Pleiotropic Immunomodulatory Effects Research Articles

New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3.

Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.

Comprehensive analysis of m6A regulators characterized by the immune microenvironment in Duchenne muscular dystrophy

BackgroundDuchenne muscular dystrophy (DMD) is an X-linked, incurable, degenerative neuromuscular disease that is exacerbated by secondary inflammation. N6-methyladenosine (m6A), the most common base modification of RNA, has pleiotropic immunomodulatory effects in many diseases. However, the role of m6A modification in the immune microenvironment of DMD remains elusive.MethodsOur study retrospectively analyzed the expression data of 56 muscle tissues from DMD patients and 26 from non-muscular dystrophy individuals. Based on single sample gene set enrichment analysis, immune cells infiltration was identified and the result was validated by flow cytometry analysis and immunohistochemical staining. Then, we described the features of genetic variation in 26 m6A regulators and explored their relationship with the immune mircoenvironment of DMD patients through a series of bioinformatical analysis. At last, we determined subtypes of DMD patients by unsupervised clustering analysis and characterized the molecular and immune characteristics in different subgroups.ResultsDMD patients have a sophisticated immune microenvironment that is significantly different from non-DMD controls. Numerous m6A regulators were aberrantly expressed in the muscle tissues of DMD and inversely related to most muscle-infiltrating immune cell types and immune response-related signaling pathways. A diagnostic model involving seven m6A regulators was established using LASSO. Furthermore, we determined three m6A modification patterns (cluster A/B/C) with distinct immune microenvironmental characteristics.ConclusionIn summary, our study demonstrated that m6A regulators are intimately linked to the immune microenvironment of muscle tissues in DMD. These findings may facilitate a better understanding of the immunomodulatory mechanisms in DMD and provide novel strategies for the treatment.

A bioinspired and high-strengthed hydrogel for regeneration of perforated temporomandibular joint disc: Construction and pleiotropic immunomodulatory effects.

Due to the lack of an ideal material for TMJ (temporomandibular joint) disc perforation and local inflammation interfering with tissue regeneration, a functional TGI/HA-CS (tilapia type I gelatin/hyaluronic acid-chondroitin sulfate) double network hydrogel was constructed in this paper. It was not only multiply bionic in its composition, structure and mechanical strength, but also endowed with the ability to immunomodulate microenvironment and simultaneously induce in situ repair of defected TMJ discs. On the one hand, it inhibited inflammatory effects of inflammasome in macrophages, reduced the extracellular matrix (ECM)-degrading enzymes secreted by chondrocytes, reversed the local inflammatory state, promoted the proliferation of TMJ disc cells and induced fibrochondrogenic differentiation of synovium-derived mesenchymal stem cells (SMSCs). On the other hand, it gave an impetus to repairing a relatively-large (6mm-sized) defect in mini pigs' TMJ discs in a rapid and high-quality manner, which suggested a promising clinical application.

Differential impact of environmental factors on systemic and localized autoimmunity.

The influence of environmental factors on the development of autoimmune disease is being broadly investigated to better understand the multifactorial nature of autoimmune pathogenesis and to identify potential areas of intervention. Areas of particular interest include the influence of lifestyle, nutrition, and vitamin deficiencies on autoimmunity and chronic inflammation. In this review, we discuss how particular lifestyles and dietary patterns may contribute to or modulate autoimmunity. We explored this concept through a spectrum of several autoimmune diseases including Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE) and Alopecia Areata (AA) affecting the central nervous system, whole body, and the hair follicles, respectively. A clear commonality between the autoimmune conditions of interest here is low Vitamin D, a well-researched hormone in the context of autoimmunity with pleiotropic immunomodulatory and anti-inflammatory effects. While low levels are often correlated with disease activity and progression in MS and AA, the relationship is less clear in SLE. Despite strong associations with autoimmunity, we lack conclusive evidence which elucidates its role in contributing to pathogenesis or simply as a result of chronic inflammation. In a similar vein, other vitamins impacting the development and course of these diseases are explored in this review, and overall diet and lifestyle. Recent work exploring the effects of dietary interventions on MS showed that a balanced diet was linked to improvement in clinical parameters, comorbid conditions, and overall quality of life for patients. In patients with MS, SLE and AA, certain diets and supplements are linked to lower incidence and improved symptoms. Conversely, obesity during adolescence was linked with higher incidence of MS while in SLE it was associated with organ damage. Autoimmunity is thought to emerge from the complex interplay between environmental factors and genetic background. Although the scope of this review focuses on environmental factors, it is imperative to elaborate the interaction between genetic susceptibility and environment due to the multifactorial origin of these disease. Here, we offer a comprehensive review about the influence of recent environmental and lifestyle factors on these autoimmune diseases and potential translation into therapeutic interventions.

Beta-blockers in patients with liver cirrhosis: Pragmatism or perfection?

With increasing decompensation, hyperdynamic circulatory disturbance occurs in liver cirrhosis despite activation of vasoconstrictors. Here, the concept of a therapy with non-selective beta-blockers was established decades ago. They lower elevated portal pressure, protect against variceal hemorrhage, and may also have pleiotropic immunomodulatory effects. Recently, the beneficial effect of carvedilol, which blocks alpha and beta receptors, has been highlighted. Carvedilol leads to "biased-signaling" via recruitment of beta-arrestin. This effect and its consequences have not been sufficiently investigated in patients with liver cirrhosis. Also, a number of questions remain open regarding the expression of beta-receptors and its intracellular signaling and the respective consequences in the intra- and extrahepatic tissue compartments. Despite the undisputed role of non-selective beta-blockers in the treatment of liver cirrhosis, we still can improve the knowledge as to when and how beta-blockers should be used in which patients.

Abstract 1298: An allosteric SHP2 inhibitor RMC-4550 induces immunogenicity in pancreatic adenocarcinoma (PDA) and enhances the cytotoxicity of CD8+ effector T cells

Abstract Background: Immunotherapy is ineffective in MSS PDA. Src homology-2 domain-containing protein tyrosine phosphatase (SHP2) mediates multiple immunosuppressive mechanisms in tumor cells and tumor microenvironment (TME). SHP2 plays an important role in oncogenic RAS signaling, the hallmark of PDA, that reduces tumor MHC-I expression and promotes immunotherapy resistance by stabilizing PD-L1. It modulates multiple T cell inhibitory pathways including PD-1 signaling via dephosphorylation of ITIM and ITSM. We hypothesize that SHP2i will increase anti-PDA immunity and help overcome resistance to PD-1 blockade when combined with gemcitabine, an active cytotoxic agent against PDA with pleiotropic immunomodulatory effects on its TME. Methods: Mouse KPC-luc cells (derived from LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre GEMM) and human RAS mutant PDA cells were treated in vitro with various concentrations of RMC-4550, a potent and selective allosteric SHP2 inhibitor, to test its cytotoxicity using cell viability assay and measure tumor MHC-I and PD-L1 expression upon IFNy stimulation. Human PBMC were used for T cells in vitro experiments to examine the effect of RMC-4550 on T-cell proliferation inhibition by PD-1 ligand (PD-L1) stimulation. In vivo antitumor activity of RMC-4550 combined with αPD-1 or with αPD-1 and gemcitabine was investigated in a syngeneic KPC-luc subcutaneous model. After treatment, tumors and spleens were harvested, digested to single cell suspensions, and immune infiltrates quantified using flow cytometry. Results: In vitro, there was no direct cytotoxicity of RMC-4550 on mouse KPC or human PDAC cells and no additive effect to gemcitabine. SHP2i increases IFNy mediated upregulation of MHC-I, and downregulates PD-L1 in both KPC mouse and MiaPaca-2 human PDA cells. In vitro, RMC-4550 reverses the PD-L1-mediated inhibition of T cell proliferation. In vivo, SHP2i with αPD-1 has a combinatorial effect on tumor growth inhibition. Gemcitabine seems to augment this effect. Preliminary data revealed no significant changes in number of immune cells in treatment groups when compared to the control group while an increase in proportion of Granzyme B+ CD8+ T cells and Ki-67+ CD8+ T cells in spleen and a decrease in proportion of PD1+ CD8+ T cells in TME was observed in RMC-4550 plus αPD-1 plus gemcitabine group compared to the control group. Conclusion: SHP2i RMC-4550 and αPD-1 combination induces significant anti-tumor benefit in an in vivo PDA tumor model, an effect that is enhanced by adding gemcitabine. SHP2i may promote antitumor immunity in part by increasing MHC-I expression and reducing PD-L1 expression in RAS mutant PDA cells. PD-L1 mediated suppression of T cell proliferation was overcome by RMC-4550. In vivo, RMC-4550 may potentiate anti-PD-1 therapy by enhancing cytotoxicity of CD8+ effector T cells. Citation Format: Agnieszka Looney, Uma Giri, Yezi Zhu, Alex Somma, Nisha Holay, Milad Soleimani, Heta Gandhi, Anna Capasso, Jeanne Kowalski, William Matsui, Carla Van Berg, S Gail Eckhardt, Todd Triplett, Kyaw Lwin Aung. An allosteric SHP2 inhibitor RMC-4550 induces immunogenicity in pancreatic adenocarcinoma (PDA) and enhances the cytotoxicity of CD8+ effector T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1298.

Antibiotics as immunomodulators: a potential pharmacologic approach for ARDS treatment.

First described in the mid-1960s, acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure with an overall mortality rate of approximately 40%. Despite significant advances in the understanding and treatment of ARDS, no substantive pharmacologic therapy has proven to be beneficial, and current management continues to be primarily supportive. Beyond their antibacterial activity, several antibiotics such as macrolides and tetracyclines exert pleiotropic immunomodulatory effects that might be able to rectify the dysregulated inflammatory response present in patients with ARDS. This review aims to provide an overview of preclinical and clinical studies that describe the immunomodulatory effects of antibiotics in ARDS. Moreover, the underlying mechanisms of their immunomodulatory properties will be discussed. Further studies are necessary to investigate their full therapeutic potential and to identify ARDS phenotypes which are most likely to benefit from their immunomodulatory effects.

Hepatoprotective properties of glycyrrhizic acid

The review is devoted to the problem of treatment of non-alcoholic fatty liver disease, which is the most common pathology of the hepato-biliary system worldwide and is characterized by an increasing frequency, including of more severe forms. A wide range of pathogenetic relationships of non-alcoholic fatty liver disease with diseases of other organ systems, primarily with diseases of the cardiovascular system, type 2 diabetes mellitus, chronic kidney disease and diseases of the biliary tract, is presented. The main mechanisms of comorbidity are insulin resistance, oxidative stress, inflammation, disorders of carbohydrate and fat metabolism. An approach to the therapy of this disease based on the concept of comorbidity has been substantiated. As a rational therapeutic choice, a molecule of glycyrrhizic acid is presented, which has pleiotropic effects, including anti-inflammatory, antioxidant, antifibrotic and immunomodulatory effects. The evidence base for glycyrrhizic acid is formed by a large array of clinical trials, including randomized placebo-controlled trials conducted both in Russia and abroad, in infectious and non-infectious liver diseases, including non-alcoholic fatty liver disease. Attention is focused on non-alcoholic fatty liver disease with intrahepatic cholestasis associated with a more severe course and high rates of disease progression. A theoretical justification for the use of a combination of glycyrrhizic acid and ursodeoxycholic acid in such patients is presented. The reason for this is the potential synergy of the two molecules, based on the induction of CYP3A4, and associated with the effect on inflammation, as a factor in the development of intrahepatic cholestasis and cholestasis itself.

Blood transcriptome profiling captures dysregulated pathways and response to treatment in neuroimmunological disease.

Blood transcriptome profiling captures dysregulated pathways and response to treatment in neuroimmunological disease.

IRAK1 Limits TLR3/4- and IFNAR-Driven IL-27 Production through a STAT1-Dependent Mechanism.

IL-27 is a cytokine exerting pleiotropic immunomodulatory effects on a broad spectrum of immune cells. Optimal IL-27 production downstream of TLR3/4 ligand stimulation relies on autocrine type I IFN signaling, defining a first and second phase in IL-27 production. This work shows that IL-1 receptor-associated kinase 1 (IRAK1) limits TLR3/4- and IFNAR-induced IL-27 production. At the mechanistic level, we identified IRAK1 as a novel regulator of STAT1, IRF1, and IRF9. We found hyperactivation of STAT1 together with increased nuclear levels of IRF1 and IRF9 in IRAK1-deficient murine macrophages compared with control cells following stimulation with LPS and poly(I:C). IRAK1-deficient human microglial cells showed higher basal levels of STAT1 and STAT2 compared with control cells. Blocking the kinase activity of TBK1/IKKε in IRAK1 knockdown human microglial cells reduced the high basal levels of STAT1/2, uncovering a TBK1/IKKε kinase-dependent mechanism controlling basal levels of STAT1/2. Stimulating IRAK1 knockdown human microglial cells with IFN-β led to increased IL-27p28 expression compared with control cells. In IRAK1-deficient murine macrophages, increased IL-27 levels were detected by ELISA following IFN-β stimulation compared with control macrophages together with increased nuclear levels of p-STAT1, IRF1, and IRF9. Treatment of wild-type and IRAK1-deficient murine macrophages with fludarabine similarly reduced TLR3/4-induced IL-27 cytokine levels. To our knowledge, this work represents the first report placing IRAK1 in the IFNAR pathway and identifies IRAK1 as an important regulator of STAT1, controlling IL-27 production downstream of TLR3/4 and IFNAR signaling pathways.

Brief Report: Statin Effects on Myocardial Fibrosis Markers in People Living With HIV.

In observational studies, patients with HIV have higher levels of soluble ST2 (sST2), galectin-3, and growth differentiation factor-15 (GDF-15) than non-HIV controls. As statins exert pleiotropic immunomodulatory effects that may affect markers of myocardial fibrosis, the objective of the current study is to determine whether biomarkers of myocardial fibrosis reflecting subclinical pathology may be modified by statin therapy in patients with HIV. Forty HIV+ men and women participated in a single center 12-month randomized, double-blind placebo-controlled trial of atorvastatin 40 mg every day vs. placebo. At baseline and 12-months, sST2, GDF-15, galectin-3 were measured. The changes in sST2 were -0.310 (-4.195, 2.075) vs. 1.163 (0.624, 4.715) ng/mL, median (interquartile range) atorvastatin vs. placebo (P = 0.04). The change in sST2 was significantly related to changes in monocyte activation marker sCD14 (r = 0.63, P < 0.0001) and MCP (r = 0.52, P = 0.0009), markers of generalized inflammation hs-IL-6 (r = 0.58, P = 0.0002), oxLDL (r = 0.49, P = 0.002), and GDF-15 (r = 0.54, P = 0.0008). sST2, a member of the IL-1 receptor family and a marker of fibrosis and inflammation increases over time among patients with HIV and this increase is attenuated by statin therapy in HIV. This effect may relate to immunomodulatory mechanisms of statins.

Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice.

The clinical pathogen Klebsiella pneumoniae is a relevant cause of nosocomial infections, and resistance to current treatment with carbapenem antibiotics is becoming a significant problem. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) used for controlling plasma cholesterol levels. There is clinical evidence showing other effects of statins, including decrease of lung inflammation. In the current study, we show that pretreatment with atorvastatin markedly attenuated lung injury, which was correlated with a reduction in the cellular influx into the alveolar space and lungs and downmodulation of the production of proinflammatory mediators in the initial phase of infection in C57BL/6 mice with K. pneumoniae However, atorvastatin did not alter the number of bacteria in the lungs and blood of infected mice, despite decreasing local inflammatory response. Interestingly, mice that received combined treatment with atorvastatin and imipenem displayed better survival than mice treated with vehicle, atorvastatin, or imipenem alone. These findings suggest that atorvastatin could be an adjuvant in host-directed therapies for multidrug-resistant K. pneumoniae, based on its powerful pleiotropic immunomodulatory effects. Together with antimicrobial approaches, combination therapy with anti-inflammatory compounds could improve the efficiency of therapy during acute lung infections.

Bortezomib in treatment of patients with relapsed/refractory autoimmune hematological disease

Relapsed/refractory autoimmune hematological diseases, belong to the thrombus and hemorrhagic disease, are characterized by autoantibody-mediated blood cells or plasma protein destruction caused by the disorder of the immune system, which have poor responses to conventional immunosuppression, including corticosteroids, immunosuppressive agents etc.. Severe illness can endanger the patient′s life and follow-up treatment is difficult. It is still a clinical challenging to explore new treatments to improve the survival rate and long term prognosis of this type of patients. Bortezomib as the only proteasome inhibitor applied to the clinical treatment of tumors has achieved good clinical results in the treatment of multiple myeloma (MM). In addition, proteasome inhibitor such as bortezomib, demonstrating pleiotropic immunomodulatory effects, including inducing apoptosis of plasma cells, influencing process of antigen cells, inhibiting proliferation of autoreactive T cells and reducing expression of inflammatory cytokines. These diverse effects have provided the feasibility for the utility of proteasome inhibitor as a salvage therapy for relapsed/refractory autoimmune hematological diseases. In recent years, some foreign studies have shown that bortezomib can be used as a salvage treatment for patients with relapsed/refractory auto immune hematological diseases. Therefore, the article summarizes the recent research progress of proteasome inhibitor treatment in relapsed/refractory autoimmune hematological diseases. Key words: Bortezomib; Proteasome inhibitor; Relapsed/refractory autoimmune hematological diseases; Autoimmune diseases; Thrombocytopenia

Human Adipose-Derived Stem Cells Suppress Elastase-Induced Murine Abdominal Aortic Inflammation and Aneurysm Expansion through Paracrine Factors

Abdominal aortic aneurysm (AAA) is a potentially lethal disease associated with immune activation-induced aortic degradation. We hypothesized that xenotransplantation of human adipose-derived stem cells (hADSCs) would reduce aortic inflammation and attenuate expansion in a murine AAA model. Modulatory effects of ADSCs on immune cell subtypes associated with AAA progression were investigated using human peripheral blood mononuclear cells (hPBMNCs) cocultured with ADSCs. Murine AAA was induced through elastase application to the abdominal aorta in C57BL/6 mice. ADSCs were administered intravenously, and aortic changes were determined by ultrasonography and videomicrometry. Circulating monocytes, aortic neutrophils, CD28− T cells, FoxP3+ regulatory T cells (Tregs), and CD206+ M2 macrophages were assessed at multiple terminal time points. In vitro, ADSCs induced M2 macrophage and Treg phenotypes while inhibiting neutrophil transmigration and lymphocyte activation without cellular contact. Intravenous ADSC delivery reduced aneurysmal expansion starting from day 4 [from baseline: 54.8% (saline) vs. 16.9% (ADSCs), n = 10 at baseline, n = 4 at day 4, p < 0.001], and the therapeutic effect persists through day 14 (from baseline: 64.1% saline vs. 24.6% ADSCs, n = 4, p < 0.01). ADSC administration increased aortic Tregs by 20-fold (n = 5, p < 0.01), while decreasing CD4+CD28− (-28%), CD8+CD28− T cells (-61%), and Ly6G/C+ neutrophils (-43%, n = 5, p < 0.05). Circulating CD115+CXCR1−LY6C+-activated monocytes decreased in the ADSC-treated group by day 7 (-60%, n = 10, p < 0.05), paralleled by an increase in aortic CD206+ M2 macrophages by 2.4-fold (n = 5, p < 0.05). Intravenously injected ADSCs transiently engrafted in the lung on day 1 without aortic engraftment at any time point. In conclusion, ADSCs exhibit pleiotropic immunomodulatory effects in vitro as well as in vivo during the development of AAA. The temporal evolution of these effects systemically as well as in aortic tissue suggests that ADSCs induce a sequence of anti-inflammatory cellular events mediated by paracrine factors, which leads to amelioration of AAA progression.

Bortezomib-based antibody depletion for refractory autoimmune hematological diseases

AbstractCertain patients with antibody-mediated autoimmune disease exhibit poor responses to conventional immunosuppression, including B-cell depletion with rituximab. Proteasome inhibitors such as bortezomib demonstrate pleiotropic immunomodulatory effects, including direct toxicity to antibody-producing cells. Here, we report preliminary evidence for the efficacy of bortezomib as salvage therapy for refractory autoimmune hematological disease. Thirteen treatment episodes in 10 patients with autoimmune hematological phenomena (autoimmune hemolytic anemia [AIHA; n = 8], acquired hemophilia (n = 1), immune thrombocytopenia (n = 1), and thrombotic thrombocytopenic purpura [TTP; n = 3]) and a median of 5 (range, 3-12) prior lines of therapy demonstrated an overall response rate of 77% (10 of 13) including 38% (5 of 13) complete remissions. The majority of clinical improvements were rapid, correlated with biomarkers of autoantibody reduction, and were associated with an acceptable safety profile. Responses appeared durable following treatment of TTP and acquired hemophilia; AIHA responses were more limited with a pattern of relapse following bortezomib cessation. These data provide proof of concept for the utility of proteasome inhibition as antibody depletion therapy in autoimmune disease.

Oral administration of a recombinant cholera toxin B subunit promotes mucosal healing in the colon.

Cholera toxin B subunit (CTB) is a component of a licensed oral cholera vaccine. However, CTB has pleiotropic immunomodulatory effects whose impacts on the gut are not fully understood. Here, we found that oral administration in mice of a plant-made recombinant CTB (CTBp) significantly increased several immune cell populations in the colon lamina propria. Global gene expression analysis revealed that CTBp had more pronounced impacts on the colon than the small intestine, with significant activation of TGFβ-mediated pathways in the colon epithelium. The clinical relevance of CTBp-induced impacts on colonic mucosa was examined. In a human colon epithelial model using Caco2 cells, CTBp, but not the non-GM1-binding mutant G33D-CTBp, induced TGFβ-mediated wound healing. In a dextran sodium sulfate (DSS) acute colitis mouse model, oral administration of CTBp protected against colon mucosal damage as manifested by mitigated body weight loss, decreased histopathological scores, and blunted escalation of inflammatory cytokine levels while inducing wound healing-related genes. Furthermore, biweekly oral administration of CTBp significantly reduced disease severity and tumorigenesis in the azoxymethane/DSS model of ulcerative colitis and colon cancer. Altogether, these results demonstrate CTBp's ability to enhance mucosal healing in the colon, highlighting its potential application in ulcerative colitis therapy besides cholera vaccination.

Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis.

Objective: To study the safety profile and characterize the immunologic effects of high- vs low-dose cholecalciferol supplementation in patients with multiple sclerosis (MS). Methods: In this double-blind, single-center randomized pilot study, 40 patients with relapsing-remitting MS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months. Assessments were performed at baseline and 3 and 6 months. Results: Mean increase of 25-hydroxyvitamin D levels from baseline to final visit was larger in the high-dose group (34.9 ng/mL; 95% confidence interval [CI] 25.0–44.7 ng/mL) than in the low-dose group (6.9 ng/mL; 95% CI 1.0–13.7 ng/mL). Adverse events were minor and did not differ between the 2 groups. Two relapses occurred, one in each treatment arm. In the high-dose group, we found a reduction in the proportion of interleukin-17 + CD4 + T cells ( p = 0.016), CD161 + CD4 + T cells ( p = 0.03), and effector memory CD4 + T cells ( p = 0.021) with a concomitant increase in the proportion of central memory CD4 + T cells ( p = 0.018) and naive CD4 + T cells ( p = 0.04). These effects were not observed in the low-dose group. Conclusions: Cholecalciferol supplementation with 10,400 IU daily is safe and tolerable in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects in MS, which include reduction of interleukin-17 production by CD4 + T cells and decreased proportion of effector memory CD4 + T cells with concomitant increase in central memory CD4 + T cells and naive CD4 + T cells. Classification of evidence: This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects.

Increased miR-155-5p expression in dermal mesenchymal stem cells of psoriatic patients: comparing the microRNA expression profile by microarray.

Mesenchymal stem cells (MSCs) have pleiotropic immuno-modulatory effects and pro-angiogenic ability, leading to the presumption that MSCs may be involved in the pathogenesis of many inflammatory or autoimmune disorders, including psoriasis. In a previous study, we reported the specific gene expression profile of dermal MSCs from psoriasis. Inflammation- and angiogenesis-related genes, such as lipopolysaccharide-induced tumor necrosis factor-alpha transcription factor (LITAF), dual-specificity protein phosphatase 1 (DUSP1), vascular endothelial growth factor α (VEGFα), and insulin-like growth factor-binding protein-5 (IGFBP5), are abnormally expressed in psoriatic dermal MSCs. As a key regulator of gene expression, miRNA are involved in a wide variety of biological processes; in fact, several miRNAs have been implicated in the development and progression of inflammatory or autoimmune disorders. In this study, we compared the miRNA expression profiles of dermal MSCs from patients with psoriasis to those in MSCs from normal individuals by microarray, and found that the pro-inflammatory miRNA miR-155 was significantly overexpressed in psoriatic MSCs (2.44 fold, P < 0.001). Additionally, the expression of miR-155 target gene TAB2 (8.47 ± 1.55 vs 6.38 ± 2.10, P < 0.01,) and the downstream gene iNOS (5.26 ± 2.58 vs 3.73 ± 1.89, P < 0.05) was found to be inhibited in psoriatic dermal MSCs by real-time PCR. Therefore, we speculated that the elevation in miR-155 levels may be an indicator of, or a key regulatory pathway in, the pathogenesis of psoriasis, resulting in functionally impaired dermal MSCs.

Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis.

To study the safety profile and characterize the immunologic effects of high- vs low-dose cholecalciferol supplementation in patients with multiple sclerosis (MS). In this double-blind, single-center randomized pilot study, 40 patients with relapsing-remitting MS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months. Assessments were performed at baseline and 3 and 6 months. Mean increase of 25-hydroxyvitamin D levels from baseline to final visit was larger in the high-dose group (34.9 ng/mL; 95% confidence interval [CI] 25.0-44.7 ng/mL) than in the low-dose group (6.9 ng/mL; 95% CI 1.0-13.7 ng/mL). Adverse events were minor and did not differ between the 2 groups. Two relapses occurred, one in each treatment arm. In the high-dose group, we found a reduction in the proportion of interleukin-17(+)CD4(+) T cells (p = 0.016), CD161(+)CD4(+) T cells (p = 0.03), and effector memory CD4(+) T cells (p = 0.021) with a concomitant increase in the proportion of central memory CD4(+) T cells (p = 0.018) and naive CD4(+) T cells (p = 0.04). These effects were not observed in the low-dose group. Cholecalciferol supplementation with 10,400 IU daily is safe and tolerable in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects in MS, which include reduction of interleukin-17 production by CD4(+) T cells and decreased proportion of effector memory CD4(+) T cells with concomitant increase in central memory CD4(+) T cells and naive CD4(+) T cells. This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects.

Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS.

BackgroundDespite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS.MethodsMOG35-55 induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses.ResultsEAE disease course was slightly attenuated in male apoE-deficient (apoE−/−) mice compared to wildtype mice (cumulative median score: apoE−/− = 2 [IQR 0.0–4.5]; wildtype = 4 [IQR 1.0–5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE−/− mice compared to wildtype mice (cumulative median score: apoE−/− = 3 [IQR 2.0–4.5]; wildtype = 3 [IQR 0.0–4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex.ConclusionsapoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0429-y) contains supplementary material, which is available to authorized users.