Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ca(2+)-regulated calcineurin/nuclear factor of activated T cells (NFAT) cascade controls alternative pathways of T-cell activation and peripheral tolerance. Here, we describe reduction of NFATc2 mRNA expression in the lungs of patients with bronchial adenocarcinoma. In a murine model of bronchoalveolar adenocarcinoma, mice lacking NFATc2 developed more and larger solid tumors than wild-type littermates. The extent of central tumor necrosis was decreased in the tumors in NFATc2((-/-)) mice, and this finding was associated with reduced tumor necrosis factor-alpha and interleukin-2 (IL-2) production by CD8(+) T cells. Adoptive transfer of CD8(+) T cells of NFATc2((-/-)) mice induced transforming growth factor-beta(1) in the airways of recipient mice, thus supporting CD4(+)CD25(+)Foxp-3(+)glucocorticoid-induced tumor necrosis factor receptor (GITR)(+) regulatory T (T(reg)) cell survival. Finally, engagement of GITR in NFATc2((-/-)) mice induced IFN-gamma levels in the airways, reversed the suppression by T(reg) cells, and costimulated effector CD4(+)CD25(+) (IL-2Ralpha) and memory CD4(+)CD127(+) (IL-7Ralpha) T cells, resulting in abrogation of carcinoma progression. Agonistic signaling through GITR, in the absence of NFATc2, thus emerges as a novel possible strategy for the treatment of human bronchial adenocarcinoma in the absence of NFATc2 by enhancing IL-2Ralpha(+) effector and IL-7Ralpha(+) memory-expressing T cells.
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PMID:A key regulatory role of the transcription factor NFATc2 in bronchial adenocarcinoma via CD8+ T lymphocytes. 1931 84

We have previously shown, in renal transplant recipients on maintenance immunosuppression, that a whole-blood assay was superior in detecting immunity towards purified protein derivative (PPD) compared with skin testing. As blood tests may have limitations during high-dose immunosuppression therapy, the present study was aimed at characterising the effect of high immunosuppressive drug levels on PPD-specific T-cell immunity. PPD-reactive CD4 T-cells from 13 renal transplant recipients were longitudinally quantified by the induction of cytokines using flow cytometry. To further address the effect of high and low maintenance immunosuppression, drug effects were studied in vitro and in 49 age-matched lung transplant recipients and 49 renal transplant recipients. Maintenance immunosuppression after renal transplantation did not affect PPD-specific T-cell detection (median T-cell frequencies 0.55% before and 0.46% >12 months after transplantation), whereas specific T-cell frequencies were significantly lower 3 months after transplantation (0.15%; p = 0.0002). Likewise, high-level maintenance immunosuppression after lung transplantation was associated with a significantly lower prevalence in PPD-specific T-cell reactivity compared with renal transplant recipients (16.7% versus 52.1%; p = 0.0005). In line with the observations made in vivo, calcineurin inhibitors analysed in vitro led to a dose-dependent decrease in antigen-specific T-cell reactivity. The flow cytometric assay is not adversely affected by low drug doses. In contrast, decreased levels of PPD-specific T-cells early after transplantation and low prevalence of PPD-reactivity in lung transplant recipients suggest a reduced sensitivity of in vitro testing during high-level immunosuppression.
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PMID:Impaired detection of Mycobacterium tuberculosis immunity in patients using high levels of immunosuppressive drugs. 1938 92

Solid organ transplantations (SOT) are performed successfully in selected HIV-infected patients. However, multiple and reciprocal drug-drug interactions are observed between antiretroviral (ARV) drugs and calcineurin inhibitors (CNIs) through CYP450 metabolization. Raltegravir (RAL), a novel HIV-1 integrase inhibitor, is not a substrate of CYP450 enzymes. We retrospectively reviewed the outcomes of 13 HIV-infected transplant patients treated by an RAL + two nucleosidic reverse transcriptase inhibitor (NRTI) regimen, in terms of tolerability, ARV efficacy (plasma viral load, CD4 cell count), drug interactions, RAL pharmacokinetics and transplant outcome. Thirteen patients with liver (n = 8) or kidney (n = 5) transplantation were included. RAL was initiated (400 mg BID) either at time of transplantation (n = 6), or after transplantation (n = 7). Median RAL trough concentration was 507 ng/mL (176-890), which is above the in vitro IC95 for wild type HIV-1 strains (15 ng/mL). Target trough levels of CNIs were promptly obtained with standard dosages of tacrolimus or cyclosporine. RAL tolerability was excellent. There was no episode of acute rejection. HIV infection remained controlled. After a median follow-up of 9 months (range: 6-14), all patients were alive with satisfactory graft function. The use of an RAL + two NRTI-based regimen is a good alternative in HIV-infected patients undergoing SOT.
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PMID:Safety and efficacy of raltegravir in HIV-infected transplant patients cotreated with immunosuppressive drugs. 1951 19

Our previous study proved that sirolimus is a potent immunosuppressant which induces long-term allograft survival depends on persistence of alloantigens. CD4(+)CD25(+) regulatory T (Treg) cells are potent suppressors in transplantation. Our objectives focus on whether combined-therapy of Tregs with immunosuppressants could prolong allograft survival in mice. The study showed that inhibition of Tregs was maintained by co-cultured with sirolimus (1 nM) in vitro, but not tacrolimus (1 nM) or CsA (1 nM). When the concentration was increased >100 nM, suppression was fallen. Based on the ability of sirolimus to target effector T cells, but retaining the inhibition of Tregs, an adoptive infusion of donor alloantigen specific Tregs combined with 30-day sirolimus (1 mg/kg) and 3-day ATG (20 mg/kg) was found to prolong heart allograft survival in mice. Even though the cell numbers of CD4(+) T cells were found to decrease in sirolimus-treated mice, sirolimus selectively enhanced the numbers of CD4(+)CD25(+) cells and increased the expression of Foxp3 in spleens and lymph nodes, respectively, in recipients. However, combined therapy with low-dose CsA (5 mg/kg) or tacrolimus (1 mg/kg) reduced significantly the expression of Foxp3 and failed to prolong the allograft survival. In summary, expanded Tregs exposed to sirolimus can survive, proliferate, and preserve inhibition in vitro. Tregs are more resistant to sirolimus than other T cells. Combined with Tregs, sirolimus rather than calcineurin inhibitors, prolongs the allograft survival. Sirolimus may be the best copartner for Tregs therapy. It also suggests calcineurin-dependent signals may be required in the development of Tregs.
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PMID:Combined therapy of CD4(+)CD25(+) regulatory T cells with low-dose sirolimus, but not calcineurin inhibitors, preserves suppressive function of regulatory T cells and prolongs allograft survival in mice. 1953 58

The mechanisms underlying maintenance of renal allografts in humans under minimal or conventional immunosuppression are poorly understood. There is evidence that CD4(+) CD25(+) regulatory T cells and clonal deletion, among other mechanisms of tolerance, could play a key role in clinical allograft survival. Twenty-four TCR-Vbeta families were assessed in CD4(+) CD25(-), CD4(+) CD25(low) and CD4(+) CD25(high) T cells from patients with long-term renal allograft survival (LTS), patients exhibiting chronic rejection (ChrRx), patients on dialysis (Dial) and healthy controls (HC) by flow cytometry. LTS patients presented a higher variability in their TCR-Vbeta repertoire, such decreased percentage of Vbeta2(+), Vbeta8a(+) and Vbeta13(+) in CD4(+) CD25(low) and (high) compared with CD4(+) CD25(-) subset and increased Vbeta4 and Vbeta7 families in CD4(+) CD25(high) T cells exclusively. Additionally, LTS patients, particularly those that were not receiving calcineurin inhibitors (CNI), had increased percentages of CD4(+) CD25(high) T cells when compared with Dial (P < 0.05) and ChrRx (P < 0.05) patients. Our results suggest that a differential expression of particular TCR-Vbeta families and high levels of circulating CD4(+) CD25(high) T cells in long-term surviving renal transplant patients could contribute to an active and specific state of immunologic suppression. However, the increase in this T cell subset with regulatory phenotype can be affected by CNI.
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PMID:T cell receptor beta chain (TCR-Vbeta) repertoire of circulating CD4(+) CD25(-), CD4(+) CD25(low) and CD4(+) CD25(high) T cells in patients with long-term renal allograft survival. 1969 99

Transforming growth factor (TGF) beta1) is an immunoregulatory cytokine involved in self-tolerance and lymphocyte homeostasis. Tgfb1 knock-out (KO) mice develop severe multi-focal autoimmune inflammatory lesions due to [Ca(2+)]i deregulation in T cells, and die within 3 weeks after birth. Because the calcineurin inhibitor FK506 inhibits the hyperresponsiveness of Tgfb1(-/-) thymocytes, and because calcineurin Abeta (CNAbeta)-deficient mice do not reject allogenic tumours, we have generated Tgfb1(-/-) Cnab(-/-) mice to address whether CNAbeta deficiency prevents T cell activation and inflammation in Tgfb1(-/-) mice. Here we show that in Tgfb1(-/-) Cnab(-/-) mice inflammation is reduced significantly relative to that in Tgfb1(-/-) mice. However, both CD4(+) and CD8(+) T cells in double knock-out (DKO) mice are activated, as revealed by up-regulation of CD11a lymphocyte function-associated antigen-1 (LFA-1), CD44 and CD69 and down-regulation of CD62L. These data suggest that deficiency of CNAbeta decreases inflammatory lesions but does not prevent activation of autoreactive T cells. Also Tgfb1(-/-) T cells can undergo activation in the absence of CNAbeta, probably by using the other isoform of calcineurin (CNAalpha) in a compensatory manner. CNAbeta-deficient T cells undergo spontaneous activation in vivo and are activated upon anti-T cell receptor stimulation in vitro. Understanding the role of calcineurin in T cell regulation should open up new therapeutic opportunities for inflammation and cancer.
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PMID:Calcineurin deficiency decreases inflammatory lesions in transforming growth factor beta1-deficient mice. 1974 9

Fibrocytes are collagen-type-I-producing cells that arise at low frequency from hematopoietic cells. We have analyzed in mice which leukocyte subsets are required for generation of fibrocytes and show that murine fibrocytes develop from the subpopulation of CD11b(+) CD115(+) Gr1(+) monocytes under the control of CD4(+) T cells. In the absence of CD4(+) T cells, differentiation of fibrocytes was markedly reduced in vitro and in vivo. In the presence of CD4(+) T cells, the characteristics of T-cell activation critically determined development of fibrocytes. Polyclonal activation of CD4(+) T cells induced the release of soluble factors that completely prevented the outgrowth of fibrocytes and could be identified as IL-2, TNF, IFN-gamma, and IL-4. Application of IL-2 and TNF significantly reduced the appearance of fibrocytes and the severity of fibrosis in the model of unilateral ureteral obstruction. In contrast, activation of CD4(+) T cells in the presence of calcineurin inhibitors, but not mTOR inhibitors, markedly enhanced the outgrowth of fibrocytes and renal deposition of collagen I. Taken together, we show that differentiation of fibrocytes is critically dependent on CD4(+) T cells and that the context of T-cell activation determines whether development of fibrocytes is supported or blocked. Our data may have implications for prevention of organ fibrosis in autoimmune diseases and transplantation.
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PMID:CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. 1981 30

T helper 17 (Th17) cells play major roles in autoimmunity and bacterial infections, yet how T cell receptor (TCR) signaling affects Th17 cell differentiation is relatively unknown. We demonstrate that CD4(+) T cells lacking Itk, a tyrosine kinase required for full TCR-induced phospholipase C-gamma (PLC-gamma1) activation, exhibit decreased interleukin-17A (IL-17A) expression in vitro and in vivo, despite relatively normal expression of retinoic acid receptor-related orphan receptor-gammaT (ROR-gammaT) and IL-17F. IL-17A expression was rescued by pharmacologically induced Ca(2+) influx or constitutively activated nuclear factor of activated T cells (NFAT). Conversely, decreased TCR stimulation or calcineurin inhibition preferentially reduced IL-17A expression. We further found that the promoter of Il17a but not Il17f has a conserved NFAT binding site that bound NFATc1 in wild-type but not Itk-deficient cells, even though both exhibited open chromatin conformations. Finally, Itk(-/-) mice also showed differential regulation of IL-17A and IL-17F in vivo. Our results suggest that Itk specifically couples TCR signaling to Il17a expression and the differential regulation of Th17 cell cytokines through NFATc1.
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PMID:Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase. 1983 81

Myasthenia gravis is an autoimmune disorder mediated by antibodies against the acetylcholine receptors of the skeletal muscles. Imbalances between T helper type 1 and type 2 cytokine production play a key role in the induction and development of several autoimmune diseases. Peripheral T helper type 1 and type 2 cells in 50 myasthenia gravis patients were estimated by intracellular cytokines. The percentage of T helper type 1 cells in CD4(+) cells was higher than that of type 2 or type 0 cells (P<0.0001). There was a significant correlation between T helper type 1/type 2 ratio and the P-glycoprotein function on CD3(+) T cells (P=0.008). In the patients treated with prednisolone alone (n=12), there was a significant correlation negatively between the percentage of change in the T helper type 1/type 2 ratio and the reduction rate of quantitative myasthenia gravis scores after 12 months of treatment (P=0.012). In contrast, all of the patients treated with prednisolone and calcineurin inhibitor in combination saw reductions in the scores. Our data suggest that the T helper type 1/type 2 ratio was involved in the disease activity of the patients treated with prednisolone alone. On the other hand, the patients treated with prednisolone and calcineurin inhibitor in combination had their disease condition improved regardless of the T helper type 1 predominance. Therefore, the data suggest that supplemental calcineurin inhibitors are effective for the myasthenia gravis patients treated with prednisolone alone when their T helper balance shifts toward to type 1.
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PMID:Clinical implications of the type 1/type 2 balance of helper T cells and P-glycoprotein function in peripheral T lymphocytes of myasthenia gravis patients. 1986 46

Previous studies have indicated that blockade of signaling through the T-cell receptor (TCR)/calcineurin/nuclear factor of activated T cells (NFAT) pathway impairs transplantation tolerance induced with anti-CD154 antibody. By using an allogeneic bone marrow transplantation model, we examined the role of the TCR/calcineurin/NFAT pathway for tolerance induction with anti-CD154. Calcineurin blockade by cyclosporine A led to a failure of CD8 but not CD4 tolerance, and experiments in NFAT1(-/-) mice replicated this effect. Studies in thymectomized mice demonstrated that blockade of the calcineurin/NFAT pathway after bone marrow transplantation led to a failure of peripheral CD8 tolerance. Moreover, CD8 adoptive transfer studies demonstrated that NFAT1 is cell-intrinsically required for peripheral CD8 tolerance. NFAT1 deficiency did not impair CD8 T-cell up-regulation of PD1, which is required for CD8 tolerance in this model. NFAT1 has previously been shown to have a role in CD4 cells for anergy induction and for programming CD4 cells to become regulatory cells. By generating mice lacking NFAT1 in CD4 but not CD8 cells, we demonstrate that NFAT1 is neither required for CD4 tolerance induction nor for their regulatory function on CD8 T cells. Thus, our study reveals a CD8 T cell-intrinsic NFAT1 requirement for CD8 tolerance in vivo.
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PMID:A CD8 T cell-intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo. 2000 5


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