Rodolfo Thomé

Thomas Jefferson University

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Liana Verinaud

Universidade Estadual de Campinas (UNICAMP)

Guang‐Xian Zhang

Thomas Jefferson University

Abdolmohamad Rostami

Thomas Jefferson University

Larissa Lumi Watanabe Ishikawa

Thomas Jefferson University

BĆ

Bogoljub Ćirić

Thomas Jefferson University

Thiago Alves da Costa

University of Colorado Denver

Catarina Rapôso

Universidade Estadual de Campinas (UNICAMP)

Amanda Pires Bonfanti

Universidade Estadual de Campinas (UNICAMP)

Giacomo Casella

Thomas Jefferson University

Rosária Di Gangi

Universidade Estadual de Campinas (UNICAMP)

Cooperative Institutions

Universidade Estadual de Campinas (UNICAMP)

Thomas Jefferson University

Hospital de Clínicas da Unicamp

Jefferson Hospital for Neuroscience

Universidade de São Paulo

Universidade Estadual Paulista (Unesp)

Shanxi Datong University

University of Pennsylvania

Shaanxi Normal University

Fundação Oswaldo Cruz

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Dimethyl fumarate suppresses granulocyte macrophage colony-stimulating factor–producing Th1 cells in CNS neuroinflammation

Neurology Neuroimmunology & Neuroinflammation (2020)

Farinaz Safavi Rodolfo Thomé Zichen Li Guang‐Xian Zhang Abdolmohamad Rostami

To study the immunomodulatory effect of dimethyl fumarate (DF) on granulocyte macrophage colony-stimulating factor (GM-CSF) production in CD4+ T cells in experimental autoimmune encephalomyelitis (EAE) and human peripheral blood mononuclear cells (PBMCs).We collected splenocytes and CD4+ T cells from C57BL/6 wild-type and interferon (IFN)-γ-deficient mice. For human PBMCs, venous blood was collected from healthy donors, and PBMCs were collected using the Percoll gradient method. Cells were cultured with anti-CD3/28 in the presence/absence of DF for 3 to 5 days. Cells were stained and analyzed by flow cytometry. Cytokines were measured by ELISA in cell supernatants. For in vivo experiments, EAE was induced by myelin oligodendrocyte glycoprotein35-55 and mice were treated with oral DF or vehicle daily.DF acts directly on CD4+ T cells and suppresses GM-CSF-producing Th1 not Th17 or single GM-CSF+ T cells in EAE. In addition, GM-CSF suppression depends on the IFN-γ pathway. We also show that DF specifically suppresses Th1 and GM-CSF-producing Th1 cells in PBMCs from healthy donors.We suggest that DF exclusively suppresses GM-CSF-producing Th1 cells in both animal and human CD4+ T cells through an IFN-γ-dependent pathway. These findings indicate that DF has a better therapeutic effect on patients with Th1-dominant immunophenotype. However, future longitudinal study to validate this finding in MS is needed.

Colony-stimulating factor

10.1212/nxi.0000000000000729

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Citations (10)

Nitric oxide plays a key role in the suppressive activity of tolerogenic dendritic cells

Cellular and Molecular Immunology (2014)

Liana Verinaud Luidy Kazuo Issayama Fábio Zanucoli Ana Carolina de Carvalho Thiago Alves da Costa

Indoleamine 2,3-dioxygenase

10.1038/cmi.2014.94

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Citations (19)

Comprehensive Analysis of the Immune and Stromal Compartments of the CNS in EAE Mice Reveal Pathways by Which Chloroquine Suppresses Neuroinflammation

Brain Sciences (2020)

Rodolfo Thomé Alexandra Boehm Larissa Lumi Watanabe Ishikawa Giacomo Casella Jaqueline Munhoz

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are neuroinflammatory diseases of the central nervous system (CNS), where leukocytes and CNS resident cells play important roles in disease development and pathogenesis. The antimalarial drug chloroquine (CQ) has been shown to suppress EAE by modulating dendritic cells (DCs) and Th17 cells. However, the mechanism of action by which CQ modulates EAE is far from being elucidated. Here, we comprehensively analyzed the CNS of CQ and PBS-treated EAE mice to identify and characterize the cells that are affected by CQ. Our results show that leukocytes are largely modulated by CQ and have a reduction in the expression of inflammatory markers. Intriguingly, CQ vastly modulated the CNS resident cells astrocytes, oligodendrocytes (OLs) and microglia (MG), with the latter producing IL-10 and IL-12p70. Overall, our results show a panoramic view of the cellular components that are affect by CQ and provide further evidence that drug repurposing of CQ will be beneficial to MS patients.

10.3390/brainsci10060348

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IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production

The Journal of Immunology (2019)

Satoshi Yoshimura Rodolfo Thomé Shingo Konno Elisabeth R. Mari Javad Rasouli

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are inflammatory diseases of the CNS in which Th17 cells play a major role in the disease pathogenesis. Th17 cells that secrete GM-CSF are pathogenic and drive inflammation of the CNS. IL-9 is a cytokine with pleiotropic functions, and it has been suggested that it controls the pathogenic inflammation mediated by Th17 cells, and IL-9R-/- mice develop more severe EAE compared with wild-type counterparts. However, the underlying mechanism by which IL-9 suppresses EAE has not been clearly defined. In this study, we investigated how IL-9 modulates EAE development. By using mice knockout for IL-9R, we show that more severe EAE in IL-9R-/- mice correlates with increased numbers of GM-CSF+ CD4+ T cells and inflammatory dendritic cells (DCs) in the CNS. Furthermore, DCs from IL-9R-/- mice induced more GM-CSF production by T cells and exacerbated EAE upon adoptive transfer than did wild-type DCs. Our results suggest that IL-9 reduces autoimmune neuroinflammation by suppressing GM-CSF production by CD4+ T cells through the modulation of DCs.

Adoptive Cell Transfer

Pathogenesis

10.4049/jimmunol.1801113

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Citations (19)

Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice

Science Translational Medicine (2020)

Giacomo Casella Javad Rasouli Alexandra Boehm Weifeng Zhang Dan Xiao

Extracellular vesicles from oligodendrocytes restore antigen-specific immune tolerance in mice models of multiple sclerosis.

Extracellular Vesicles

10.1126/scitranslmed.aba0599

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The impact of metabolic reprogramming on dendritic cell function

International Immunopharmacology (2018)

Livia de Lima Thomaz Gabriela Peron Janine Oliveira Larissa Camargo da Rosa Rodolfo Thomé

Reprogramming

10.1016/j.intimp.2018.07.031

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Intravenous tolerance induces T cell anergy/apoptosis via IFN-γ/IL-27/PD-L1 axis

The Journal of Immunology (2020)

Giacomo Casella Javad Rasouli Rodolfo Thomé Jorge I. Alvarez Christopher A. Hunter

Abstract The induction of peripheral tolerance by intravenous injection (i.v.) of auto-Ags has shown to suppress experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis, by eliciting tolerogenic APCs, Tregs, and suppressing self-reactive T cells. The programmed cell death protein (PD)-1 and its ligands, PD-L1 and PD-L2, regulate the balance between T cell activation and immune tolerance. Although PD-L1 and PD-L2 are expressed on a variety of cell types, however, the mechanisms related to peripheral tolerance that induce these molecules are still unclear. Here we show that PD-L1, but not PD-L2, is critical for inducing peripheral tolerance in EAE, and that PD-L1-dependent tolerance relies on both IFN-γ and IL-27. I.v. administration of auto-Ag(s) attenuates the progression of EAE, by inducing PD-L1 expression in monocyte-derived DCs (moDCs) in the CNS, via IFN-γ/ IL-27-dependent mechanism. Indeed, when PD-L1 is blocked, autoantigen(s)/i.v treatment becomes ineffective. Following IFN-γ−/− CD4+ T cell transfer into Rag1−/− mice, i.v. tolerance treatment failed to suppress EAE. Moreover, loss of IFN-γR signaling in classical DCs type I (cDCs I) compromised IL-27 production and consequent PD-L1 expression by moDCs. We also show that IL-27 stimulates moDCs to over-express PD-L1, in a STAT-3-dependent way. Indeed, in CCR2−/−/WSX−/− (CD45.2) → CD45.1 radiation-induced bone marrow chimera mice, auto-Ag(s)/i.v. treatment failed to suppress EAE. Similarly, EAE mice that expressed mutant STAT-3 (muSTAT-3) in CCR2+ cells were also insensitive to i.v. tolerance induction. Our data reveal a mechanism whereby IFN-γ and IL-27 are the key factors in PD-L1 induction and subsequent peripheral tolerance restoration.

Peripheral tolerance

10.4049/jimmunol.204.supp.78.15

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Pregabalin protects neurons of pro-inflammatory action of the T lymphocytes encephalitogenic

Perspectivas Médicas (2014)

Gustavo Ferreira Simões Rodrigo Fabrizzio Inácio Giuliano Roberto Gonçalves Taize Machado Augusto Rodolfo Thomé

Pregabalin

10.6006/perspectmed.20140303.0265557174

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Components from spider venom activate macrophages against glioblastoma cells: new potential adjuvants for anticancer immunotherapy

The Journal of Biochemistry (2021)

Jaqueline Munhoz Gabriela Peron Amanda Pires Bonfanti Janine Oliveira Thomaz Augusto Alves da Rocha e Silva

Abstract Immunomodulation has been considered an important approach in the treatment of malignant tumours. However, the modulation of innate immune cells remains an underexplored tool. Studies from our group demonstrated that the Phoneutria nigriventer spider venom (PnV) administration increased the infiltration of macrophage in glioblastoma, in addition to decreasing the tumour size in a preclinical model. The hypothesis that PnV would be modulating the innate immune system led us to the main objective of the present study: to elucidate the effects of PnV and its purified fractions on cultured macrophages. Results showed that PnV and the three fractions activated macrophages differentiated from bone marrow precursors. Further purification generated 23 subfractions named low weight (LW-1 to LW-12) and high weight (HW-1 to HW-11). LW-9 presented the best immunomodulatory effect. Treated cells were more phagocytic, migrated more, showed an activated morphological profile and induced an increased cytotoxic effect of macrophages on tumour cells. However, while M1-controls (LPS) increased IL-10, TNF-alpha and IL-6 release, PnV, fractions and subfractions did not alter any cytokine, with the exception of LW-9 that stimulated IL-10 production. These findings suggest that molecules present in LW-9 have the potential to be used as immunoadjuvants in the treatment of cancer.

Cancer Immunotherapy

10.1093/jb/mvab020

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Citations (6)

Hypoglycemic, hypolipidemic and antioxidant effects of iridoid glycosides extracted from Corni fructus: possible involvement of the PI3K–Akt/PKB signaling pathway

RSC Advances (2018)

Jiefang Kang Chen Guo Rodolfo Thomé Ning Yang Yuan Zhang

Iridoid glycosides (CIG) are the major component of Corni fructus. In this work, we researched the antioxidative, hypoglycemic and lowering blood lipids effects of CIG on diabetic mice induced by a high-fat diet (HFD) and streptozotocin (STZ). Furthermore, to investigate the molecular mechanism of action, the phosphorylation and protein expression of phosphoinositide 3-kinase (PI3K) and its downstream proteins, such as insulin receptor (INSR), protein kinase B (Akt/PKB) and glucose transporter 4 (GLUT4) have been detected. The results showed that CIG significantly improved oral glucose tolerance in diabetic mice. Biochemical indices also revealed that CIG had a positive effect on lipid metabolism and oxidative stress. In addition, CIG can significantly enhance the expression level of the PI3K-Akt/PKB pathway related proteins in skeletal muscle, which is the key pathway of insulin metabolism. These findings show that CIG can improve the hyperglycemia and hyperlipidemia of HFD-STZ-induced diabetic mice through the PI3K-Akt/PKB signaling pathway, and CIG might be a potential medicine or functional food for type 2 diabetes mellitus remedies.

GLUT4

10.1039/c8ra06045b

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Citations (15)