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Beta-interferon (beta-IFN) has a proven treatment effect on relapsing–remitting multiple sclerosis (MS), presumably through its regulatory properties on T-cell activation and cytokine production. This paper examines whether combination therapy of beta-IFN with prednisone would enhance immunoregulatory effects of beta-IFN by measuring serum levels of selected proinflammatory cytokines and soluble T-cell activation markers associated with MS. The selected markers were analyzed in MS patients treated with beta-IFN alone (n = 22) and beta-IFN combined with a low daily dose of prednisone (n =33), as compared with those in 27 healthy controls at baseline and at a three-month interval for one year. The study confirmed that beta-IFN treatment inhibited serum levels of tumor necrosis factor-alpha (TNFα) and intracellular adhesion molecule-1 (IC AM-1) in patients with MS. However, combination therapy did not significantly enhance the inhibitory effect of beta-IFN treatment on the production of TNFα, interleukin (IL)-12, IL-2R, and ICAM-1, while the addition of prednisone antagonized the effect of beta-IFN on up-regulation of IL-10 and soluble CD95. No difference in the occurrence of binding antibodies to beta-IFN was found between the two treatment groups. The findings are important for the understanding of the role of combination therapy in the treatment of MS. [ABSTRACT FROM AUTHOR]

Summary Interleukins (IL) regulate differentT-cell surface Ag known as activation markers that have distinct functionalroles. In this paper, while studying the influence of some cytokines(IL-12, IL-2 and IL-4) on the expression of several markers [CD69,CD25, CD26, CD3, human leukocyte antigen (HLA-DR), CD45R0] in in vitro activatedhuman T lymphocytes, we observed two groups of donors respondingto phytohaemagglutinin (PHA) activation with high or low HLA-DRAg expression. We also found that CD4 and CD8 populations had differentHLA-DR densities under PHA activation (particularly the high HLA-DR-expressinggroup). Interleukins, in a dose-dependent manner (IL-2 partially),upregulated these HLA-DR levels. In 5 day cultures, IL-12and IL-2 enhanced the CD8/CD4 ratio of activated T cells,which was responsible, in part, for the IL-dependent HLA-DR upregulation.IL-12 and IL-2 also upregulated the HLA-DR expression at the molecularlevel on CD8, and IL-12 downregulated it on CD4 cells. It seemsthat IL-4 upregulated HLA-DR by shortening the mitogen-dependent regulationkinetics. We hypothesize that the different effect of each IL onHLA-DR expression might be related to the regulation of the doseof antigenic peptide presentation and, thus, also influence TH1 /TH2 dominance. [ABSTRACT FROM AUTHOR]

This paper will serve as a contribution to the current reassessment of the relative roles of clonal selection and regulation in specific immunologic tolerance. We review basic studies in the Waksman laboratory that first established the importance of the thymus in tolerance and the possible contribution of regulatory cells generated in the thymus to self-tolerance. Experimental evidence is presented to suggest that there exists a wide range of immunoregulatory mechanism, many of which deserve more intensive investigation in relation to the tolerance question. These include regulation based on idiotype-specific recognition, multiple forms of immune deviation, two well-described and quite distinct forms of T-cell receptor αΒ "suppressor cell", and several regulatory systems involving multiple cells acting in concert. We do not comment on more recently described regulatory cells, such as certain γδ T-cell subsets, natural killer T cells, CD4[sup-]CD8[sup-] T cells, and others. Basic studies in our laboratory and in other laboratories pointed to antigen-presenting cells (APC) generated in the thymus as possible mediators of tolerance. Certain cytokines, first described in our laboratory, including lymphotoxin and the "inhibitor of DNA synthesis" produced by T cells and interleukin-1 produced by macrophages, may act as significant components of regulatory systems. The rapid entry of exogenous and self-antigens into the thymus and the free migration of specific regulatory T cells and of APC in both directions between thymus and periphery are also stressed. [ABSTRACT FROM AUTHOR]

SummaryFlaky skin (fsn) is an autosomal recessive mutation on mouse chromosome 17 that causes severe anaemia, forestomach papillomatosis and a papulosquamous skin disease that resembles psoriasis in humans. In the present paper, it is reported that fsn causes peripheral lymphadenopathy, CD4/CD8 imbalance and hyperresponsiveness to T cell growth factors. Peripheral lymph nodes (PLN) of adult mutant (fsn/fsn) mice were found to contain almost 10-fold more leucocytes than PLN from phenotypically normal littermates (+/fsn or +/+, hereafter referred to as +/?). Analysis of PLN cells using mAbs and flow cytometry revealed that this predominantly lymphoid hyperplasia was characterized by approximately equivalent increases in the numbers of CD3+ T cells and CD19+ B cells. However, expansion within the T cell compartment was non-random, because fsn/fsn PLN had a considerably reduced ratio of CD4+ to CD8+ T cells (1.08 ± 0.37) compared to +/? PLN (2.47 ± 0.44, P < 0.0001). In vitro assays of cellular proliferation in response to T and B cell growth factors showed that fsn/fsn PLN cells were hyperresponsive to IL-2, IL-4 and IL-7 when compared with PLN cells from +/? mice. Studies using mesenteric lymph node and peripheral blood cells showed that hyperresponsive cells are widely distributed in fsn/fsn mice. Experiments in newborn mice showed that the lymphoid disturbances caused by fsn are established at least as early as 2 weeks of age, a time that precedes the onset of the earliest clinical skin lesions. These data implicate a role for the fsn gene product in regulating the size and content of the peripheral lymphoid compartment. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcoma is the most common primary bone tumor and has a poor prognosis. Therefore, it is important to understand the mechanism of the development of osteosarcoma to overcome therapy resistance. Several mathematical models have been developed to study the initiation and progression of many cancer types. However, there are currently no mathematical models for the progression of osteosarcoma, to the best of our knowledge. In this work, we develop a data-driven mathematical model to analyze the impact of the immune cell interactions on the growth of osteosarcoma tumors that have distinct immune patterns. Our model provides a foundation for investigating the effect of various treatments on the dynamics of key players in the primary tumor, including immune cells and cytokines, and ultimately the whole tumor. As the immune system has a significant role in tumor progression, in this paper, we develop a data-driven mathematical model to study the interactions between immune cells and the osteosarcoma microenvironment. Osteosarcoma tumors are divided into three clusters based on their relative abundance of immune cells as estimated from their gene expression profiles. We then analyze the tumor progression and effects of the immune system on cancer growth in each cluster. Cluster 3, which had approximately the same number of naive and M2 macrophages, had the slowest tumor growth, and cluster 2, with the highest population of naive macrophages, had the highest cancer population at the steady states. We also found that the fastest growth of cancer occurred when the anti-tumor immune cells and cytokines, including dendritic cells, helper T cells, cytotoxic cells, and IFN- γ , switched from increasing to decreasing, while the dynamics of regulatory T cells switched from decreasing to increasing. Importantly, the most impactful immune parameters on the number of cancer and total cells were the activation and decay rates of the macrophages and regulatory T cells for all clusters. This work presents the first osteosarcoma progression model, which can be later extended to investigate the effectiveness of various osteosarcoma treatments. [ABSTRACT FROM AUTHOR]

Background Selected cytokines produced by allergen specific CD4+ T cells from atopic individuals contribute to both the specific and non-specific effector mechanisms of the allergic immune response. The chemokine family of cytokines and tumour necrosis factor (TNF)-α are leucocyte regulatory and proinflammatory molecules. The chemokines include interleukin (IL)-8 and the RANTES/SIS cytokines. Objective There bas been no systematic survey of chemokine production in T-cell subtypes. Because of their wide range of biological properties, it might be expected that they would be closely regulated by T cells. This paper illustrates one way (through the characterization of T-cell clones) these questions might be addressed. Methods Northern blot analysis was used to quantitate steady state transcription of selected cytokine genes and enzyme linked immunosorbent assay (ELISA) was used to quantitate soluble product. Results mRNA expression of the chemokines (IL-8. HuMIP-lα and HuMIP-lβ) and TNFα is upregulated in TH2-like cloned house dust mite reactive human CD4+ T cells under conditions of activation and during the induction phase of anergy. Although the development of anergy superinduces mRNA for both IL-8 and TNFα, protein production is low compared with that released during activation. In contrast, RANTES, a chemoattractant for CD4+ /CD45RO+ memory T cells, eosinophils and basophils, is constitutively expressed at the RNA level by the T cells and not modulated by signals of activation and anergy induction. The production of IL-2, IL-4 and IL-5 mRNA and proteins during the induction of anergy peaks at 2h after stimulation, whereas the kinetics following activation of the T cells is delayed in comparison. Conclusion These data show that the induction of the anergic state coincides with post-transcriptional regulation of selected cytokine genes. Further study of these phenomena will impact on our understanding of the mechanisms of induction of anergy and the regulation of allergic immune responses in desensitization. [ABSTRACT FROM AUTHOR]

It is now well documented that the mode of primary stimulation in the mouse determines the ratio of Th1-, Th0- or Th2-type T cells obtained. In this paper we determine whether driving and cloning human peripheral blood mononuclear cells (PBMC) non-specifically with interleukin-2 (IL-2) and/ or IL-4 and mitogen, will differentially select T cells for IL-10 production. The presence of IL-2 during culture (with or without IL-4) yielded predominantly Th1-type clones (81% of clones with IL-2 alone and 77% with IL-2 + IL-4) and a low frequency of Th0-type clones (19% of clones with IL-2 and 10% of clones with IL-2 + IL-4), whereas IL-4 alone increased the yield of the IL-4 producing Th0 (35%) clones. The proportions of IL-2-producing clones did not alter with treatment; however, the combination of IL-2 + IL-4 altered the proportions of IL-10-producing clones. 47% of IL-2-cultured cells and 51% of IL-4-cultured cells produced IL-10 respectively, whereas only 22% of clones driven with IL-2 + IL-4 produced detectable levels of IL-10. Thus in the preliminary experiments described here we have demonstrated that the cytokines used to initially drive out human T cells and maintain the T-cell growth can skew the Th1/Th2/Th0 cytokine profiles of the clones obtained from mitogen-stimulated cultures. Moreover and unexpectedly the proportion of IL-10-producing cells is altered. These results are important in interpreting analysis of the cytokine profiles of human T cells and raise questions concerning how we should derive T-cell clones for a cytokine analysis that truly reflects the in vivo situation. [ABSTRACT FROM AUTHOR]

CD27 is a T-cell surface antigen expressed on the majority of peripheral T cells and belongs to a newly defined receptor family including the iow-affinity nerve growth factor receptor, tumour necrosis factor (TNF) receptors, the B-cell activation antigen CD40, and the Fas antigen. Although the function of CD27 has not been defined, several experimental observations support the notion that this molecule plays an important role in the process of T-cell activation. In this paper, we have demonstrated that a rapid hyperphosphorylation of CD27 is induced by a cyclic AMP-inducing agent, forskolin, and a membrane-permeable cAMP analogue, 8-bromo-cAMP, as well as phorbol 12-myristate 13-acetate (PMA). In addition, increased phosphorylation of CD27 in T-cell activation either via CD2 or CD3 pathways was strongly suppressed by a cyclic nucleotide-dependent kinase inhibitor, H-8, but only slightly by a protein kinase C inhibitor, staurosporine. These results suggest that protein kinase A might be a key kinase responsible for CD27 phosphorytation in the process of T-cell activation. CD27 is the first T-cell surface antigen demonstrated to be phosphorylated by the cyclic AMP-protein kinase A-mediated pathway. [ABSTRACT FROM AUTHOR]

Abstract: In the past decade it has been established that regulatory T cells (Tregs) control all immune responses. As the induction and effector mechanisms used by Tregs are being unraveled, it is emerging that a reciprocal population of CD4+ T lymphocytes exists in the immune system that produces inflammatory cytokine IL-17, and coined "Th17 cells". Th17 cells have been implicated in the pathogenesis of many forms of human disease. The development, function, mechanism of action, and homeostasis of Tregs and Th17 cells, and the reciprocal control between Tregs and Th17 cells were presented at the Second International Conference on Regulatory T Cells and Th17 Cells and Clinical Application in Human Diseases in Shanghai on 17–20 July 2010 (China Tregs/Th17 2010). In this Special Issue of International Immunopharmacology, several paper submitted to the conference will highlight the biology of Tregs and Th17 cells, and their clinical application in human disease. [Copyright &y& Elsevier]

Natural Killer (NK) cells are innate lymphocytes that contribute to immune protection by cytosis, cytokine secretion, and regulation of adaptive responses of T cells. NK cells distinguish between healthy and ill cells, and generate a cytotoxic response, being cumulatively regulated by environmental signals delivered through their diverse receptors. Recent advances in biomaterials and device engineering paved the way to numerous artificial microenvironments for cells, which produce synthetic signals identical or similar to those provided by the physiological environment. In this paper, we review recent advances in materials and devices for artificial signaling, which have been applied to regulate NK cells, and systematically study the role of these signals in NK cell function. [ABSTRACT FROM AUTHOR]

The article discusses two research papers concerned with how subsets of T cells that mediate acute and long-term protection to infection are derived from a single precursor. Effector cells are short-lived and numerous T cells that can deploy a variety of cytokine and cell contact-dependent cytotoxic mechanisms to control acute infection. Memory T cells effectively respond to reinfection by the same pathogen. These are both subsets of CD8+ cells. One paper shows that the T cell receptor, which is a heterodimeric protein that serves as the antigen-specific sensor for T cells, helps to generate the signals that allow a primed T cell to differentiate into a memory cell.

The authors discuss papers that examine aspects of immunology in association with pulmonary arterial hypertension (PAH) such as natural killer (NK) T cell dysfunction and interleukin-1β (IL-1β) signaling. One study notes an increase in the percentage of the functionally deficient CD56- CD16+ NK T cells in idiopathic PAH. Moreover, the authors cite the significance of the papers in the study of altered cellular composition and cytokine secretion in experimental and human disease.

High titer of anti-β2-glycoprotein I antibodies (anti-β2GPI Ab) plays a pathogenic role in antiphospholipid syndrome (APS). Numerous studies have focused on the pathological mechanism in APS; however, little attention is paid to the immune mechanism of production of anti-β2GPI antibodies in APS. Our previous study demonstrated that Toll-like receptor 4 (TLR4) plays a vital role in the maturation of bone marrow-derived dendritic cells (BMDCs) from the mice immunized with human β2-glycoprotein I (β2GPI). TLR4 is required for the activation of B cells and the production of autoantibody in mice treated with β2GPI. However, TLR4 provides a third signal for B cell activation and then promotes B cells better receiving signals from both B cell antigen receptor (BCR) and CD40, thus promoting B cell activation, surface molecules expression, anti-β2GPI Ab production, and cytokines secretion and making B cell functioning like an antigen presenting cell (APC). At the same time, TLR4 also promotes B cells producing antibodies by upregulating the expression of B-cell activating factor (BAFF). In this paper, we aim to review the functions of TLR4 in B cell immune response and antibody production in autoimmune disease APS and try to find a new way for the prevention and treatment of APS. [ABSTRACT FROM AUTHOR]

This article presents information about current research in the field of dermatology. According to a research paper published in a 2004 issue of the "British Journal of Dermatology," envelope proteins of the human endogenous retroviruses family are expressed in human normal, psoriatic and atopic skin by immunostaining and western blotting and that their expressions are regulated by ultra violet irradiation. Another study published in a 2004 issue of the "British Journal of Dermatology," looked at which T cell attracting chemokines are involved in allergic contact dermatitis models in mice which differ in their cytokine expression profiles.

The Janus kinases (JAKs) are essential for cytokine receptor signalling and their dephosphorylation represents a potent inhibitory mechanism. A new paper highlights the T-cell tyrosine phosphatase as an important JAK inhibitor. [Copyright &y& Elsevier]