Acupuncture for radiation-induced toxicity in head and neck squamous cell carcinoma: a systematic review based on PICO criteria.

Purpose: In head and neck squamous cell carcinoma (HNSCC), the potential mitigating effect of complementary medicine interventions such as acupuncture for radiation-induced toxicity is unknown. This study aimed to assess the impact of acupuncture on the incidence and degree of severity of common radiation-induced side effects.

Methods: In accordance with pre-specified PICO criteria, a systematic review was performed.

T Cell Response Toward Tissue-and Epidermal-Transglutaminases in Coeliac Disease Patients Developing Dermatitis Herpetiformis.

The reason why only few coeliac patients develop the cutaneous manifestation of the disease, named dermatitis herpetiformis (DH), is still unknown. Epidermal transglutaminase (TG3) has been described as the main autoantigen of humoral immunity in DH but the mechanisms leading to this autoimmune response remain obscure. Here we characterized T cells from skin, gut and peripheral blood of DH and coeliac disease (CD) patients, evaluated the impact of the gluten-free diet on circulating T lymphocytes' phenotype and investigated antigen specific T cell response toward epidermal and tissue transglutaminase (TG2).

Hematological and Genetic Markers in the Rational Approach to Patients With HCV Sustained Virological Response With or Without Persisting Cryoglobulinemic Vasculitis.

Background And Aims: Direct-acting antivirals (DAAs) usually lead to improvement/remission of cryoglobulinemic vasculitis (CV), although symptoms may persist/recur after a sustained virological response (SVR). We evaluated hematological and genetic markers in patients with HCV-SVR vasculitis with and without persisting/recurring symptoms to early predict the CV outcome.

Approach And Results: Ninety-eight patients with HCV-CV were prospectively enrolled after a DAA-induced SVR: Group A: 52 with complete clinical response; Group B: 46 with symptom maintenance/recurrence.

The intestinal expansion of TCRγδ and disappearance of IL4 T cells suggest their involvement in the evolution from potential to overt celiac disease.

Celiac disease (CD) is characterized by a spectrum of intestinal inflammatory lesions. Most patients have villous atrophy (overt-CD), while others have a morphologically normal mucosa, despite the presence of CD-specific autoantibodies (potential-CD). As the mechanism responsible for villous atrophy is not completely elucidated, we investigated biomarkers specific for the different celiac lesions.

Eomes controls the development of Th17-derived (non-classic) Th1 cells during chronic inflammation.

It is well accepted that Th17 cells are a highly plastic cell subset that can be easily directed toward the Th1 phenotype in vitro and also in vivo during inflammation. However, there is an ongoing debate regarding the reverse plasticity (conversion from Th1 to Th17). We show here that ectopic ROR-γt expression can restore or initiate IL-17 expression by non-classic or classic Th1 cells, respectively, while common pro-Th17 cytokine cocktails are ineffective.

Therapeutic Efficacy of Autologous Non-Mobilized Enriched Circulating Endothelial Progenitors in Patients With Critical Limb Ischemia - The SCELTA Trial.

Background: The therapeutic efficacy of bone marrow mononuclear cells (BM-MNC) autotransplantation in critical limb ischemia (CLI) has been reported. Variable proportions of circulating monocytes express low levels of CD34 (CD14CD34cells) and behave in vitro as endothelial progenitor cells (EPCs). The aim of the present randomized clinical trial was to compare the safety and therapeutic effects of enriched circulating EPCs (ECEPCs) with BM-MNC administration.

Musculin inhibits human T-helper 17 cell response to interleukin 2 by controlling STAT5B activity.

We recently demonstrated that human T-helper (Th) 17 cells, unlike Th1 cells, do not proliferate in response to T-cell receptor stimulation, mainly because of their reduced capacity to produce and respond to IL-2. In this study, we show that their lower responsiveness to IL-2 is due to the selective expression of Musculin (MSC), a member of the basic helix-loop-helix transcription factors. We show that MSC expression in human Th17 cells is retinoic acid orphan receptor (ROR)γt-dependent, and allows the upregulation of PPP2R2B, a regulatory member of the protein phosphatase 2A (PP2A) enzyme.

Chitinase 3-like-1 is produced by human Th17 cells and correlates with the level of inflammation in juvenile idiopathic arthritis patients.

Background: CHI3L1 is a chitinase-like protein without enzymatic activity, produced by activated macrophages, chondrocytes, neutrophils. Recent studies on arthritis, asthma, and inflammatory bowel diseases suggest that chitinases are important in inflammatory processes and tissue remodeling, but their production by human T cells, has never been reported.

Methods: A microarray analysis of gene expression profile was performed on Th17 and classic Th1 cell clones and CHI3L1 was found among the up-regulated genes on Th17 cells.

Immunosuppressive Activity of Abatacept on Circulating T Helper Lymphocytes from Juvenile Idiopathic Arthritis Patients.

Background: Abatacept is used in the treatment of juvenile idiopathic arthritis (JIA) patients, but the activity of the drug on T helper cell function is not yet fully known.

Methods: The ability of abatacept to affect cytokine production in vitro and the proliferative response to both recall antigens and polyclonal stimulation was firstly assessed in healthy donors. Then, 10 JIA patients who were due to start abatacept treatment were recruited and longitudinally evaluated during the first 90 days of therapy.

Human circulating group 2 innate lymphoid cells can express CD154 and promote IgE production.

Background: Protection against helminths consists of adaptive responses by T2 cells and innate responses by group 2 innate lymphoid cells (ILC2s), with these latter being well characterized in mice but less so in human subjects.

Objective: We sought to characterize human circulating ILC2s and compare their functional profile with that of autologous T2 cells.

Methods: Circulating ILC2s and T2 cells were isolated by means of fluorescence-activated cell sorting and magnetic cell sorting and expanded in vitro.

Th1-Induced CD106 Expression Mediates Leukocytes Adhesion on Synovial Fibroblasts from Juvenile Idiopathic Arthritis Patients.

This study tested the hypothesis that subsets of human T helper cells can orchestrate leukocyte adhesion to synovial fibroblasts (SFbs), thus regulating the retention of leukocytes in the joints of juvenile idiopathic arthritis (JIA) patients. Several cell types, such as monocytes/macrophages, granulocytes, T and B lymphocytes, SFbs and osteoclasts participate in joint tissue damage JIA. Among T cells, an enrichment of classic and non-classic Th1 subsets, has been found in JIA synovial fluid (SF), compared to peripheral blood (PB).

Demethylation of the RORC2 and IL17A in human CD4+ T lymphocytes defines Th17 origin of nonclassic Th1 cells.

Th17-derived Th1 lymphocytes, termed nonclassic, differ from classic Th1 cells because of the presence of retinoic acid orphan receptor (ROR)C2 and the surface expression of CD161 and CCR6. We demonstrate in this article that nonclassic Th1 cells, like Th17 cells, have a marked RORC2 and IL17A demethylation, whereas classic Th1 cells exhibit a complete methylation of these genes. The analysis of RORC2 DNA methylation in the CD4(+)CD161(+) and CD4(+)CD161(-) naive Th subsets from umbilical cord blood surprisingly revealed comparable hypermethylation levels.

Mesenchymal stem cells are enriched in head neck squamous cell carcinoma, correlates with tumour size and inhibit T-cell proliferation.

Background: Cancer is a multifactorial disease not only restricted to transformed epithelium, but also involving cells of the immune system and cells of mesenchymal origin, particularly mesenchymal stem cells (MSCs). Mesenchymal stem cells contribute to blood- and lymph- neoangiogenesis, generate myofibroblasts, with pro-invasive activity and may suppress anti-tumour immunity.

Methods: In this paper, we evaluated the presence and features of MSCs isolated from human head neck squamous cell carcinoma (HNSCC).

Th17 plasticity: pathophysiology and treatment of chronic inflammatory disorders.

CD4+ T cells can be classified from a functional point of view in different lineages, the most extensively studied being the Th1, Th2, and Th17. Recent evidence suggest that the acquisition of a certain phenotype is not irreversible, and lymphocytes can acquire features of different effector fates upon adequate stimuli. In particular, Th17 lymphocytes in inflammatory conditions can start to produce IFN-γ or IL-4, shifting towards a Th17/Th1 or Th17/Th2 phenotype, respectively.

Brief report: etanercept inhibits the tumor necrosis factor α-driven shift of Th17 lymphocytes toward a nonclassic Th1 phenotype in juvenile idiopathic arthritis.

Objective: To evaluate the effects of etanercept on the phenotype of CD4+ T helper lymphocytes from patients with juvenile idiopathic arthritis (JIA).

Methods: We compared the proportions of various Th cell subsets in peripheral blood (PB) from etanercept-treated and untreated JIA patients. An in vitro study was performed on PB mononuclear cells (PBMCs) from 15 children with untreated JIA, in which we evaluated the proliferative response of these cells, as well as their cytokine production profile, in the presence of various stimuli with or without etanercept.

IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells.

Human Th17 cells have a limited proliferative capacity compared to other T-cell subsets. We have shown that human Th17 cells display impaired IL-2 production due to IL-4-induced gene 1 (IL4I1) upregulation. Here, we show that in human Th17 cells, IL4I1 also maintains high levels of Tob1, a member of the Tob/BTG (B-cell traslocation gene) antiproliferative protein family, which prevents cell-cycle progression mediated by TCR stimulation.

Reasons for rarity of Th17 cells in inflammatory sites of human disorders.

T helper 17 (Th17) cells have been reported to be responsible for several chronic inflammatory diseases. However, a peculiar feature of human Th17 cells is that they are very rare in the inflammatory sites in comparison with Th1 cells. The first reason for this rarity is the existence of some self-regulatory mechanisms that limit their expansion.

T helper cells plasticity in inflammation.

CD4+ T cells can be subdivided from a functional point of view into two main subsets: effector cells, which provide protection against exogenous offending agents, and regulatory T (Treg) cells whose function is to avoid autoimmune reactions and to stop the effector response against exogenous antigens, when the response itself becomes dangerous for the host. Human effector CD4+ T lymphocytes can be additionally classified into lineages based mainly on their immunological functions that are supported by distinct profile of cytokine, transcription factor, and homing receptors expression. In the last years, beyond the well known populations of human T helper (Th) lymphocytes, Th1 and Th2 cells, other populations have been discovered and phenotypically characterized.

IL-1 and T Helper Immune Responses.

CD4 T cells play a critical role in mediating adaptive immunity to a variety of pathogens as well as in tumor immunity. If not adequately regulated, CD4 T cells can be also involved in autoimmunity, asthma, and allergic responses. During TCR activation in a particular cytokine milieu, naïve CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, and Th17, as defined by their pattern of cytokine production and function.

CD4+CD161+ T lymphocytes infiltrate Crohn's disease-associated perianal fistulas and are reduced by anti-TNF-α local therapy.

Background: Crohn's disease (CD) is an idiopathic inflammatory bowel disease (IBD) in the pathogenesis of which both Th1 and Th17 lymphocytes have been described as being involved. The NK-associated molecule CD161 has recently been described as a marker of IL-17-producing lymphocytes. In this work we assessed the presence and the functional features of CD161 T helper lymphocytes infiltrating CD-associated perianal fistulas, both before and after inoculation of anti-TNF-α mAbs along the fistula.

Distinctive features of classic and nonclassic (Th17 derived) human Th1 cells.

T helper17 (Th17) lymphocytes represent a third arm of the CD4(+) T-cell effector responses, in addition to Th1 and Th2 cells. Th17 cells have been found to exhibit high plasticity because they rapidly shift into the Th1 phenotype in inflammatory sites. In humans, Th1 cells derived from Th17 cells express CD161, whereas classic Th1 cells do not; these Th17-derived Th1 cells have been termed nonclassic Th1 cells.

Rarity of human T helper 17 cells is due to retinoic acid orphan receptor-dependent mechanisms that limit their expansion.

The reason why CD4(+) T helper 17 (Th17) cells, despite their well-known pathogenic role in chronic inflammatory disorders, are very rare in the inflammatory sites remains unclear. We demonstrate that human Th17 cells exhibit low ability to proliferate and to produce the T cell growth factor interleukin-2 (IL-2), in response to combined CD3 and CD28 stimulation. This was due to the upregulated expression of IL-4-induced gene 1 (IL4I1) mRNA, a secreted L-phenylalanine oxidase, which associated with a decrease in CD3ζ chain expression and consequent abnormalities in the molecular pathway that allows IL-2 production and cell proliferation.

Evidence of the transient nature of the Th17 phenotype of CD4+CD161+ T cells in the synovial fluid of patients with juvenile idiopathic arthritis.

Objective: To investigate the phenotype and function of CD4+ T cells in synovial fluid (SF) from the affected joints of children with oligoarticular-onset juvenile idiopathic arthritis (JIA), and to establish a possible link with disease activity.

Methods: CD4+ T cells were obtained from the peripheral blood (PB) and SF of 23 children with oligoarticular-onset JIA, as well as from the PB of 15 healthy children. The cells were analyzed for the expression of CXCR3, CCR6, and CD161 and for the production of interferon-γ and interleukin-17A (IL-17A).

Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma.

Objective: • To compare the frequency of T regulatory cells (Tregs) in peripheral blood of patients (pPB) affected by renal cell carcinoma (RCC) both with the frequency of Tregs found in PB of healthy donors (hPB) and that of Tregs present in tumour infiltrating lymphocytes (TILs). To verify in vitro the inhibitory activity of tumour isolated Tregs on the effector T cells and, finally, to assess the prognostic role of Treg frequency determination.

Patients And Methods: • Treg frequency in hPB, pPB and TILs was evaluated in 30 patients and 20 healthy controls by measuring both membrane-CD25 and intracytoplasmic-Foxp3 expression by flow cytometry.

CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC.

We have previously shown that human Th17 lymphocytes are characterized by the selective expression of IL-23 receptor (IL-23R), CCR6, CD161, and the transcription factor retinoic acid-related orphan receptor C (RORC), and originate from a CD161(+)CD4(+) naïve T-cell precursor in response to the combined activity of IL-1β and IL-23. We show here that not only CD4(+)TCRαβ(+), but also CD8(+)TCRαβ(+), CD4(-)CD8(-) TCRαβ(+), and CD4(-)CD8(-) TCRγδ(+) circulating lymphocytes that produce IL-17 express the distinctive marker CD161 on their surface. In addition, we demonstrate that CD161 expression identifies CD8(+) and CD4(-)CD8(-) umbilical cord blood T cells that already express RORC and IL-23R mRNA and that can be induced to differentiate into IL-17-producing cells in the presence of IL-1β and IL-23.