Curcumin inhibits colon cancer malignant progression and promotes T cell killing by regulating miR-206 expression.

Colon cancer is a great threat to human health. Curcumin, as a traditional Chinese medicine extract with anti-tumor and anti-inflammatory effects, can affect the development of diverse human diseases including cancer. The aim of this research was to probe the mechanism by which curcumin regulates colon cancer progression. Colon cancer cells were processed with graded concentrations of curcumin. The proliferation and apoptosis of the treated cells were determined by MTT, colony formation assay and flow cytometry. Expression of signaling pathway-related proteins and programmed death-ligand 1 (PD-L1) was measured by western blotting. The effect of curcumin on tumor cell growth was verified through T cell-mediated killing and ELISA assays. The relationship between target gene expression and the survival rate of colon cancer patients was analyzed by a survival curve. Curcumin treatment restrained proliferation and accelerated apoptosis of colon cancer cells. It elevated miR-206 expression, which in turn affected colon cancer cell function. miR-206 enhanced colon cancer cell apoptosis and inhibited PD-L1 expression; thus, curcumin enhanced the killing effect of T cells on tumor cells by suppressing PD-L1 through inhibiting the JAK/STAT3 pathway. Patients with high expression of miR-206 had better survival rates than those with low expression. Curcumin can regulate miR-206 expression and inhibit the malignant behavior of colon cancer cells and enhance T cell killing through the JAK/STAT3 pathway.

Elevated Sera IL-6 and NK-T Cells Associated With Increased Pathological Complete Response in HER2-positive Breast Cancer With Carboplatin-based Neoadjuvant Therapy.

Context: Neoadjuvant therapy is the primary treatment for stage II to III breast cancer (BC). The heterogeneity of BC challenges the identification of effective neoadjuvant regimens and of the related sensitive populations. Objective: The study intended to explore the predictive role of inflammatory cytokines, immune-cell subsets, and tumor-infiltrating lymphocytes (TILs) for the accomplishment of the pathological complete response (pCR) after a neoadjuvant regimen. Design: The research team conducted a phase II, single-armed, open-label trial. Setting: The study took place at the Fourth Hospital of Hebei Medical University in Shijiazhuang, Hebei, China. Participants: Participants were 42 patients at the hospital receiving treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) between November 2018 and October 2021. Intervention: Participants received neoadjuvant therapy of six cycles of docetaxel, carboplatin, and trastuzumab (TCbH). Outcome Measures: The research team: (1) measured 13 cytokines and immune-cell populations in peripheral blood prior to neoadjuvant therapy administration; (2) measured TILs in tumor tissues; (3) analyzed correlations among biomarkers and pCR. Results: Of the 42 participants, 18 achieved pCR (42.9%) after the neoadjuvant therapy, with 37 having an overall response rate (ORR) of 88.1%. All participants experienced at least one short-term adverse event. The most common toxicity was leukopenia, with 33 participants (78.6%), while no cardiovascular dysfunction occurred. Compared with the non-pCR group, the pCR group had higher serum levels of tumor necrosis factor alpha (TNF-ɑ), with P = .013; interleukin 6 (IL-6), with P = .025; and IL-18, with P = .0004. Univariate analysis showed that IL-6 (OR, 3.429; 95% CI,1.838-6.396; P = .0001) had a significant correlation with pCR. Participants in the pCR group had a higher level of natural killer T (NK-T) cells (P = .009) and a lower ratio of cluster of differentiation 4 (CD4):CD8 (P = .0014) before neoadjuvant therapy. Univariate analysis linked a high population of NK-T cells (OR, 0.204; 95% CI,0.052-0.808; P = .018), a low CD4:CD8 ratio (OR, 10.500; 95% CI, 2.475-44.545; P = .001), and TILs expression (OR, 0.192; 95% CI, 0.051-0.731; P = .013) to pCR. Conclusions: Immunological factors, including IL-6, NK-T cells, CD4+ T versus CD8+ T ratio, and TILs expression were significant predictors for response to TCbH neoadjuvant therapy with carboplatin.

T-cell-lymphoma presented as a solitary subcutaneous mass in the ventral cervical region of an adult llama- diagnostic and treatment.

BACKGROUND: Neoplasm in South American camelids (SAC) are commonly described. The most frequently reported type of neoplasm are lymphomas and difference in the age suffering from lymphomas of and llamas is seen. This report describes a case of a solitary lymphoma in a 5 years and 9 month old llama mare displaying the approach of diagnostic imaging and successful surgical treatment. CASE PRESENTATION: The llama was referred to the clinic for dyspnoea and inspiratory abnormal respiratory sounds. The clinical examination comprised blood cell count, ultrasonographic and radiographic examinations, endoscopy and fine needle aspiration cytology of a mass detected in the mid cervical region. The mass was surgically removed. Histopathological examination of the surgically removed mass diagnosed a malignant T-cell- lymphoma. According to the results of the clinical, ultrasonographic and radiographic examinations no tumor invasion was apparent in distant organs and the llama was discharged from the clinic seven days after surgery. CONCLUSION: Lymphoma has been reported to be the most common neoplasia in camelids and are more often described in young alpacas and in adult llamas. To the author´s knowledge the case presented here is the first that described a broad panel of diagnostic tools including ultrasound, radiographs, endoscopy, fine needle aspiration cytology and histopathoogical examination as well as a successful surgical treatment of a solitary lymphoma in camelids.

Maoto, a traditional Japanese medicine, controls acute systemic inflammation induced by polyI:C administration through noradrenergic function.

Maoto, a traditional Japanese medicine (Kampo), is widely used to treat upper respiratory tract infections, including influenza virus infection. Although maoto is known to inhibit pro-inflammatory responses in a rodent model of acute inflammation, its underlying mechanism remains to be determined. In this study, we investigated the involvement of immune responses and noradrenergic function in the inhibitory action of maoto. In a mouse model of polyI:C-induced acute inflammation, maoto was administered orally in conjunction with intraperitoneal injection of PolyI:C (6 mg/kg), and blood was collected after 2 h for measurement of plasma cytokines by ELISA. Maoto significantly decreased PolyI:C-induced TNF-α levels and increased IL-10 production. Neither pretreatment with IL-10 neutralizing antibodies nor T-cell deficiency using nude mice modified the inhibitory effect of maoto, indicating that the anti-inflammatory effects of maoto are independent of IL-10 and T cells. Furthermore, the inhibitory effects of maoto on PolyI:C-induced TNF-α production were not observed in ex vivo splenocytes, suggesting that maoto does not act directly on inflammatory cells. Lastly, pretreatment with a ß-adrenergic receptor antagonist partially cancelled the anti-inflammatory effects of maoto. Collectively, these results suggest that maoto mediates its anti-inflammatory effects via ß-adrenergic receptors in vivo.

1,25-Dihydroxyvitamin D3 and 20-Hydroxyvitamin D3 Upregulate LAIR-1 and Attenuate Collagen Induced Arthritis.

Vitamin D plays a crucial role in regulation of the immune response. However, treatment of autoimmune diseases with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] doses sufficient to be effective is prohibitive due to its calcemic and toxic effects. We use the collagen-induced arthritis (CIA) model to analyze the efficacy of the noncalcemic analog of vitamin D, 20S-hydroxyvitamin D3 [20S(OH)D3], as well as 1,25(OH)2D3, to attenuate arthritis and explore a potential mechanism of action. Mice fed a diet deficient in vitamin D developed a more severe arthritis characterized by enhanced secretion of T cell inflammatory cytokines, compared to mice fed a normal diet. The T cell inflammatory cytokines were effectively suppressed, however, by culture of the cells with 20S(OH)D3. Interestingly, one of the consequences of culture with 1,25(OH)2D3 or 20S(OH)D3, was upregulation of the natural inhibitory receptor leukocyte associated immunoglobulin-like receptor-1 (LAIR-1 or CD305). Polyclonal antibodies which activate LAIR-1 were also capable of attenuating arthritis. Moreover, oral therapy with active forms of vitamin D suppressed arthritis in LAIR-1 sufficient DR1 mice, but were ineffective in LAIR-1-/- deficient mice. Taken together, these data show that the effect of vitamin D on inflammation is at least, in part, mediated by LAIR-1 and that non-calcemic 20S(OH)D3 may be a promising therapeutic agent for the treatment of autoimmune diseases such as Rheumatoid Arthritis.

Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes.

Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRß), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRß-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1ß release by FRß+ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.

6,7,4[Formula: see text]-Trihydroxyflavanone Prevents Methamphetamine-Induced T Cell Deactivation by Protecting the Activated T Cells from Apoptosis.

Methamphetamine (METH) is an extremely addictive drug that has raised serious public health concerns recently. METH addiction not only results in neuronal cytotoxicity, but it also affects immune cell activity, including T lymphocytes. 6,4,7[Formula: see text]-trihydroxyflavanone (THF), isolated from Dalbergia odorifera, has been studied for its antibacterial activity, but evidence for whether THF has an anti-cytotoxic and protective effect on T cell activation exposed to METH is lacking. In this study, results showed that treatment with THF was not cytotoxic to Jurkat T cells but dose-dependently mitigated the cytotoxicity induced by exposure to METH. The Western blot results demonstrating pre-treatment with THF maintained the expression of anti-apoptotic proteins and phosphorylation of PI3K/Akt/mTOR downregulated by treatment with METH. Furthermore, we found that decreased expression of IL-2 and CD69 by METH exposure was partially restored, and viability was significantly prevented by pre-treatment with THF in activated T cells. These findings were involved in re-elevated expression of anti-apoptotic proteins as well as recovered pathways including MAPK/PI3K/Akt/mTOR in activated T cells pre-exposed to METH. Our results suggest beneficial effects of THF against the cytotoxic and immune-modulating effect of METH on T cells and therapeutic potential of THF for patients with immunodeficiency caused by METH addiction.

Atopic dermatitis.

Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense itch. The disorder affects people of all ages and ethnicities, has a substantial psychosocial impact on patients and relatives, and is the leading cause of the global burden from skin disease. Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders. The pathophysiology is complex and involves a strong genetic predisposition, epidermal dysfunction, and T-cell driven inflammation. Although type-2 mechanisms are dominant, there is increasing evidence that the disorder involves multiple immune pathways. Currently, there is no cure, but increasing numbers of innovative and targeted therapies hold promise for achieving disease control, including in patients with recalcitrant disease. We summarise and discuss advances in our understanding of the disease and their implications for prevention, management, and future research.

Immunoactive polysaccharides produced by heterotrophic mutant of green microalga Parachlorella kessleri HY1 (Chlorellaceae).

Hot water extract from biomass of heterotrophic mutant green alga Parachlorella kessleri HY1 (Chlorellaceae) was deproteinised, and three polysaccharidic fractions were obtained by preparative chromatography. The low-molecular fraction (1.5 × 104g mol-1) was defined mainly as branched O-2-ß-xylo-(1→3)-ß-galactofuranan where xylose is partially methylated at O-4. Two high-molecular fractions (3.05 × 105 and 9.84 × 104g mol-1) were complex polysaccharides containing α-l-rhamnan and xylogalactofuranan parts in different ratios. The polysaccharides were well soluble in hot water and, upon cooling, tended to self-segregate. Immunomodulatory activities of the obtained fractions were preliminary tested using ELISA, FACS and ImmunoSpot kits. The polysaccharides increased the TNF-α production in melanoma bearing mice with much higher intensity than in healthy mice. This was in agreement with the FACS results on T and B cells indicating their possibly secondary activation by innate immunity cells.

Parental Uveitis Influences Offspring With an Increased Susceptibility to the Experimental Autoimmune Uveitis.

Purpose: Previous studies have shown that parental abnormal physiological conditions such as inflammation, stress, and obesity can be transferred to offspring. The purpose of this study was to investigate the impact of parental uveitis on the development and susceptibility to experimental autoimmune uveitis (EAU) in offspring. Methods: Parental male and female B10RIII mice were immunized with interphotoreceptor retinoid binding protein (IRBP) 161-180 in complete Freund's adjuvant and were immediately allowed to mate. Gross examination of the offspring gestated with EAU was performed to determine the influence of parental uveitis on offspring development after birth. Gene expression profiles were analyzed in the affected eyes of offspring under EAU to identify differentially expressed genes (DEGs). Adult offspring were given 5, 25, and 50 µg IRBP161-180 to compare their susceptibility to EAU. Immunized mice were clinically and pathologically evaluated for the development of EAU. Ag-specific T-cell proliferation and IL-17 production from spleens and lymph nodes were evaluated on day 14 or 35 after immunization. Results: Hair loss, delay of eye opening, and swollen spleens in the offspring from parents with uveitis were observed from day 14 to 39 after birth. DEGs were involved in the immune system process, muscle system process, and cell development. The altered antigen processing and presentation, cell adhesion molecules, and phagosome in the eyes of the offspring from uveitis-affected parents were enriched. Offspring gestated with EAU showed a susceptibility to EAU and an earlier onset and higher severity of EAU compared to the control group mice. IRBP-specific lymphocyte proliferation and IL-17 production were observed in the EAU offspring with exposure to parental uveitis. Conclusions: The results suggest that mouse parents with uveitis can increase their offspring's susceptibility to EAU, probably through altering cell adhesion molecules and antigen processing and presentation related to the T-cell proliferation and Th17 response.

A scoring system for the electrostatic complementarities of T-cell receptors and cancer-mutant amino acids: multi-cancer analyses of associated survival rates.

The anti-tumor immune response is considered to be due to the T-cell receptor (TCR) binding to tumor antigens, which can be either wild-type, early stem cell proteins, presumably foreign to a developed immune system; or mutant peptides, foreign to the immune system because of a mutant amino acid (aa) or otherwise somatically altered aa sequence. Recently, very large numbers of TCR complementarity-determining region-3 (CDR3) aa sequences obtained from tumor specimens have become available. We developed a novel algorithm for assessing the complementarity of tumor mutant peptides and TCR CDR3s, based on the retrieval of TCR CDR3 aa sequences from both tumor specimen and patient blood exomes and by using an automated process of assessing CDR3 and mutant aa electrical charges. Results indicated many instances where high electrostatic complementarity was associated with a higher survival rate. In particular, our approach led to the identification of specific genes contributing significantly to the complementary, TCR CDR3-mutant aa. These results suggest a novel approach to tumor immunoscoring and may lead to the identification of high-priority neo-antigen, peptide vaccines; or to the identification of ex vivo stimulants of tumor-infiltrating lymphocytes.

Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target.

We investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6-/- cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

The extracts of Astragalus membranaceus enhance chemosensitivity and reduce tumor indoleamine 2, 3-dioxygenase expression.

Astragalus membranaceus has been shown to possess anti-inflammation and antitumor properties. Several studies have indicated that extracts of Astragalus membranaceus (PG2) have growth inhibitory effects on tumor. However, the effect of PG2 on enhancing the chemotherapy, modulating tumor immune escape and their mechanism of action is unknown and need further investigation. Connexin (Cx) 43 is ubiquitous in cells and involved in facilitating the passage of chemotherapeutic drugs to bystander tumor cells. The indoleamine 2, 3-dioxygenase (IDO) depletes tryptophan, reduces the active T cell number and destroys immune surveillance. Herein, we provide evidence that the treatment of PG2 induced Cx43 expression, decreases IDO expression and enhances the distribution of chemotherapeutic drug. However, the effects of combination therapy (PG2 plus cisplatin) in animal models significantly retarded tumor growth and prolonged the survival. We believe that the information provided in this study may aid in the design of future therapy of PG2, suggest suitable combinations with chemotherapies.

T-cell activation by transgenic rice seeds expressing the genetically modified Japanese cedar pollen allergens.

Transgenic rice seeds that contain genetically modified Cry j 1 and Cry j 2, the two major allergens of Cryptomeria japonica (Japanese cedar; JC), have been developed as immunotherapeutic candidates for JC pollinosis. Because the transgenic rice (TG-rice) seeds express allergens containing whole amino acid sequences of Cry j 1 and Cry j 2 in the endosperm tissue (edible part of rice grain), they can potentially target all Cry j 1- and Cry j 2-specific T-cells. However, it was unknown whether antigenicity of Cry j 1 and Cry j 2 could be completely preserved in TG-rice seeds. We verified the antigenicity of TG-rice seeds to T-cells through the analysis of the proliferative responses of T-cells in Cry j 1- or Cry j 2-immunized mice or T-cell lines to TG-rice seed extract. First, four mouse strains were immunized with Cry j 1 or Cry j 2. T-cells in the immunized mice proliferated on treatment with TG-rice seed extract, but not non-transgenic wild-type rice (WT-rice) seed extract. Furthermore, T-cell lines were established from the spleen cells of the immunized mice. Each T-cell line resulted in a proliferative response to TG-rice seed extract, but not to WT-rice seed extract, suggesting that TG-rice seeds certainly express T-cell epitopes corresponding to T-cell lines. Considering the modified amino acid sequences of Cry j 1 and Cry j 2 in TG-rice seeds, the expression of specific T-cell epitopes suggested that TG-rice seeds express all possible T-cell epitope repertoires of Cry j 1 and Cry j 2.

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases.

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.

New therapy with XLQ® to suppress chronic prostatitis through its anti-inflammatory and antioxidative activities.

Chronic prostatitis is a common urological disease. The etiology of this disease and effective therapy for its treatment are yet to be elucidated. We investigated the functions of XLQ® in chronic nonbacterial prostatitis using a complete Freund's adjuvant-induced rat model. Prostates and blood samples were collected for further evaluation after oral gavage with XLQ ® or a vehicle for 4 weeks. The results showed that XLQ ® significantly decreased the prostate index, ameliorated the histopathologic changes, and reduced CD3+ and CD45+ cell infiltration in the prostate stroma. Further study showed that XLQ ® suppressed the expression of proinflammatory cytokines, such as interleukin (IL)-1ß, IL-2, IL-6, IL-17A, monocyte chemoattractant protein-1, and tumor necrosis factor-α. XLQ ® showed a strong antioxidant capacity by enhancing the activities of antioxidative enzymes (e.g., total superoxide dismutase, catalase, and glutathione peroxidase) and decreasing the level of lipid peroxidation products (malondialdehyde). Moreover, XLQ ® can suppress the activation of nuclear factor-κB and P38-mitogen-activated protein kinase signaling pathways. In summary, XLQ ® has affirmative effects on chronic prostatitis, which could be attributed to its anti-inflammatory and antioxidative capacities. On the basis of these results, XLQ ® can be developed as an effective and safe therapy for chronic prostatitis.

[Acrally emphasized papules-a case report]. / Akral betonte Papeln ­ ein Fallbericht.

Syringotropic mycosis fungoides (STMF) is an extremely rare form of cutaneous T­cell lymphoma with 51 published cases so far. Clinically STMF is manifested similarly to folliculotropic mycosis fungoides (MF), whereby the course of STMF is much milder. Histopathologically, it shows a prominent tropism of the T­cell lymphocytic infiltrate for the eccrine epithelium. We report the case of a 65-year-old woman with multiple small papules on the feet, shinbones and back.

The pathogenesis of thyroid autoimmune diseases: New T lymphocytes - Cytokines circuits beyond the Th1-Th2 paradigm.

Autoimmune thyroid disease (AITD) is one of the most common organ-specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves' disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs.

Notch signaling mediated by Delta-like ligands 1 and 4 controls the pathogenesis of chronic GVHD in mice.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) and remains an area of unmet clinical need with few treatment options available. Notch blockade prevents acute GVHD in multiple mouse models, but the impact of Notch signaling on cGVHD remains unknown. Using genetic and antibody-mediated strategies of Notch inhibition, we investigated the role of Notch signaling in complementary mouse cGVHD models that mimic several aspects of human cGVHD in search of candidate therapeutics. In the B10.D2→BALB/c model of sclerodermatous cGVHD, Delta-like ligand 4 (Dll4)-driven Notch signaling was essential for disease development. Antibody-mediated Dll4 inhibition conferred maximum benefits when pursued early in a preventative fashion, with anti-Dll1 enhancing early protection. Notch-deficient alloantigen-specific T cells showed no early defects in proliferation or helper polarization in vivo but subsequently exhibited markedly decreased cytokine secretion and enhanced accumulation of FoxP3+ regulatory T cells. In the B6→B10.BR major histocompatibility complex-mismatched model with multi-organ system cGVHD and prominent bronchiolitis obliterans (BO), but not skin manifestations, absence of Notch signaling in T cells provided long-lasting disease protection that was replicated by systemic targeting of Dll1, Dll4, or both Notch ligands, even during established disease. Notch inhibition decreased target organ damage and germinal center formation. Moreover, decreased BO-cGVHD was observed upon inactivation of Notch1 and/or Notch2 in T cells. Systemic targeting of Notch2 alone was safe and conferred therapeutic benefits. Altogether, Notch ligands and receptors regulate key pathogenic steps in cGVHD and emerge as novel druggable targets to prevent or treat different forms of cGVHD.

Dietary supplementation with blueberry partially restores T-cell-mediated function in high-fat-diet-induced obese mice.

Blueberry, rich in antioxidant and anti-inflammatory phytochemicals, has been demonstrated to lower inflammatory status in adipose induced by high-fat diet (HFD) and obesity. The effect of blueberry on systemic immune functions has not been examined. C57BL/6 mice were randomised to one of three diets - low-fat diet (LFD), HFD and HFD plus 4 % (w/w) blueberry (HFD+B) - for 8 or 12 weeks. Ex vivo T-cell mitogens (concanavalin A (Con A); phytohaemagglutinin), T-cell antibody (anti-CD3; anti-CD3/CD28)-stimulated T-cell proliferation and cytokine production were assessed. After 8 weeks, both HFD groups weighed more (>4 g) than the LFD group; after 12 weeks, HFD+B-fed mice weighed more (>6 g) and had 41 % more adipose tissue than HFD-fed mice (P<0·05). After 12 weeks, T-cell proliferation was less in both HFD groups, compared with the LFD group. HFD-associated decrements in T-cell proliferation were partially (10-50 %) prevented by blueberry supplementation. At 12 weeks, splenocytes from HFD mice, but not from HFD+B mice, produced 51 % less IL-4 (CD3/CD28) and 57 % less interferon-γ (Con A) compared with splenocytes from LFD mice (P<0·05). In response to lipopolysaccharide challenge, splenocytes from both HFD groups produced 24-30 % less IL-6 and 27-33 % less TNF-α compared with splenocytes from LFD mice (P<0·05), indicating impaired acute innate immune response. By demonstrating deleterious impacts of HFD feeding on T-cell proliferation and splenocyte immune responses, our results provide insights into how HFD/obesity can disrupt systemic immune function. The protective effects of blueberry suggest that dietary blueberry can buttress T-cell and systemic immune function against HFD-obesity-associated insults.