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T cell growth factor [keywords]
- Serum concentrations of interleukin-2 and tumour necrosis factor-α under cyclosporine versus acitretin treatment in plaque-type psoriasis. [JOURNAL ARTICLE]
- J Int Med Res 2014 Aug 20.
A prospective, randomized clinical study to compare the short-term effects of cyclosporin and acitretin on psoriasis severity, and serum interleukin (IL)-2 and tumour necrosis factor (TNF)-α concentrations.Patients with moderate-to-severe plaque-type psoriasis were randomly assigned to receive either 3 mg/kg per day cyclosporine or 0.3-0.5 mg/kg per day acitretin for 8 weeks. Disease severity (psoriasis area severity index [PASI] score) and serum IL-2 and TNF-α concentrations were determined before and after treatment.PASI scores and serum IL-2 and TNF-α concentrations were significantly decreased after treatment with either cyclosporine (n = 21) or acitretin (n = 25). There were no statistically significant between-group differences in any parameter.Acitretin and cyclosporine are equally effective in the treatment of moderate-to-severe plaque-type psoriasis.
- Tacrolimus Pharmacodynamics and Pharmacogenetics along the Calcineurin Pathway in Human Lymphocytes. [EDITORIAL]
- Clin Chem 2014 Aug 20.
Although therapeutic drug monitoring has improved the clinical use of immunosuppressive drugs, there is still interpatient variability in efficacy and toxicity that pharmacodynamic monitoring may help to reduce. To select the best biomarkers of tacrolimus pharmacodynamics, we explored the strength and variability of signal transduction and the influence of polymorphisms along the calcineurin pathway.Peripheral blood mononuclear cells from 35 healthy volunteers were incubated with tacrolimus (0.1-50 ng/mL) and stimulated ex vivo. Inhibition of NFAT1 (nuclear factor of activated T cells 1) translocation to the nucleus and intracellular expression of interleukin-2 in CD4(+) and CD8(+) T cells and the surface activation marker CD25 in CD3(+) cells were measured by flow cytometry. We sequenced the promoter regions of immunophilins and calcineurin subunits and characterized selected single nucleotide polymorphisms in the genes of the calcineurin pathway with allelic discrimination assays.All responses closely fitted an I/Imax sigmoid model. Large interindividual variability (n = 30) in I0 and IC50 was found for all biomarkers. Moreover, strong and statistically significant associations were found between tacrolimus pharmacodynamic parameters and polymorphisms in the genes coding cyclophilin A, the calcineurin catalytic subunit α isoenzyme, and CD25.This study demonstrates the consistency and large interindividual variability of signal transduction along the calcineurin pathway, as well as the strong influence of pharmacogenetic polymorphisms in the calcineurin cascade on both the physiological activity of this route and tacrolimus pharmacodynamics.
- A sharp T-cell antigen receptor signaling threshold for T-cell proliferation. [JOURNAL ARTICLE]
- Proc Natl Acad Sci U S A 2014 Aug 18.
T-cell antigen receptor (TCR) signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR signaling specifically and efficiently. We have also characterized a fluorescent reporter Nur77-eGFP transgenic mouse line in which T cells up-regulate GFP uniquely in response to TCR stimulation. The combination of these technologies unmasked a sharp TCR signaling threshold for commitment to cell division both in vitro and in vivo. Further, we demonstrate that this threshold is independent of both the magnitude of the TCR stimulus and Interleukin 2. Similarly, we identify a temporal threshold of TCR signaling that is required for commitment to proliferation, after which T cells are able to proliferate in a Zap70 kinase-independent manner. Taken together, our studies reveal a sharp threshold for the magnitude and duration of TCR signaling required for commitment of T cells to proliferation. These results have important implications for understanding T-cell responses to infection and optimizing strategies for immunomodulatory drug delivery.
- Activation Effects of Polysaccharides of Flammulina velutipes Mycorrhizae on the T Lymphocyte Immune Function. [Journal Article]
- J Immunol Res 2014.:285421.
Flammulina velutipes mycorrhizae have increasingly been produced with increasing of F. velutipes production. A mouse model was thus used to examine potential effect of F. velutipes mycorrhizae on the immune function. Fifty female Wistar mice (5-weeks-old) weighed 15-20 g were randomly allocated into five groups. Polysaccharide of F. velutipes mycorrhizae were treated with mice and mice spleen lymphocytes. The levels of CD3(+), CD4(+), and CD8(+) T lymphocyte, interleukin-2 (IL-2), and tumor necrosis factor-a (TNF-α) were determined. The results showed that the proportions of CD3(+), and CD4(+) T lymphocyte, the ratio of CD4(+)/CD8(+), and the levels of IL-2 and TNF-a were significantly increased in polysaccharide of F. velutipes mycorrhizae, while the proportion of CD8(+) T lymphocyte was decreased in polysaccharide of F. velutipes mycorrhizae-dose dependent manner. Our findings indicated that a long term exposure of polysaccharide of F. velutipes mycorrhizae could activate the T lymphocyte immune function. Polysaccharide of F. velutipes mycorrhizae was expected to develop into the immune health products.
- Immunosuppression in lung transplantation. [Journal Article, Review]
- J Thorac Dis 2014 Aug; 6(8):1039-53.
Lung transplantation can be a life-saving procedure for those with end-stage lung diseases. Unfortunately, long term graft and patient survival are limited by both acute and chronic allograft rejection, with a median survival of just over 6 years. Immunosuppressive regimens are employed to reduce the rate of rejection, and while protocols vary from center to center, conventional maintenance therapy consists of triple drug therapy with a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative agents [azathioprine (AZA), mycophenolate, sirolimus (srl), everolimus (evl)], and corticosteroids (CS). Roughly 50% of lung transplant centers also utilize induction therapy, with polyclonal antibody preparations [equine or rabbit anti-thymocyte globulin (ATG)], interleukin 2 receptor antagonists (IL2RAs) (daclizumab or basiliximab), or alemtuzumab. This review summarizes these agents and the data surrounding their use in lung transplantation, as well as additional common and novel therapies in lung transplantation. Despite the progression of the management of lung transplant recipients, they continue to be at high risk of treatment-related complications, and poor graft and patient survival. Randomized clinical trials are needed to allow for the development of better agents, regimens and techniques to address above mentioned issues and reduce morbidity and mortality among lung transplant recipients.
- [Analysis of factors influencing the occurrence of infusion reaction after initial treatment with rituximab]. [English Abstract, Journal Article]
- Gan To Kagaku Ryoho 2014 Aug; 41(8):975-9.
We investigated factors influencing the occurrence of infusion reactions after initial treatment with rituximab. We included patients who were administered rituximab for the treatment of B-cell non-Hodgkin's lymphoma at the Gifu Municipal Hospital Hematology from February 2010 to March 2013. Fifty-one patients were included; their median age was 72(44-87)years, and 31 were men and 20 were women. We defined the index of infusion reaction as the maximal change in body temperature within 24 hours from the administration of rituximab and evaluated the correlation with change in body temperature and each factor, and differences of change in body temperature between the upper and lower groups divided by standard value of each factor by using the t test without correspondence. The "2,000 U/mL or less group"of soluble interleukin-2 receptor(sIL- 2R)levels and the "over 2,000 U/mL group"showed significant different(p=0.014). The "double value or less group"of a standard value(211 IU/L)and "over double value group"showed significantly different lactate dehydrogenase(LDH)levels (p=0.017). The "lower limit or less group"of the standard value(men: 13 g/dL, women: 12 g/dL)and the "over lower limit group"showed significantly different hemoglobin(Hb)levels(p=0.020). In conclusion, the levels of sIL-2R, LDH, and Hb may predict the occurrence of infusion reaction after the initial administration of rituximab in patients with B-cell non-Hodg- kin's lymphoma.
- Persistent inflammation and its relationship to leptin and insulin in phases of bipolar disorder from acute depression to full remission. [JOURNAL ARTICLE]
- Bipolar Disord 2014 Aug 11.
A proinflammatory phase with various immunomodulatory mechanisms has been noted in bipolar mania and major depression. Weight gain and increased production of leptin may be associated with immunomodulation and insulin resistance in bipolar disorder. However, immunomodulation and its linkage with leptin and insulin in the depressive episode of bipolar disorder remain unclear. We investigated alterations in inflammatory markers and their relationship with leptin and insulin levels in patients with phases of bipolar disorder from acute depression to full remission.Thirty-two physically healthy bipolar I depressed patients aged <45 years and age- and sex-matched healthy controls participated in this study. We measured their circulating levels of leptin, insulin, high-sensitivity C-reactive protein (hs-CRP), soluble interleukin-2 receptor (sIL-2R), soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor receptor 1 (sTNF-R1), and interleukin-1 receptor antagonist (IL-1Ra) in three phases, i.e., acute depression, subsequent partial remission, and full remission.In acute depression, subsequent partial remission, and full remission, patients with bipolar disorder had significantly higher mean levels of hs-CRP, IL-1Ra, sTNF-R1, and sIL-2R compared with control subjects. The IL-1Ra and sTNF-R1 levels in various affective phases were significantly correlated to body mass index, leptin level, circulating lipids, and medication status. The sIL-2R levels in the three affective phases were all independent of other inflammatory markers and clinical and laboratory variables. Patients showed no alteration of sIL-6R levels through the depressive episode.Patients with bipolar disorder in depressive episodes may exhibit persistent inflammation with elevated levels of hs-CRP, IL-1Ra, sTNF-R1, and sIL-2R but not sIL-6R from the acute phases to full remission. Only sIL-2R production seems to be tightly linked with the pathophysiology of bipolar depression and is independent of insulin and leptin levels.
- Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. [JOURNAL ARTICLE]
- Nat Med 2014 Aug 17.
Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies. Genome-wide association studies (GWAS) implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic CD8(+)NKG2D(+) T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ-producing CD8(+)NKG2D(+) effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rβ) prevented disease development, reducing the accumulation of CD8(+)NKG2D(+) T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and γc cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA.
- Complex interactions of transcription factors in mediating cytokine biology in T cells. [Journal Article]
- Immunol Rev 2014 Sep; 261(1):141-56.
T-helper (Th) cells play critical roles within the mammalian immune system, and the differentiation of naive CD4(+) T cells into distinct T-helper subsets is critical for normal immunoregulation and host defense. These carefully regulated differentiation processes are controlled by networks of cytokines, transcription factors, and epigenetic modifications, resulting in the generation of multiple CD4(+) T-cell subsets, including Th1, Th2, Th9, Th17, Treg, and Tfh cells. In this review, we discuss the roles of transcription factors in determining the specific type of differentiation and in particular the role of interleukin-2 (IL-2) in promoting or inhibiting Th differentiation. In addition to discussing master regulators and subset-specific transcription factors for distinct T-helper cell populations, we focus on signal transducer and activator of transcription (STAT) proteins and on the cooperative action of interferon regulatory factor 4 (IRF4) with activator protein 1 (AP-1) family proteins and STAT3 in the assembly of complexes that broadly influence T-cell differentiation.
- Inhibition of Interleukin-2 Gene Expression by Human Herpesvirus 6B U54 Tegument Protein. [JOURNAL ARTICLE]
- J Virol 2014 Aug 13.
Human Herpesvirus 6B (HHV-6B) is a ubiquitous pathogen causing life-long infections in approximately 95% of humans worldwide. To persist within its host, HHV-6B developed several immune evasion mechanisms such as latency during which minimal proteins are expressed and also by disturbing innate and adaptive immune responses. The primary cellular targets of HHV-6B are CD4+ T cells. Previous studies by Flamand et al. reported on the capacity of HHV-6A, as well as UV-irradiated HHV-6A at inhibiting interleukin-2 (IL-2) synthesis in CD4+ lymphocytes suggesting that viral structural components could be responsible for this effect. In the present study, we have identified the HHV-6B U54 tegument protein (U54) to be capable of inhibiting IL-2 expression. U54 binds the calcineurin (CaN) phosphatase enzyme causing improper dephosphorylation and nuclear translocation of nuclear factor of activated T cells (NFAT) proteins, resulting in sub-optimal IL-2 gene transcription. The U54 GISIT motif (aa 293-297), analogous to the NFAT PxIxIT motif, contributed to the inhibition of NFAT activation.Human herpesvirus-6A (HHV-6A) and HHV-6B are associated with an increasing number of pathologies. These viruses have developed strategies to avoid the immune response allowing them to persist into host. Several studies have illustrated mechanisms by which HHV-6A and HHV-6B are able to disrupt host defenses. Previous work informed us that HHV-6A is able to suppress interleukin-2 (IL-2) synthesis, a key immune growth factor essential for adequate T lymphocyte proliferation and expansion. We provide evidence that HHV-6B also inhibits IL-2 gene expression and identified the mechanisms by which it does so. Our work led us to the identification of U54, a virion-associated tegument protein, as being responsible for suppression of IL-2. Consequently, we have identified HHV-6B U54 protein as playing a role in immune evasion. These results further contribute to our understanding of HHV-6 interactions with its human host and the efforts deployed to ensure its long-term persistence.