintenance of self-tolerance.
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PMID:Regulation of lymphocyte growth by antagonists of interleukin-2 or its cellular receptor. 313 98

Granulomatous tissue reactions appear in athymic mouse skin, indicating that initiation of granuloma formation may be T-cell independent. To further evaluate the relationships between granuloma formation and T-cell function, we treated euthymic BALB/c mice with cyclosporine (Cs), a potent immunosuppressive drug, injected intramuscularly (150 mg/kg/day) 5 times a week. Hepatic granulomas were isolated from mice with schistosomiasis and transplanted into the skin of mice treated with Cs for 2 weeks. Cyclosporine injection was continued for 3 additional weeks. Blood levels of the drug increased during treatment (489 ng/ml at 2 weeks and 822 ng/ml at 5 weeks). Morphologically identical granulomas developed in both treated and untreated mice. Examination for T-cell functions showed that by the end of 2 weeks treatment, concanavalin A, phytohemagglutinin responses, and IL-2 activity were markedly depressed, and IL-2 receptor expression was not detected in either lymph nodes or spleen of the Cs-treated mice; however, after hepatic granuloma graft, T-cell functions in regional lymph nodes, but not in spleen, as well as peripheral blood eosinophilia were stimulated in Cs-treated mice. These data strongly suggest that intact T-cell activity is not essential for the initiation of granuloma formation. In addition, granuloma grafts appear to stimulate Cs-resistant T-cell activation locally, which amplifies and organizes the granulomatous response.
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PMID:Skin granuloma formation in mice immunosuppressed by cyclosporine. 335 30

A possible selective therapeutic approach to corneal graft rejection will aim at IL-2 receptor-bearing antigen-activated T-lymphocytes with monoclonal anti IL-2R antibodies. In a rat penetrating keratoplasty model (Lewis x Lewis-BN) comparing to controls (median, 8 days), a significant delay of the allograft reaction was achieved by applying a therapeutic dose (15 mg/kg bw) of cyclosporin A (median, 18 days; p < 0.01), an intraperitoneal (1.0 mg/kg bw) (median, 13.5 days; p < 0.05) or a subconjunctival injection of IL-2R mab (0.5 mg/kg bw ART-18) (median, 16 days; p < 0.01) with low-dose Cyclosporin A (1.5 mg/kg bw). In pharmacokinetic experiments, the corneal radioactivity 24 h after intraperitoneal injection of 125I-labeled ART-18 was < 1% (p < 0.01) of the values obtained by subconjunctival injection, whereas the serum radioactivity values (p > 0.05) were in the same range. The above results suggest that the onset of an allograft reaction in perforating keratoplasty seems to depend on the locally achievable antibody concentration and can be delayed with a high level of IL-2 R mab present in the immediate surrounding of the foreign antigen-expressing cells.
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PMID:Interleukin-2 receptor--targeted therapy by monoclonal antibodies in the rat corneal graft. 799 69

Despite the increasing numbers of paediatric transplants performed, little is known about the immune responses of T lymphocytes in human neonates. Here we have compared the effects of cyclosporine on the phytohaemagglutinin (PHA) response of immature (cord) and mature (adult) lymphocytes using the following parameters of activation: (i) proliferation, measured by 3H-thymidine uptake; (ii) expression of cell surface IL-2 receptor; (iii) release of IL-2 into the supernatant. Cyclosporine was added to cultures of PHA-stimulated lymphocytes at doses ranging from 5 to 5000 ng/ml. The proliferative response of cord lymphocytes was considerably more sensitive to cyclosporine at each dose, so that 50% inhibition was achieved by 6 ng/ml and 21.5 ng/ml doses of cyclosporine on cord and adult lymphocytes, respectively. Expression of the IL-2 receptor by PHA-activated T cells and their subsets was assessed by flow cytometry. Cyclosporine inhibited IL-2 receptor expression to a significantly greater degree in cord CD4 and CD8 cells (49.7% and 70.1%) than in adults (17.9% and 30.0%). Biologically active IL-2 release was measured using the IL-2-dependent cell line CTLL-2. Cyclosporine at doses 50-5000 ng/ml produced 80-99% inhibition of both cord and adult responses. However, at very low doses (5 ng/ml) cyclosporine produced 69.3% inhibition of cord lymphocytes, compared with 42.0% of adult lymphocytes. These results suggest that the T cells of neonates are considerably more sensitive to cyclosporine than are adult T cells.
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PMID:Increased cyclosporine sensitivity of T cells from cord blood compared with those from the adult. 813 49

The focus of progress in transplantation immunosuppression is to achieve more specific immunosuppression with monoclonal antibodies. We have already shown that the efficacy of 33B3.1, a rat monoclonal Ig2A directed against the human IL-2 receptor, was similar to that of rabbit antithymocyte globulin in the prevention of acute rejection in first kidney transplants. A similar comparative analysis has been made in 40-sec renal transplants. ATG (1 mg/kg/day) or 33B3.1 (10 mg/day) was administered during the first 10 days postgrafting in association with corticosteroids and azathioprine. Cyclosporine was introduced on day 9 and azathioprine/CsA constituted the patient's maintenance treatment after day 45. Rejection treatment consisted of equine antilymphocyte globulin in both cases and of steroid boluses when patients were under Cyclosporine. One patient in each group died. Graft survival was 90%, 85%, and 79% in the ATG group (n = 20) and 100%, 89%, and 89% in the 33B3.1 group (n = 20) at 3, 12, and 24 months, respectively. Of the ATG group patients, 45% and 40% in the 33B3.1 group had at least one rejection episode, half the episodes in the MoAb cohort occurring under 33B3.1, vs. none in the ATG group. Transplant function was similar in both groups. Viral infections appeared to be more frequent with ATG (60%) than with 33B3.1 (12%), with CMV accounting for half of these in the ATG group, and none in the MoAb group. Tolerance of both agents was good. Of the 33B3.1 recipients, 70% developed anti-33B3.1 antibodies. From these data, we conclude that this anti-IL-2 receptor MoAb seems less effective than rabbit ATG as induction treatment in second kidney transplant patients.
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PMID:Prevention of acute rejection episodes with an anti-interleukin 2 receptor monoclonal antibody. II. Results after a second kidney transplantation. 831 May 8

Cyclosporin A (CSA), an immunosuppressive agent used in organ transplantation and to treat some autoimmune diseases, blocks the Ca2+-dependent steps involved in T cell receptor triggering leading to interleukin (IL)-2 production. Considering that the early steps of T cell activation are insensitive to CSA, we asked whether the initial activation achieved in presence of this immunosuppressor could affect the capacity of the T cell to respond to a mitogenic restimulation. We found that T cells activated by concanavalin A (ConA) for 48 h in the presence of CSA retain the capacity to proliferate in response to ConA once the immunosuppressor is removed. These cells are able to transcribe anew the IL-2 gene, without the requirement of new protein synthesis, and to up-regulate the alpha chain of the IL-2 receptor. Furthermore, we present the first direct evidence that the nuclear factor AP-1 is present in the nucleus of the T cells primed for 48 h in presence of CSA and that withdrawal of the immunosuppressor leads to the translocation of NFATp from the cytoplasm to the nucleus.
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PMID:T cell activation by concanavalin A in the presence of cyclosporin A: immunosuppressor withdrawal induces NFATp translocation and interleukin-2 gene transcription. 876 50

According to the widely accepted classification, human TH cell clones can be divided into two mutually exclusive subsets, TH1 and TH2, based on their profile of cytokine production. The intracellular difference between these clones is not clear. To characterize the biochemical nature of T-cell receptor (TCR)/CD3 complex-mediated signal transduction pathways, we introduced several human TH cell clones of THO- or TH1-like phenotype and analyzed the effects of various drugs and antibodies on cytokine production or proliferation of these clones. The tyrosine kinase inhibitor herbimycin inhibited the production of interferon-gamma (IFN-gamma) by THO-like clone, after stimulation with anti-CD3 monoclonal antibody alpha CD3-mAb) or with phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore A23187. However, whereas herbimycin strongly inhibited the production of IL-4 and IL-5 by alpha CD3 mAb stimulated T cells, it did not affect the production of these cytokines after PMA/A23187 stimulation. Cyclosporin A inhibited the proliferation as well as the production of the cytokines, including that of IL-2, IL-4, IL-5, and IFN-gamma, irrespective of the mode of stimulation. A23187, which synergizes with PMA in the induction of IL-4 and IFN-gamma, inhibited PMA-induced IL-10 production in a dose-dependent manner. Transforming growth factor-beta and anti-IL-2 receptor monoclonal antibody partially inhibited alpha CD3 mAb-mediated T-cell proliferation, but had no effect on the proliferation induced by PMA and A23187. Cyclic adenosine monophosphate (cAMP)-elevating drugs, like prostaglandin E2 and dibutyryl cAMP, inhibited the TCR-mediated cytokine production but shifted the cytokine production profile from a TH0 to a TH2 type after stimulation with PMA and A23187. Finally, we analyzed the induction of activity of two transcription factors, nuclear factor-kappa B (NF-kappa B) and nuclear factor of activated T cells, involved in the regulation of cytokine gene expression, after a different mode of activation. The induction of NF-kappa B (p50/p65 heterodimer) by using alpha CD3-mAb stimulation but not by using PMA/A23187 stimulation was found to be inhibited by using cAMP-elevating drugs.
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PMID:Factors affecting the cytokine production of human T cells stimulated by different modes of activation. 897 24

As it has been suggested that an autocrine mechanism may control tumour cell growth, in this work cells from a spontaneous murine T lymphocyte leukaemia (LB) expressing the interleukin-2 receptor (IL-2R) (CD25) were evaluated in vitro for IL-2-mediated autocrine growth. Cells grew readily in culture and proliferation was enhanced by the addition of recombinant IL-2 but inhibited by monoclonal antibodies against either IL-2 or IL-2 receptor, in the absence of exogenous IL-2. Cyclosporin A also inhibited LB cell growth. However, when exogenous IL-2 was added together with cyclosporin A, cell proliferation proved similar to controls. Using reverse transcription polymerase chain reaction (PCR), mRNA for IL-2 was found to be present in tumour cells. Our findings support the hypothesis that LB tumour cell proliferation is mediated by an autocrine pathway involving endogenous IL-2 generation, despite the fact that these cells are not dependent on exogenous IL-2 to grow in culture.
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PMID:Interleukin 2 exerts autocrine stimulation on murine T-cell leukaemia growth. 908 28

1. Staphylococcal enterotoxine B (SEB; superantigen) accelerated the onset of arthritis in mice preimmunized with type II collagen (SEB-potentiated collagen-induced arthritis). Cyclosporin A and FK-506 inhibited the induction and development of clinical signs and histopathological changes of SEB-potentiated collagen-induced arthritis in mice. 2. Simultaneously, both cyclosporin A and FK-506 inhibited the development of humoral and cellular immunity to type II collagen. 3. The expression of IL-2 receptor (CD25) by SEB on splenocyte T cells from collagen-preimmunized mice was inhibited by both agents in ex vivo experimentation.
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PMID:Cyclosporin A and FK-506 inhibit development of superantigen-potentiated collagen-induced arthritis in mice. 955 34

The effects of simultaneous administrations of Cyclosporin A (CsA) and Glyburide on the immune system of rats has been evaluated in terms of Interleukin-2 (IL-2) production by Concanavalin A (ConA) stimulated splenocytes and exogenous IL-2 binding capacity. The inhibitory effect of Cyclosporin A on IL-2 production of lymphoid cells is well known. Spleen cells from rats receiving CsA had reduced levels of IL-2 when compared to untreated controls or rats receiving Glyburide only. Splenocytes from rats receiving both drugs had reduced levels of IL-2 when they were sacrificed 24 hours after one or three CsA administrations; instead when the animals were sacrificed 6 days after three CsA administrations, their ability of producing IL-2 is increased as well as increasing exogenous IL-2 binding capacity. These findings let us hypothesize that when there are lower concentrations of CsA in lymphocytes there is an increase of cellular metabolism induced by Glyburide that leads to an increase in IL-2 secretion and in IL-2 receptor expression on cellular surface restoring these levels to normal or slightly above normal levels.
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PMID:Effects of glyburide-cyclosporin A interaction on interleukin-2 production in rats. 1046 81


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