Th1-type Cytokine Profile Research Articles

The link between immune thrombocytopenia and the cytokine profile: a bridge to new therapeutical targets

Immune thrombocytopenia (ITP) manifests as depleted platelet reserves, primarily due to the immune-mediated destruction of platelets. The pathogenesis of ITP is complex and involves dysregulation of the immune system. This review aimed to summarize the current knowledge of the cytokine profile in ITP and its potential implications for diagnosis, treatment, and prognosis. Several studies have reported that ITP patients have an altered cytokine profile from that of healthy individuals. Specifically, there is evidence of an imbalance of pro-inflammatory (interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ) and anti-inflammatory cytokines (IL-10, TGF-β). The cytokine profile in ITP appears to be heterogeneous, with different patterns observed in different subsets of patients. For example, some studies have reported a Th1-type cytokine profile, characterized by elevated levels of IFN-γ and TNF-α, while others have reported a Th2-type cytokine profile, characterized by elevated levels of IL-4 and IL-10. There is also evidence of a shift from a Th1 to a Th2 cytokine profile in some patients over time. The cytokine profile in ITP may have important implications for diagnosis, treatment, and prognosis. Targeting specific cytokines or cytokine pathways may also represent a promising therapeutic approach for ITP. Further studies are needed to better understand the heterogeneity of the cytokine profile in ITP and its potential implications for clinical management.

Epi-P-04 - Cutaneous T-cell lymphoma (CTCL) exacerbation after viral vector COVID-19 vaccination

Introduction:We are living an ongoing global COVID-19 pandemic associated with a considerable number of fatal cases worldwide. Cancer patients seem to exhibit exacerbated conditions and higher mortality rates. Vaccines are a promising solution to minimize the problem amongst cancer patients but there are limitations to be considered.Case summary:Herein, we present two cutaneous T-cell lymphoma (CTCL) cases which were in long-term remission and experienced a flare after immunization with a viral vector COVID-19 vaccine (Vaxzevria, Oxford/AstraZeneca). The first case was a 60-year-old male with early-stage (T1a) folliculotropic mycosis fungoides (MF) clinically presented as alopecia areata-like lesions. The patient was in clinical remission during the last two years, maintaining a T1aN0M0 stage with only a single, stable alopecic patch on the scalp. Four weeks after the first COVID-19 vaccine dose, a minor lichenoid induration was observed in the periphery of the lesion, while a week after the second dose, small nodules surrounding the lesion were also noted. Histology confirmed the diagnosis of CD30+ Large cell transformation (LCT) of tumor-stage MF. The second case was a 73-year-old female with early-stage MF (T1a/IA) and Lymphomatoid papulosis (LyP). Clinically, she presented with pruritic erythematous patches and nodules on the trunk and upper legs. The patient was successfully treated with psoralen plus ultraviolet A (PUVA) phototherapy remaining in clinical remission for six years. After vaccination, she developed multiple erythematous papules and nodules on the trunk and limbs. A flare of LyP was confirmed from the pathology, which correlated to her clinical picture.Discussion:These cases raise the question of whether and via which pathways the vaccine might induce disease exacerbation of both MF and LyP. According to the literature, the education of T (CD4+ and CD8+) and B cells against SARS-CoV-2 spike protein appears to be the main strategy for COVID-19 vaccine production. Both cancers and viral infections can provide a chronic and persistent antigenic load, leading to up-regulated programmed cell death protein 1 (PD1) expression and ultimately T cell exhaustion. CD30 is known to be expressed in a small subset of activated T and B cells, as well as a variety of lymphoid neoplasms. Initial studies showed that CD30 expression on lymphocytes could be induced via in vitro antigenic stimulation by mitogens or viruses. CD30 expression also appears to be higher on CD4+ and CD8+ T cells producing a Th2-type cytokine profile. In our cases, the viral vector-based vaccines used do not contain a live virus but specific parts of the coronavirus attached to adenovirus, which can also stimulate an anti-viral immune response.Conclusion:The reported cases suggest that disease flare-ups may be associated with overproduction and exhaustion of CD4+/CD8+ T cells expressing CD30 after stimulation by the adenovirus. Expression of CD30, which can be a marker for disease progression, was high in biopsy samples of our patients.

IL-4 and IL-17 Are Required for House Dust Mite-Driven Airway Hyperresponsiveness in Autoimmune Diabetes-Prone Non-Obese Diabetic Mice.

Allergic asthma is characterized by airway inflammation with a Th2-type cytokine profile, hyper-IgE production, mucus hypersecretion, and airway hyperreactivity (AHR). It is increasingly recognized that asthma is a heterogeneous disease implicating complex immune mechanisms resulting in distinct endotypes observed in patients. In this study, we showed that non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, undergo more severe allergic asthma airway inflammation and AHR than pro-Th2 BALB/c mice upon house dust mite (HDM) sensitization and challenge. The use of IL-4-deficient NOD mice and the in vivo neutralization of IL-17 demonstrated that both IL-4 and IL-17 are responsible by the exacerbated airway inflammation and AHR observed in NOD mice. Overall, our findings indicate that autoimmune diabetes-prone NOD mice might become useful as a new HDM-induced asthma model to elucidate allergic dysimmune mechanisms involving Th2 and Th17 responses that could better mimic some asthmatic endoytpes.

Prolactin Induces IL-2 Associated TRAIL Expression on Natural Killer Cells from Chronic Hepatitis C Patients In vivo and In vitro.

Natural killer cells (NKC) are a major component of the innate immune response to HCV, mediating their effects through TRAIL and IFN-γ. However, their function is diminished in chronic HCV patients (HCVp). Prolactin is an immunomodulatory hormone capable of activating NKC. The study aims to explore if hyperprolactinemia can activate NKC in HCVp. We treated twelve chronic HCVp (confidence level =95%, power =80%) for 15 days with Levosulpiride plus Cimetidine to induce mild hyperprolactinemia. Before and after treatment, we determined TRAIL and NKG2D expression on peripheral blood NKC, along with cytokine profiles, viral loads and liver function. We also evaluated in vitro effects of prolactin and/or IL-2 on NKC TRAIL or NKG2D expression and IFN-γ levels on cultured blood mononuclear cells from 8 HCVp and 7 healthy controls. The treatment induced mild hyperprolactinemia and increased TRAIL expression on NKC as well as the secretion of IL-1ra, IL-2, PDGF and IFN-γ. Viral loads decreased in six HCVp. IL-2 and TRAIL together explained the viral load decrease. In vitro, prolactin plus IL-2 synergized to increase TRAIL and NKG2D expression on NKC from HCVp but not in controls. Levosulpiride/Cimetidine treatment induced mild hyperprolactinaemia that was associated with NKC activation and Th1-type cytokine profile. Also, an increase in TRAIL and IL-2 was associated with viral load decrease. This treatment could potentially be used to reactivate NKC in HCVp.

Th1/Th2-type cytokine profile in C57 black mice inoculated with live Echinococcus granulosus protoscolices.

Cystic echinococcosis (CE) is a widespread parasitic disease caused by infection with the larval stage of a tapeworm, Echinococcus granulosus. The immune response to hydatid cyst in intermediate hosts is a complex and contradictory issue. It is suggested that a Th2 response would favor the establishment of the parasite, whereas a Th1 response would be lethal for the parasite. Thus, the aim of the present study was to evaluate the levels of IL2, TNFα, and IFNγ as T helper (Th)1-type cytokines, IL4 as a Th2-type cytokine, and total IgG in C57/black mice inoculated with E. granulosus protoscoleces (PSCs). In this experimental study, six C57/black mice were intraperitoneally inoculated with live E. granulosus PSCs and a control group consist of six C57/black mice received normal saline. The quantitative concentrations of IL2, TNFα, IFNγ, and IL4 were determined in the first, second, fourth, eighth and 12th-week post inoculation in both case and control groups. The results showed that at the early post-infection phase (3-4 weeks) the Th1-type cytokine profile was predominant, however the shift to Th2-type cytokine took place in the 4th week. Based on the results of the present study, we can suggest that the shift from Th1 to Th2 reactivity may be associated with persistent of the disease because Th2 reactivity may be less effective than Th1 reactivity in countering the parasite.

Mining the Proteome of Leishmania donovani for the Development of Novel MHC Class I Restricted Epitope for the Control of Visceral Leishmaniasis.

Although, the precise host defence mechanism(s) is not completely understood, T cell-mediated immune responses is believed to play a pivotal role in controlling parasite infection. Here we target the stage dependent over expressed gene. Here, the consensus based computational approach was adopted for the screening of potential major histocompatibility complex class I restricted epitopes. Based on the computational analysis and previously published report, a set 19 antigenic proteins derived from Leishmania donovani were screened for further characterization as vaccine candidates. A total of 49 epitopes were predicted, which revealed a comprehensive binding affinity to the 40 different MHC class I supertypes. Based on the population coverage and HLA cross presentation, nine highly promiscuous epitopes such as LTYDDVWTV (P1), FLFPQRTAL(P2), FLFSNGAVV (P3), YIYNFGIRV (P4), YMTAAFAAL (P5), KLLRPFAPL (P6), FMLGWIVTI (P7), SLFERNKRV (P8), and SVWNRIFTL (P9) which have either a high or an intermediate TAP binding affinity were selected for further analysis. Theoretical population coverage analysis of polytope vaccine (P1-P9) revealed more than 92% population. Stimulation with the cocktail of peptide revealed a proliferative CD8+ T cell response and increased IFN-γ production. An upregulated NF-κB activity is thought to be play a pivotal role in T cell proliferation against the selected peptide. The Th1-type cytokine profile (presence of IFN-γ and absence of IL-10) suggests the potentiality of the cocktail of epitope as a subunit vaccine against leishmaniasis. However, the efficiency of these epitopes to trigger other Th1 cytokines and chemokines in a humanized mice model could explore its plausibility as a vaccine candidate. J. Cell. Biochem. 119: 378-391, 2018. © 2017 Wiley Periodicals, Inc.

How pregnancy can affect autoimmune diseases progression?

Autoimmune disorders are characterized by tissue damage, caused by self-reactivity of different effectors mechanisms of the immune system, namely antibodies and T cells. Their occurrence may be associated with genetic and/or environmental predisposition and to some extent, have implications for fertility and obstetrics. The relationship between autoimmunity and reproduction is bidirectional. This review only addresses the impact of pregnancy on autoimmune diseases and not the influence of autoimmunity on pregnancy development. Th17/Th1-type cells are aggressive and pathogenic in many autoimmune disorders and inflammatory diseases. The immunology of pregnancy underlies the role of Th2-type cytokines to maintain the tolerance of the mother towards the fetal semi-allograft. Non-specific factors, including hormonal changes, favor a switch to Th2-type cytokine profile. In pregnancy Th2, Th17/Th2 and Treg cells accumulate in the decidua but may also be present in the mother’s circulation and can regulate autoimmune responses influencing the progression of autoimmune diseases.

Immunomodulation of Lactobacillus rhamnosus GG (LGG)-derived soluble factors on antigen-presenting cells of healthy blood donors

Lactobacillus rhamnosus GG (LGG) cells have been shown to promote type-1 immune responsiveness; however knowledge of immunomodulation of soluble factors secreted by LGG is limited. This is the first study to investigate whether LGG soluble factors promote a comparable immune responsiveness as the bacterial cells. Both treatments − LGG conditioned medium with (CM + LGG) or without (CM) LGG cells, in this study increased expression of several toll-like receptors (TLRs) in all studied cell types and antigen presentation-associated receptor HLA-DR in macrophages and “intermediate” monocytes; but decreased that of activation markers on monocytes and macrophages and production of IL-10, IL-12 and TNFα in macrophages. In co-culture with mononuclear cells, CM increased Th1-type cytokine profile but not as pronounced as CM + LGG. This study suggests that LGG soluble factors exert similar immunomodulatory effects as the intact cells, but cells may be required for optimal type-1 immune responsiveness polarizing capacity of this probiotic strain.

Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury.

Interleukin-33 (IL-33) is a member of the interleukin-1 cytokine family and highly expressed in the naïve mouse brain and spinal cord. Despite the fact that IL-33 is known to be inducible by various inflammatory stimuli, its cellular localization in the central nervous system and role in pathological conditions is controversial. Administration of recombinant IL-33 has been shown to attenuate experimental autoimmune encephalomyelitis progression in one study, yet contradictory reports also exist. Here we investigated for the first time the pattern of IL-33 expression in the contused mouse spinal cord and demonstrated that after spinal cord injury (SCI) IL-33 was up-regulated and exhibited a nuclear localization predominantly in astrocytes. Importantly, we found that treatment with recombinant IL-33 alleviated secondary damage by significantly decreasing tissue loss, demyelination and astrogliosis in the contused mouse spinal cord, resulting in dramatically improved functional recovery. We identified both central and peripheral mechanisms of IL-33 action. In spinal cord, IL-33 treatment reduced the expression of pro-inflammatory tumor necrosis factor-alpha and promoted the activation of anti-inflammatory arginase-1 positive M2 microglia/macrophages, which chronically persisted in the injured spinal cord for up to at least 42 days after the treatment. In addition, IL-33 treatment showed a tendency towards reduced T-cell infiltration into the spinal cord. In the periphery, IL-33 treatment induced a shift towards the Th2 type cytokine profile and reduced the percentage and absolute number of cytotoxic, tumor necrosis factor-alpha expressing CD4+ cells in the spleen. Additionally, IL-33 treatment increased expression of T-regulatory cell marker FoxP3 and reduced expression of M1 marker iNOS in the spleen. Taken together, these results provide the first evidence that IL-33 administration is beneficial after CNS trauma. Treatment with IL33 may offer a novel therapeutic strategy for patients with acute contusion SCI.

Immunosuppression in cervical cancer with special reference to arginase activity

IntroductionCervical cancer is characterized by an immunosuppressive microenvironment and a Th2-type cytokine profile. Expression of arginase (ASE), the enzyme that converts l-arginine into l-ornithine and urea, is stimulated by Th2-type cytokines. ObjectiveTo assess the association of ASE activity and l-Arg metabolism products with cervical cancer. MethodsSera of 87 and 41 women with histologically confirmed by colposcopy-directed biopsy SCC and CIN3 respectively and 79 with normal cytology or Low-Grade Squamous Intraepithelial Lesion (LSIL), were evaluated. Cytokines were measured using Milliplex Human cytokine/chemokine kit. Arginase (ASE) activity was determined using an enzymatic assay. Levels of l-arginine, l-ornithine, putrescine and spermine were determined by HPLC. ResultsSignificantly higher levels of ASE activity were observed in women with CIN3 (age-adjusted OR: 24.3; 95%CI: 3.82–155) and SCC (AOR: 9.8; 95%CI: 2.34–40.8). As expected, possibly due to high levels of ASE activity, higher levels of l-Arg were negatively associated with CIN3 (AOR: 0.03; 95%CI: 0.004–0.19) and SSC (AOR: 0.06; 95%CI: 0.02–0.24). Consistent with the role of ASE in the conversion of l-arginine to l-ornithine and polyamine production therefrom, women with cervical cancer had higher levels of spermine and putrescine. A correlation analysis revealed a significant albeit weak relationship between high levels of IL-10 and high levels of ASE (Pearson r=0.32, p-value=0.003) in women with cervical cancer. ConclusionThis study indicates that ASE activity and l-Arg degradation mechanisms of immunosuppression are present in cervical cancer. The results foster research in the design of possible strategies to inhibit ASE activity for therapy of cervical cancer.

Differential Role of Th1 and Th2 Cytokines in Autotoxicity Driven by CD19-Specific Second-Generation Chimeric Antigen Receptor T Cells in a Mouse Model

T cells engrafted with chimeric AgRs (CAR) are showing exciting potential for targeting B cell malignancies in early-phase clinical trials. To determine whether the second-generation CAR was essential for optimal antitumor activity, two CD28-based CAR constructs targeting CD19 were tested for their ability to redirect mouse T cell function against established B cell lymphoma in a BALB/c syngeneic model system. T cells armed with either CAR eliminated A20 B cell lymphoma in vivo; however, one construct induced a T cell dose-dependent acute toxicity associated with a raised serum Th1 type cytokine profile on transfer into preconditioned mice. Moreover, a chronic toxicity manifested as granuloma-like formation in spleen, liver, and lymph nodes was observed in animals receiving T cells bearing either CD28 CAR, albeit with different kinetics dependent upon the specific receptor used. This phenotype was associated with an expansion of CD4+ CAR+ T cells and CD11b+ Gr-1(+) myeloid cells and increased serum Th2-type cytokines, including IL-10 and IL-13. Mouse T cells engrafted with a first-generation CAR failed to develop such autotoxicity, whereas toxicity was not apparent when T cells bearing the same receptors were transferred into C57BL/6 or C3H animals. In summary, the adoptive transfer of second-generation CD19-specific CAR T cells can result in a cell dose-dependent acute toxicity, whereas the prolonged secretion of high levels of Th2 cytokines from these CAR T cells in vivo drives a granulomatous reaction resulting in chronic toxicity. Strategies that prevent a prolonged Th2-cytokine biased CAR T cell response are clearly warranted.

The relationship between the antitumor effect of the IL-12 gene therapy and the expression of Th1 cytokines in an HPV16-positive murine tumor model.

Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16-positive murine tumor model and the association with the IL-12's antitumor effect. Methods. Mice were injected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-β1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1. Conclusions. The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer.

Pathogenesis of Chagas Cardiomyopathy: Role of Inflammation and Oxidative Stress

Described by the Brazilian scientist Carlos Chagas more than a century ago, Chagas disease (ChD) currently affects 8 to 10 million persons and causes more than 10 000 deaths each year.[1][1] Originally confined to Latin American countries, ChD had been considered an exotic disease and received less

Peripheral Blood Mononuclear Cells of Mycetoma Patients React Differently to Madurella mycetomatis Antigens than Healthy Endemic Controls

Peripheral Blood Mononuclear Cells of Mycetoma Patients React Differently to Madurella mycetomatis Antigens than Healthy Endemic Controls

Abstract 449: Progesterone-induced immunosuppression thwarts immunosurveillance to tumors and promotes lung metastasis in a breast cancer model.

Abstract Exposure to sexual hormones is one of the strongest risk factors for breast cancer. Increased risk is entwined with a greater number of reproductive cycles and the use of progestin-containing hormone replacement therapy. In addition, the importance of progesterone in dampening immune response was illustrated in several models of infection and pregnancy. Based on the tolerogenic properties of progesterone (Pg) and its promoting role in breast cancer, in this work we investigated whether progesterone may thwart immunosurveillance and promote tumor metastasis by fostering an immunosuppressive microenvironment in breast cancer. Exogenously added Pg: (10−8M) or its synthetic analogue medroxiprogesterone acetate (MPA: 10−8M) induced the expression of the immunosuppressive protein galectin-1 (Gal1) in the hormone-dependent human breast cancer cell lines T47D and MCF-7 and in the mouse mammary adenocarcinoma C4HD. This effect was abrogated by pre-treatment with RU486 (10−7M) indicating that the progesterone receptor (PR) was involved. Interestingly, in vitro MPA treatment of human PBMC or mouse splenocytes controlled the expansion of regulatory T cells (Tregs) (CD4+CD25+Foxp3+) and skewed the balance toward a Th2-type cytokine profile. Furthermore, differentiation from naive T-cells to Tregs cells was enhanced in the presence of MPA, IL-2 and suboptimal concentrations of TGF-β. In addition, in vivo treatment with MPA (15mg 30-day release depot) of C4HD tumor-bearing mice increased both the expression of Gal1 and the frequency of Treg cells in tumor-draining lymph nodes and the tumor microenvironment. While the increase in Treg cell frequency was associated with an effect on Treg cell SMAD4 expression that potentiates TGF-β signalling, homing of Treg cells to tumor sites was supported through the induction of tumor-derived CCL22. Finally, we used a PR negative breast tumor model (4T1) to evaluate the effect of MPA on the tumor microenvironment and the consequences of this effect on tumor progression. In vivo treatment with MPA promoted lung metastasis by inducing an invasive phenotype in breast cancer cells. Co-culture of Treg cells differentiated in vivo in the presence of MPA with 4T1 cells promoted its invasive activity and modulate several genes associated with EMT, including SNAIL. In summary, these results demonstrate that progesterone hierarchically fosters an immunosuppressive tumor microenvironment that promotes metastasis by co-ordinately regulating Gal1 expression, stimulating the TGF-β pathway and augmenting the frequency of Treg cells. Our findings provide new insights into the role of progesterone in breast cancer as a crucial promoter of tumor-immune escape. Citation Format: Mariana Salatino, Tomás Dalotto, Diego O. Croci, Santiago P. Mendez Huergo, Sebastian L. Dergan Dylon, Juan P. Cerliani, Marta A. Toscano, Gabriel A. Rabinovich. Progesterone-induced immunosuppression thwarts immunosurveillance to tumors and promotes lung metastasis in a breast cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 449. doi:10.1158/1538-7445.AM2013-449

OT-II TCR transgenic mice fail to produce anti-ovalbumin antibodies upon vaccination

OT-II mice were evaluated as a transgenic strain-specific model to assess T-cell help for B-cell responses. OT-II CD4+ T-cells express transgenic OVA-specific αβ-TCRs. This high frequency of antigen-specific helper T-lymphocytes may augment induction of B-cell responses. Unexpectedly, OT-II mice did not produce OVA-specific antibodies after intranasal immunization. However, B-cells expressed normal antigen-presenting function in vitro for activation of OVA-specific T-cell responses. These OT-II T-cell responses produced a Th1-type cytokine profile with significantly reduced Th2 or Th17 responses. These data suggest that OT-II B-cells are not defective as APCs, however, downstream antibody responses are abrogated in this transgenic strain.

Modulation of phenotypic and functional maturation of dendritic cells by intestinal bacteria and gliadin: relevance for celiac disease

DC maturation and functions are influenced by microbial and environmental stimuli, which could contribute to immune dysfunction. Here, we have investigated the role of enterobacteria (Escherichia coli CBL2 and Shigella CBD8) isolated from CD patients, bifidobacteria (Bifidobacterium longum CECT 7347 and Bifidobacterium bifidum CECT 7365), and gliadins on phenotypic and functional features of MDDCs and in coculture with Caco-2 cells. The ultimate goal of our study is to understand the roles played by specific components of the gut microbiota in CD. Enterobacteria induced marked alterations in MDDC morphology, inducing podosome dissolution and dendrites, and activated MDDC adhesion and spreading. Enterobacteria also induced inflammatory cytokine production (IFN-γ, TNF-α, and IL-12), partially resembling the gliadin-induced Th1-type cytokine profile. B. longum CECT 7347 and B. bifidum CECT 7365 induced minor MDDC morphological changes and activated adhesion and spreading and inflammatory cytokine production to a lesser extent compared with enterobacteria. B. longum CECT 7347 also induced lower CD86 and CD40 expression on MDDCs than the two enterobacteria. The aforementioned bifidobacterial strain also reduced gliadin-induced IFN-γ production and increased IL-10 secretion when both stimuli were combined. Similar trends were detected for MDDCs cocultured with Caco-2 cells. B. longum CECT 7347 reversed the gliadin-reduced ZO-1 expression in Caco-2 cells. Thus, our results suggest that specific components of the gut microbiota may influence phenotypic and functional maturation of DCs differently and their interactions with epithelial cells. This could ultimately define the role of DCs in CD progression.

Regulatory role of miR‐2909 in cell‐mediated immune response

Keeping in view the micromanagement of immune response by micro RNAs, the present study was directed to explore the role of miR-2909 in the differentiation and maturation of T-lymphocytes within the population of normal human peripheral blood mononuclear cells maintained in in vitro culture. The results of such a study revealed that miR-2909 had the inherent capacity to significantly increase Treg (CD4+CD25+Foxp3+) cell population and dominant Th1-type cytokine (especially with decrease in IL-4 level and higher levels of INF-β and INF-γ) profile. Based upon these results, we propose that miR-2909 may modulate native immunity in general and help in providing protective immunity against viral infections in particular.

Preclinical efficacy of sodium narcistatin to reduce inflammation and joint destruction in rats with adjuvant-induced arthritis

Current therapies for the treatment of rheumatoid arthritis (RA) do not work for all patients, can lose efficacy over time, and can have significant side effects. The discovery of new, effective therapies for RA remains an unmet medical need. The Amaryllidaceae isocarbostyril narciclasine was previously shown to prophylactically reduce paw swelling in rats with adjuvant-induced arthritis (AA). In this study, the efficacy of sodium narcistatin (SNS), a water-soluble cyclic phosphate pro-drug of narciclasine, was assessed in AA rats for anti-inflammatory and bone-sparing properties after disease onset. AA rats were given daily intraperitoneal injections of SNS (1.75, 3.5, or 5 mg/kg/day, in 500 μl sterile endotoxin-free saline) or saline from disease onset through severe disease stages. Footpad widths and radiographic scoring were used as indicators of inflammation and joint destruction, respectively. Ex vivo cytokine production by peripheral blood mononuclear cells (PMBC), splenocytes, and draining lymph node (DLN) cells were determined using ELISAs. SNS treatment dose-dependently reduced joint inflammation (~70%) and bone loss (~50%) compared with AA controls. SNS treatment also reduced spleen weight (without affecting body weight), pro-inflammatory cytokine production by PMBC, splenocytes, and DLN cells, and site-dependently altered T-helper (Th)1-/Th2-type and anti-inflammatory cytokine profiles. SNS dramatically reduces inflammation and has bone-sparing properties, possibly by reducing immune cell pro-inflammatory cytokine production. Our findings support the development of SNS as a therapeutic for RA.

Activation of Toll-like receptor 9 attenuates unilateral ureteral obstruction-induced renal fibrosis

to study whether activation of TLR9 by CpG-ODN would protect against and/or reverse renal fibrosis. animals were treated with CpG-ODN before or after undergoing a unilateral ureteral obstruction (UUO) procedure. The interstitial fibrotic lesions of obstructed kidneys were evaluated using histology and immunohistostaining. The Th2-type cytokine profile and the expression and activity of sma and mad related protein (Smad)3, signal transducers and activators of transcription (Stat)3, extracellular regulated protein kinases (ERK), and p38 kinase were determined using RT-PCR or Western blot. the obstructed kidneys displayed a significant increase in interstitial fibrosis, an infiltration of macrophages in the interstitium, and an enhanced expression of Th2 cytokines. Prophylactic application of CpG-ODN (40 microg/kg every 3 days from 2 h before UUO until the 14th day after UUO) suppressed the expression of α-smooth muscle actin, collagen deposition, and hydroxyproline in the UUO kidneys of rats. Moreover, CpG-ODN not only decreased the infiltration of macrophages but also inhibited the expression of chemokines CCL2 and CCL5, the Th2 cytokine IL-13, and the profibrogenic cytokines transforming growth factor (TGF)-β1 and plasminogen activator inhibitor (PAI)-1 in UUO kidneys of rats. Importantly, therapeutic administration of CpG-ODN (10 microg/mouse, ip, every 3 days from the 4th day to 21st day after UUO) reversed the established renal fibrosis, which was accompanied by significant reductions in the activity of ERK, Smad3, and Stat3 and an increase in the activity of p38 kinase. the activation of TLR9 by CpG-ODN attenuates UUO-induced renal fibrosis by reversing an immunosuppressive microenvironment in the fibrotic renal tissue, which might be a novel therapeutic strategy against fibrotic renal diseases.