The impact of the tumor immune microenvironment and tumor-infiltrating lymphocyte subgroups on laryngeal cancer prognosis.

The absence of improvement in survival rates across various cancers, including laryngeal cancer, has led to an increasing interest in understanding the immune response to cancer. In head and neck cancers, immune modulatory mechanisms such as immune microenvironment and immune infiltration are important in cancer pathogenesis. This study aims to explore the distribution of tumor-infiltrating lymphocyte (TIL) subgroups in the immune microenvironment and evaluate their impact on tumor histopathological characteristics and prognosis. The study included 50 patients who underwent laryngectomy for laryngeal squamous cell carcinoma, in Istanbul University - Cerrahpasa, Faculty of Medicine Department of Otorhinolaryngology, between January 2016 and January 2018. Pathology specimens were evaluated using immunohistochemistry to assess the expressions of the CD3, CD20, CD8, CD4, CD25, and FoxP3 markers, identifying subgroups of TILs. The investigation aimed to uncover how these subgroups influence tumor histopathological features and survival outcomes. The high infiltration of CD3, CD20, and CD4 had a positive impact on disease-specific survival, disease-free survival, and recurrence-free survival. In addition, overall survival was positively affected by high CD3 and CD4 infiltrations. However, no significant relationship was observed between the expressions of CD8, FoxP3, and CD25 and any of the survival parameters. The infiltration of CD3, CD20, and CD4 positive cells indicative of a robust antitumoral immune response-emerged as favorable prognostic factors in laryngeal cancer. These findings suggest that enhancing the infiltration of CD3, CD20, and CD4 lymphocytes could be a therapeutic strategy worth exploring in clinical trials.

Imbalanced IL10/TGF-ß production by regulatory T-lymphocytes in patients with HTLV-1-associated myelopathy/ tropical spastic paraparesis.

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regulatory T lymphocytes (Tregs) may control of inflammation through the production of regulatory cytokines, including IL10 and TGF-ß. In this study we determined the frequencies of CD4 + and CD8 + Tregs in a HAM/TSP population, compared to asymptomatic carriers and uninfected individuals, as well as investigated the profiles of regulatory and inflammatory cytokines. METHODS: Asymptomatic HTLV-1 carriers and HAM/TSP patients were matched by sex and age. The frequencies of IL10- and/or TGF-ß-producing Tregs were quantified by flow cytometry. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify HTLV-1 proviral load and the mRNA expression of cytokines and cellular receptors in peripheral blood mononuclear cells. RESULTS: Total frequencies of CD4 + Tregs, as well as the IL10-producing CD4 + and CD8 + Treg subsets, were statistically higher in patients with HAM/TSP compared to asymptomatic HTLV-1-infected individuals. In addition, a positive correlation was found between the frequency of CD4 + IL10 + Tregs and proviral load in the HAM/TSP patients evaluated. A positive correlation was also observed between gene expression of proinflammatory versus regulatory cytokines only in HAM / TSP group. CONCLUSIONS: A higher frequencies of IL10-producing Tregs were identified in patients with HAM/TSP. Imbalanced production of IL10 in relation to TGF-ß may contribute to the increased inflammatory response characteristically seen in HAM/TSP patients.

[Efficacy of Decitabine Combined with Preexcitation Regimen in Treatment of Newly Diagnosed AML Patients Who Did not Respond to Initial Standard Induction Chemotherapy].

OBJECTIVE: To investigate the efficacy of decitabine combined with preexcitation regimen in the treatment of newly diagnosed acute myeloid leukemia (AML) patients who have not been relieved by the first standard induction chemotherapy and its influence on the relative content of regulatory T lymphocytes (Tregs). METHODS: The clinical data of 102 newly diagnosed AML patients (except acute promyelocytic leukemia) who did not relieve after initial standard induction chemotherapy in Shaanxi Provincial People's Hospital from March 2013 to March 2019 were retrospectively analyzed. Fifty-one patients who accepted pre-excitation regimen were divided into regular group, while another 51 patients treated with decitabine combined with pre-excitation regimen were divided into combination group. The efficacy, incidence of toxic and side effects, Core Scale of Quality of Life (QLQ-C30) score before and after treatment, T lymphocyte subsets (CD3+, CD4+, CD4+/CD8+, Tregs) and 3-year overall survival (OS) rate were compared between the two groups. RESULTS: The total effective rate of combination group was 80.39%, which was significantly higher than 62.75% of regular group (P < 0.05). After treatment, the QLQ-C30 score of combination group was 60.27±6.96, which was significantly lower than 65.73±7.96 of regular group (P < 0.001). There was no statistical difference in the incidence of toxic and side effects between the two groups (P >0.05). After treatment, the levels of CD3+, CD4+, CD4+/CD8+ in the combination group were higher than those in the regular group (all P < 0.001), while Treg was lower (P < 0.001). The 3-year OS rate in the combination group was 72.55%, which was significantly higher than 52.94% in the regular group (P < 0.001). CONCLUSION: Decitabine combined with preexcitation regimen has a significant effect on AML patients who have not been alleviated by standard induction chemotherapy in the first course of treatment. It can reduce anti-tumor immune suppression and improve immune function by regulating the relative content of Tregs, thus prolongs survival time and improves life quality of patients without increasing adverse reactions.

A novel GARP humanized mouse model for efficacy assessment of GARP-targeting therapies.

Although breakthroughs have been achieved with immune checkpoint inhibitors (ICI) therapy, some tumors do not respond to those therapies due to primary or acquired resistance. GARP, a type I transmembrane cell surface docking receptor mediating latent transforming growth factor-ß (TGF-ß) and abundantly expressed on regulatory T lymphocytes and platelets, is a potential target to render these tumors responsive to ICI therapy, and enhancing anti-tumor response especially combined with ICI. To facilitate these research efforts, we developed humanized mouse models expressing humanized GARP (hGARP) instead of their mouse counterparts, enabling in vivo assessment of GARP-targeting agents. We created GARP-humanized mice by replacing the mouse Garp gene with its human homolog. Then, comprehensive experiments, including expression analysis, immunophenotyping, functional assessments, and pharmacologic assays, were performed to characterize the mouse model accurately. The Tregs and platelets in the B-hGARP mice (The letter B is the first letter of the company's English name, Biocytogen.) expressed human GARP, without expression of mouse GARP. Similar T, B, NK, DCs, monocytes and macrophages frequencies were identified in the spleen and blood of B-hGARP and WT mice, indicating that the humanization of GARP did not change the distribution of immune cell in these compartments. When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP/TGF-ß1 complexes demonstrated enhanced in vivo anti-tumor activity compared to monotherapy with either agent. The novel hGARP model serves as a valuable tool for evaluating human GARP-targeting antibodies in immuno-oncology, which may enable preclinical studies to assess and validate new therapeutics targeting GARP. Furthermore, intercrosses of this model with ICI humanized models could facilitate the evaluation of combination therapies.

Novel therapeutic role of Ganoderma Polysaccharides in a septic mouse model - The key role of macrophages.

Ganoderma lucidum polysaccharides (G. PS) have been recognized for their immune-modulating properties. In this study, we investigated the impact of G. PS in a sepsis mouse model, exploring its effects on survival, inflammatory cytokines, Treg cell differentiation, bacterial load, organ dysfunction, and related pathways. We also probed the role of macrophages through chlorphosphon-liposome pretreatment. Using the cecal ligation and puncture (CLP) model, we categorized mice into normal, PBS, and G. PS injection groups. G. PS significantly enhanced septic mouse survival, regulated inflammatory cytokines (TNF-α, IL-17A, IL-6, IL-10), and promoted CD4+Foxp3+ Treg cell differentiation in spleens. Additionally, G. PS reduced bacterial load, mitigated organ damage, and suppressed the NF-κB pathway. In vitro, G. PS facilitated CD4+ T cell differentiation into Treg cells via the p-STAT5 pathway. Chlorphosphon-liposome pretreatment heightened septic mortality, bacterial load, biochemical markers, and organ damage, emphasizing macrophages' involvement. G. PS demonstrated significant protective effects in septic mice by modulating inflammatory responses, enhancing Treg cell differentiation, diminishing bacterial load, and inhibiting inflammatory pathways. These findings illuminate the therapeutic potential of G. PS in sepsis treatment.

[The role of microbiota and flavonoids in maintaining the balance of helper and regulatory T-lymphocytes associated with the intestinal immune barrier].

The gastrointestinal tract is a barrier, represented by dynamic and mutually regulating components (microbial, chemical, physical and immune) for the selective penetration of luminal contents into the internal environment. From the point of view of immunologists, even in a physiological condition, the epithelium of the intestinal wall is in a state of mild inflammation, which is explained by the constant invasion of antigens (food, microbial) and, in turn, the constant readiness of the immune system to respond. The purpose of this review was to analyze information about the formation of microbial and immunological barriers, immunological tolerance to microbiota and the possible role of flavonoids in this. Material and methods. The literature search was carried out using PubMed, ResearchGate, Elibrary databases mainly for the last 10 years, using the following keywords: flavonoid, gut microbiome/microbiota, Th17, Treg, RORγt, immunity, segmented filamentous bacteria. Results. During the immune response, a significant role in maintaining the intestinal barrier function is assigned to helper T lymphocytes type 17 (Th17). The intestinal microbiome is a key element in the formation of the immune barrier. Th17 differentiation in the intestine is fully triggered by commensals (apparently, the main role belongs to segmented filamentous bacteria) after weaning and the start of complementary feeding. Pro-inflammatory Th17 effectors in the gut are controlled by anti-inflammatory regulatory T-cells (Treg). In recent years, it has been established that despite the opposing functions of regulatory cells and effector Th17 cells, their differentiation is similar and is characterized by the expression of the common transcription factor RORγt. The main part of the peripheral regulatory lymphocytes of the intestine is a population that stably expresses not only FOXP3, but also RORγt. Flavonoids, which are plant secondary metabolites of the polyphenolic structure, are able to inhibit intracellular kinases and, as a result, influence the activation and implementation of effector functions of immunocompetent cells. Some flavonoids promote RORγt expression and appear to be able to reprogram the effector phenotype of Th17 cells, reducing their pathogenicity. Conclusion. Understanding the interactions between the microbiota, immune cells, and factors involved in their regulation, which are critical for the maintenance of tolerance, may facilitate progress in the prevention and therapeutic approaches to treat immunoinflammatory and autoimmune diseases.

MyD88 exacerbates inflammation-induced bone loss by modulating dynamic equilibrium between Th17/Treg cells and subgingival microbiota dysbiosis.

BACKGROUND: This study aimed to investigate the contribution of myeloid differentiation primary-response gene 88 (MyD88) on the differentiation of T helper type 17 (Th17) and regulatory T (Treg) cells and the emerging subgingival microbiota dysbiosis in Porphyromonas gingivalis-induced experimental periodontitis. METHODS: Alveolar bone loss, infiltrated inflammatory cells, immunostained cells for tartrate-resistant acid phosphatase (TRAP), the receptor activator of nuclear factor-kB ligand (RANKL), and osteoprotegerin (OPG) were quantified by microcomputerized tomography and histological staining between age- and sex-matched homozygous littermates (wild-type [WT, Myd88+/+] and Myd88-/- on C57BL/6 background). The frequencies of Th17 and Treg cells in cervical lymph nodes (CLNs) and spleen were determined by flow cytometry. Cytokine expression in gingival tissues, CLNs, and spleens were studied by quantitative polymerase chain reaction (qPCR). Analysis of the composition of the subgingival microbiome and functional annotation of prokaryotic taxa (FAPROTAX) analysis were performed. RESULTS: P. gingivalis-infected Myd88-/- mice showed alleviated bone loss, TRAP+ osteoclasts, and RANKL/OPG ratio compared to WT mice. A significantly higher percentage of Foxp3+CD4+ T cells in infected Myd88-/- CLNs and a higher frequency of RORγt+CD4+ T cells in infected WT mice was noted. Increased IL-10 and IL-17a expressions in gingival tissue at D14-D28 then declined in WT mice, whereas an opposite pattern was observed in Myd88-/- mice. The Myd88-/- mice exhibited characteristic increases in gram-positive species and species having probiotic properties, while gram-negative, anaerobic species were noted in WT mice. FAPROTAX analysis revealed increased aerobic chemoheterotrophy in Myd88-/- mice, whereas anaerobic chemoheterotrophy was noted in WT mice after P. gingivalis infection. CONCLUSIONS: MyD88 plays an important role in inflammation-induced bone loss by modulating the dynamic equilibrium between Th17/Treg cells and dysbiosis in P. gingivalis-induced experimental periodontitis.

Transforming growth factor-ß1 and soluble co-inhibitory immune checkpoints as putative drivers of immune suppression in patients with basal cell carcinoma.

The current study compared the levels and possible associations between systemic soluble immune checkpoints (sICPs, n = 17) and a group of humoral modulators of immune suppressor cells (n = 7) in a cohort of patients with basal cell carcinoma (BCC, n = 40) and a group of healthy control subjects (n = 20). The seven humoral modulators of immunosuppressor cells were represented by the enzymes, arginase 1 and fibroblast activation protein (FAP), the chemokine, RANTES (CCL5) and the cytokines, interleukin-10 and transforming growth factor-ß1 (TGF-ß1), as well as the M2-type macrophage markers, soluble CD163 (sCD163) and sCD206. The plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, sTIM-3 and sPD-L2 were significantly elevated in the cohort of BCC patients (p<0.001-p<0.00001), while that of sBTLA was significantly decreased (p<0.006). Of the co-stimulatory sICPs, sCD27 and sGITR were significantly increased (p<0.0002 and p<0.0538) in the cohort of BCC patients, while the others were essentially comparable with those of the control participants; of the dual active sICPs, sHVEM was significantly elevated (p<0.00001) and TLR2 comparable with the control group. A correlation heat map revealed selective, strong associations of TGF-ß1 with seven co-stimulatory (z = 0.618468-0.768131) and four co-inhibitory (z = 0.674040-0.808365) sICPs, as well as with sTLR2 (z = 0.696431). Notwithstanding the association of BCC with selective elevations in the levels of a large group of co-inhibitory sICPs, our novel findings also imply the probable involvement of TGF-ß1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells. Notably, these abnormalities were present in patients with either newly diagnosed or recurrent disease.

Profiling regulatory T lymphocytes within the tumor microenvironment of breast cancer via radiomics.

OBJECTIVE: To generate an image-driven biomarker (Rad_score) to predict tumor-infiltrating regulatory T lymphocytes (Treg) in breast cancer (BC). METHODS: Overall, 928 BC patients were enrolled from the Cancer Genome Atlas (TCGA) for survival analysis; MRI (n = 71 and n = 30 in the training and validation sets, respectively) from the Cancer Imaging Archive (TCIA) were retrieved and subjected to repeat least absolute shrinkage and selection operator for feature reduction. The radiomic scores (rad_score) for Treg infiltration estimation were calculated via support vector machine (SVM) and logistic regression (LR) algorithms, and validated on the remaining patients. RESULTS: Landmark analysis indicated Treg infiltration was a risk factor for BC patients in the first 5 years and after 10 years of diagnosis (p = 0.007 and 0.018, respectively). Altogether, 108 radiomic features were extracted from MRI images, 4 of which remained for model construction. Areas under curves (AUCs) of the SVM model were 0.744 (95% CI 0.622-0.867) and 0.733 (95% CI 0.535-0.931) for training and validation sets, respectively, while for the LR model, AUCs were 0.771 (95% CI 0.657-0.885) and 0.724 (95% CI 0.522-0.926). The calibration curves indicated good agreement between prediction and true value (p > 0.05), and DCA shows the high clinical utility of the radiomic model. Rad_score was significantly correlated with immune inhibitory genes like CTLA4 and PDCD1. CONCLUSIONS: High Treg infiltration is a risk factor for patients with BC. The Rad_score formulated on radiomic features is a novel tool to predict Treg abundance in the tumor microenvironment.

The Role of the Intestinal Microbiome in Multiple Sclerosis-Lessons to Be Learned from Hippocrates.

Based on recent advances in research of chronic inflammatory conditions, there is a growing body of evidence that suggests a close correlation between the microbiota of the gastrointestinal tract and the physiologic activity of the immune system. This raises the idea that disturbances of the GI ecosystem contribute to the unfolding of chronic diseases including neurodegenerative pathologies. Here, we overview our current understanding on the putative interaction between the gut microbiota and the immune system from the aspect of multiple sclerosis, one of the autoimmune conditions accompanied by severe chronic neuroinflammation that affects millions of people worldwide.

The IL-25/ILC2 axis promotes lung cancer with a concomitant accumulation of immune-suppressive cells in tumors in humans and mice.

Background: Group 2 innate lymphoid cells (ILC2) can be activated by interleukin (IL)-33 or IL-25. IL-25-activated ILC2 cells help protect the host against helminth infection while exacerbating allergic-like inflammation and tissue damage in the lung. In the context of cancer, IL-33-activated ILC2 cells were found to bear anti-tumoral functions in lung cancer while IL-25-activated ILC2 cells promoted tumorigenesis in colorectal cancer. The role of IL-25-activated ILC2 cells in lung cancer remains to be addressed. Methods: We examined the overall survival of human non-small cell lung cancer (NSCLC) patients according to IL25 expression as well as the distribution of ILC2 cells and regulatory T cells (Tregs) in various NSCLC patient tissues and peripheral blood (PB) of healthy donors (HDs). We analyzed the effect of adoptive transfer of IL-25-activated ILC2 cells on tumor growth, metastasis and survival in a heterotopic murine model of lung cancer. Results: We report that human NSCLC patients with high IL-25 expression have reduced overall survival. Moreover, NSCLC patients bear increased frequencies of ILC2s compared to HDs. Frequencies of Tregs were also increased in NSCLC patients, concomitantly with ILC2s. In mice bearing heterotopic lung cancer, adoptive transfer of IL-25-activated ILC2s led to increased tumor growth, increased metastasis and reduced survival. The frequencies of monocytic myeloid-derived suppressor cells (M-MDSCs) were found to be increased in the tumors of mice that received ILC2s as compared to controls. Conclusion: Overall, our results indicate that the IL-25/ILC2 axis promotes lung cancer potentially by recruiting immune-suppressive cells to the tumors both in humans and in mice, and that it may therefore represent a suitable novel target for NSCLC immunotherapeutic development.

Does molecular scarring in psoriasis exist? A review of the literature.

Plaque psoriasis is a chronic inflammatory dermatosis characterized by a tendency to recur in the same locations after discontinuation of treatment. The implementation of therapy with drugs targeting cytokines like interleukin (IL) 17A (IL-17A) and IL-23 has revolutionized the treatment of psoriasis and enabled the achievement of skin without lesions. However, despite the clinical resolution of psoriatic eruptions, cells that maintain the local memory of the disease remain in the dermis and epidermis, constituting a kind of molecular scar. The cells responsible for maintaining memory in the skin of patients and influencing the rapid relapse of the disease after the triggering factor are primarily tissue resident memory T cells (TRM), but it seems that regulatory T lymphocytes (Treg), dendritic cells (DC), and Langerhans cells (LC) may also play an important role in this process. We reviewed the literature to explain the concept of molecular scarring in psoriasis, and to assess the effect of various therapies on immune memory.

Randomized, Double-Blind, Placebo-Controlled Trial of Vitamin D Supplementation in the Build-up Phase of House Dust Mite-Specific Immunotherapy.

PURPOSE: Vitamin D (VitD) is an immunomodulatory molecule capable of alleviating allergic symptoms. However, the effectiveness of allergen-specific immunotherapy (AIT) is not commonly evidenced in the early build-up phase. The aim of the study was to determine the potential of VitD supplementation in this treatment phase. METHODS: Thirty-four house dust mite (HDM)-allergic adult patients treated with subcutaneous AIT were randomized to receive VitD2 60,000 IU/week or placebo for 10 weeks and followed up for 10 weeks. The primary endpoints were the symptom-medication score (SMS) and the treatment response rate. The secondary endpoints were eosinophil count and levels of plasma IL-10, Der p 2-specific IgG4, and dysfunctional regulatory T (CRTH2+ Treg) cells. RESULTS: Of 34 patients, 15 in each group completed the study. Patients with VitD deficiency receiving a VitD supplement showed significantly lower mean change SMS than the placebo group in weeks 10 (mean difference -54.54%, P = 0.007) and 20 (mean difference -42.69%, P = 0.04). The percentage of treatment responders reached 78% and 50% in the VitD and placebo groups, respectively, and the effect remained in week 20 (89% and 60%). No significant difference was observed for the tested immunological read-outs, with the exception of the frequency of CRTH2+ Treg cells, which was remarkably reduced in the VitD-treated patients. Moreover, improvement in SMS was correlated to the number of CRTH2+ Treg cells. Our in vitro experiment indicated that VitD downregulated activation markers, whereas it improved the function of CRTH2+ Treg cells. CONCLUSIONS: VitD supplementation in the build-up phase of AIT could relieve symptoms and decrease Treg cell dysfunction, especially in patients with VitD deficiency.

Research advances on targeted-Treg therapies on immune-mediated kidney diseases.

The primary function of regulatory T cells (Tregs) is blocking the pathogenic immunological response mediated by autoreactive cells, establishing and maintaining immune homeostasis in tissues. Kidney diseases are often caused by Immune imbalance, including alloimmune graft damage after renal transplantation, direct immune-mediated kidney diseases like membranous nephropathy (MN) and anti-glomerular basement membrane (anti-GBM) glomerulonephritis, as well as indirect immune-mediated ones like Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAVs), IgA nephropathy (IgAN) and lupus nephritis (LN). Treg cells are deficient numerically and/or functionally in those kidney diseases. Targeted-Treg therapies, including adoptive Tregs transfer therapy and low-dose IL-2 therapy, have begun to thrive in treating autoimmune diseases in recent years. However, the clinical use of targeted Treg-therapies is rarely mentioned in those kidney diseases above except for kidney transplantation. This article mainly discusses the newest progressions of targeted-Treg therapies in those specific examples of immune-mediated kidney diseases. Meanwhile, we also reviewed the main factors that affect Treg development and differentiation, hoping to inspire new strategies to develop target Tregs-therapies. Lastly, we emphasize the significant impediments and prospects to the clinical translation of target-Treg therapy. We advocate for more preclinical and clinical studies on target Tregs-therapies to decipher Tregs in those diseases.

Age-Dependent Effect of Calcitriol on Mouse Regulatory T and B Lymphocytes.

The hormonally active vitamin D3 metabolite, calcitriol, functions as an important modulator of the immune system. We assumed that calcitriol exerts different effects on immune cells and cytokine production, depending on the age of the animal; therefore, we analyzed its effects on regulatory T lymphocytes and regulatory B lymphocytes in healthy young and old female C57Bl/6/Foxp3GFP mice. In the lymph nodes of young mice, calcitriol decreased the percentage of Tregs, including tTregs and pTregs, and the expression of GITR, CD103, and CD101; however, calcitriol increased the level of IL-35 in adipose tissue. In the case of aged mice, calcitriol decreased the percentages of tTregs and CD19+ cells in lymph nodes and the level of osteopontin in the plasma. Additionally, increases in the levels of IgG and the lowest levels of IFN-γ, IL-10, and IL-35 were observed in the adipose tissue of aged mice. This study showed that calcitriol treatment had different effects, mainly on Treg phenotypes and cytokine secretion, in young and old female mice; it seemed that calcitriol enhanced the immunosuppressive properties of the lymphatic organs and adipose tissue of healthy young mice but not of healthy aged mice, where the opposite effects were observed.

BAFF blockade attenuates acute graft-versus-host disease directly via the dual regulation of T- and B-cell homeostasis.

Introduction: B-cell-activating factor (BAFF) is associated with donor-specific antibodies and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the effects of BAFF on T-cell physiological function have not been fully elucidated in acute GVHD. Methods: We examined the effects of belimumab, a monoclonal antibody targeting BAFF, for the treatment of acute GVHD. We examined the effects of T cells and B cells separately when inducing GVHD in mouse model. Results: Therapeutic functional manipulation of endogenous BAFF can improve acute GVHD during the early post-transplant period. In this study, BAFF was shown to increase the proportions of CD4+IL-17+, CD4+IL-6+ Th17, and CD4+IFN-γ+ Th1 cells and to reduce the proportion of regulatory T (Treg) cells. Furthermore, the belimumab therapy group showed increased B220+IgD+IgM+ mature B cells but decreased B220+IgD-IgM- memory B cells, B220+Fas+GL-7+ germinal center formation, and B220+IgD-CD138+ plasma cells. These results indicate that BAFF can alleviate acute GVHD by simultaneously regulating T and B cells. Interestingly, the BAFF level was higher in patients with acute GVHD after HSCT compared with patients receiving chemotherapy. Conclusion: This study suggests that BAFF blockade might modulate CD4 +T-cell-induced acute GVHD early after allo-HSCT and the possibility of simultaneously controlling chronic GVHD, which may appear later after allo-HSCT.

Tag7-Mts1 Complex Activates Chemotaxis of Regulatory T Cells.

One of the basic features of immune system is the ability to sustain balance between activation and suppression of effector lymphocytes. In this process a key role belongs to the subpopulation of cells called regulatory T cells (Treg). Many cancer and autoimmune diseases are caused by malfunctions of Treg, and investigation of this subpopulation is important for development of new therapeutic approaches. In this study, we demonstrate that regulatory T cells can migrate along the concentration gradient of Tag7-Mts1 complex, and also they produce agents that induce blood cells migration.

Local assessment of the immunohistochemical expression of Foxp3+ regulatory T lymphocytes in the different pathological forms associated with bovine paratuberculosis.

BACKGROUND: Mycobacterium avium subsp. paratuberculosis infected animals show a variety of granulomatous lesions, from focal forms with well-demarcated granulomas restricted to the gut-associated lymphoid tissue (GALT), that are seen in the initial phases or latency stages, to a diffuse granulomatous enteritis, with abundant (multibacillary) or scant (paucibacillary) bacteria, seen in clinical stages. Factors that determine the response to the infection, responsible for the occurrence of the different types of lesion, are still not fully determined. It has been seen that regulatory T cells (Treg) play an important role in various diseases where they act on the limitation of the immunopathology associated with the immune response. In the case of paratuberculosis (PTB) the role of Treg lymphocytes in the immunity against Map is far away to be completely understood; therefore, several studies addressing this subject have appeared recently. The aim of this work was to assess, by immunohistochemical methods, the presence of Foxp3+ T lymphocytes in intestinal samples with different types of lesions seen in cows with PTB. METHODS: Intestinal samples of twenty cows showing the different pathological forms of PTB were evaluated: uninfected controls (n = 5), focal lesions (n = 5), diffuse paucibacillary (n = 5) and diffuse multibacillary (n = 5) forms. Foxp3+ lymphocyte distribution was assessed by differential cell count in intestinal lamina propria (LP), gut-associated lymphoid tissue (GALT) and mesenteric lymph node (MLN). RESULTS: A significant increase in the number of Foxp3+ T cells was observed in infected animals with respect to control group, regardless of the type of lesion. However, when the different categories of lesion were analyzed independently, all individuals with PTB lesions showed an increase in the amount of Foxp3+ T lymphocytes compared to the control group but this increase was only significant in cows with focal lesions and, to a lesser extent, in animals with diffuse paucibacillary forms. The former showed the highest numbers, significantly different from those found in cows with diffuse lesions, where no differences were noted between the two forms. No specific distribution pattern was observed within the granulomatous lesions in any of the groups. CONCLUSIONS: The increase of Foxp3+ T cells in focal forms, that have been associated with latency or resistance to infection, suggest an anti-inflammatory action of these cells at these stages, helping to prevent exacerbation of the inflammatory response, as occurs in diffuse forms, responsible for the appearance of clinical signs.

Pathogenesis-oriented therapy of psoriasis using biologics.

INTRODUCTION: Psoriasis is currently regarded an immune-mediated inflammatory disease. The central pathogenic axis comprises interleukin-23, TH17-lymphocytes differentiating under its influence, and interleukin-17A as a key effector cytokine of these T-lymphocytes. All of these can selectively be targeted using biological therapies, thus potentially increasing efficacy and reducing adverse events when compared to conventional systemic therapeutics. AREAS COVERED: We review the current concept of psoriasis as an immune-mediated inflammatory disease, assessing the evidence for a role of elements of the innate and adaptive immune system. We then correlate the pharmacological effects of biologics in psoriasis in light of the known physiologic as well as pathophysiological role of the respective targets. This is done on the basis of an extensive literature search of publications since 2018 which describe the role of the above-mentioned elements in health and disease or the effects of blocking these as an attempt to treat psoriasis. EXPERT OPINION: Biologics targeting the above-mentioned central pathogenic axis provide a particularly effective and safe way to treat psoriasis. Given the impact of comorbidities on therapeutic decision-making, and the efficacy of some biologics also on certain comorbidities, these drugs represent a first step toward personalized medicine in the management of psoriasis.

The Efficacy of a New Protocol of Oral Immunotherapy to Wheat for Desensitization and Induction of Tolerance.

Oral immunotherapy (OIT) is a novel approach to desensitization and tolerance induction in food allergy patients. This study aimed to design and implement a new wheat OIT protocol, evaluate its efficacy in tolerance induction, and assess specific immunoglobulin-E (IgE) and regulatory T cell changes. From 2015 to 2017, 26 patients with confirmed IgE-mediated hypersensitivity to wheat were treated via oral immunotherapy (OIT). Patients with prior anaphylactic episodes underwent OIT using the rush method. Specific IgE concentrations and the number of regulatory T cells (CD4+ CD25+ FOXP3+ T cells) were measured using Allergy Screen immunoblot assay and flow cytometry, respectively. This study was registered in the Iranian Registry of Clinical Trials (IRCT20181220042066N1). The results revealed success rates of 100% and 93.3% for desensitization and tolerance. Specific IgE was significantly reduced after 12 months of OIT. No significant change in regulatory T cell numbers was observed. In view of the promising findings of this study, the proposed OIT protocol could be viewed as an effective and valuable method to induce tolerance and desensitization in wheat allergic patients.