Novel CD28 antagonist mPEG PV1-Fab’ mitigates experimental autoimmune uveitis by suppressing CD4+ T lymphocyte activation and IFN-γ production

ABSTRACT Infection of cattle with Neospora caninum protozoa, the causative agent of bovine protozoal abortion, results in robust cellular and humoral immune responses, particularly CD4+ T-lymphocyte activation and gamma interferon (IFN-γ) secretion. In the present study, N. caninum SRS2 (NcSRS2) T-lymphocyte-epitope-bearing subunits were incorporated into DNA and peptide preparations to assess CD4+ cell proliferation and IFN-γ T-lymphocyte-secretion immune responses in cattle with predetermined major histocompatibility complex (MHC) genotypes. In order to optimize dendritic-cell processing, NcSRS2 DNA vaccine was delivered with granulocyte macrophage-colony-stimulating factor and Flt3 ligand adjuvant. The synthesized NcSRS2 peptides were coupled with a palmitic acid molecule (lipopeptide) and delivered with Freund's adjuvant. Cattle vaccinated with NcSRS2 DNA vaccine alone did not induce T-lymphocyte activation or IFN-γ secretion, whereas subsequent booster inoculation with NcSRS2-lipopeptides induced robust NcSRS2-specific immune responses. Compared to the response in control animals, NcSRS2-lipopeptide-immunized cattle had significantly increased NcSRS2-specific T-lymphocyte proliferation, numbers of IFN-γ-secreting peripheral blood mononuclear cells, and immunoglobulin G1 (IgG1) and IgG2a antibody levels. The findings show that N. caninum NcSRS2 subunits bearing T-lymphocyte epitopes induced cell-mediated immune responses similar to the protective immune responses previously described against live parasite infection, namely T-lymphocyte activation and IFN-γ secretion. The findings support the investigation of NcSRS2 immunogens for protection against N. caninum-induced fetal infection and abortion in cattle.

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Dynamics of Intraocular IFN-γ, IL-17 and IL-10-Producing Cell Populations during Relapsing and Monophasic Rat Experimental Autoimmune Uveitis

PLoS ONE ◽

10.1371/journal.pone.0049008 ◽

2012 ◽

Vol 7 (11) ◽

pp. e49008 ◽

Cited By ~ 26

Author(s):

Ulrike Kaufmann ◽

Maria Diedrichs-Möhring ◽

Gerhild Wildner

Keyword(s):

Cell Populations ◽

Experimental Autoimmune Uveitis ◽

Autoimmune Uveitis ◽

Ifn Γ ◽

Experimental Autoimmune

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Aminooxy-Acetic Acid Inhibits Experimental Autoimmune Uveitis by Modulating the Balance between Effector and Regulatory Lymphocyte Subsets

Current Molecular Medicine ◽

10.2174/1566524020666200211112219 ◽

2020 ◽

Vol 20 (8) ◽

pp. 624-632

Author(s):

Suyin Mei ◽

Yike Huang ◽

Na Li ◽

Zongren Xu ◽

Jing Xu ◽

...

Keyword(s):

Acetic Acid ◽

Lymphocyte Subsets ◽

Treg Cells ◽

Molecular Compound ◽

Experimental Autoimmune Uveitis ◽

Blood Retinal Barrier ◽

Autoimmune Uveitis ◽

Functional Studies ◽

Ifn Γ ◽

Experimental Autoimmune

Purpose: A small molecular compound, aminooxy-acetic acid (AOA), has been shown to modulate experimental autoimmune encephalomyelitis (EAE). The current study was designed to investigate whether AOA has a similar effect on the development of experimental autoimmune uveitis (EAU) and to further explore underlying mechanisms of this drug. Methods: EAU was induced in C57BL/6J mice by immunization with interphotoreceptor retinoid-binding protein peptide 651-670 (IRBP 651-670). AOA (500μg or 750μg) or vehicle was administered by intraperitoneal injection from day 10 to 14 after EAU induction. The severity was assessed by clinical and histological scores. The integrity of the blood retinal barrier was detected with Evans Blue. Frequencies of splenic Th1, Th17 and Foxp3+ Treg cells were examined by flow cytometry. The production of cytokines was tested by ELISA. The mRNA expression of IL-17, IFN-γ and IL-10 was detected by RT-PCR. The expression of p-Stat1 and NF-κB was detected by Western Blotting. Results: AOA was found to markedly inhibit the severity of EAU, as determined by clinical and histopathological examinations. AOA can relieve the leakage of blood retinal barrier (BRB). Functional studies found a decreased frequency of Th1 and Th17 cells and an increased frequency of Treg cells in EAU mice as compared with controls. Further studies showed that AOA not only downregulated the production of the proinflammatory cytokines including IFN-γ and IL-17 but also upregulated the expression of an anti-inflammatory cytokine such as IL-10, which might be caused by inhibiting the expressions of p-Stat1 and NF-κB. Conclusion: This study shows that AOA inhibits the severity and development of EAU by modulating the balance between regulatory and pathogenic lymphocyte subsets.

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IFN-γ up-regulation of IL-12 beta 2 receptor is associated with experimental autoimmune uveitis susceptible B10.A mice, but not in EAU resistant BALB/c mice

Journal of Neuroimmunology ◽

10.1016/s0165-5728(03)00071-7 ◽

2003 ◽

Vol 137 (1-2) ◽

pp. 154-163 ◽

Cited By ~ 5

Author(s):

Y Wu

Keyword(s):

Experimental Autoimmune Uveitis ◽

Autoimmune Uveitis ◽

Ifn Γ ◽

Beta 2 ◽

Experimental Autoimmune

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IL‐18‐independent cytotoxic T lymphocyte activation and IFN‐γ production during experimental acute graft‐versus‐host disease

International Immunology ◽

10.1093/intimm/14.5.503 ◽

2002 ◽

Vol 14 (5) ◽

pp. 503-511 ◽

Cited By ~ 11

Author(s):

Diana Arnold ◽

Christoph Wasem ◽

Pierre Juillard ◽

Pierre Graber ◽

Igor Cima ◽

...

Keyword(s):

T Lymphocyte ◽

Graft Versus Host Disease ◽

Cytotoxic T Lymphocyte ◽

Lymphocyte Activation ◽

Host Disease ◽

Graft Versus Host ◽

T Lymphocyte Activation ◽

Ifn Γ ◽

Acute Graft

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Dendritic cells and regulatory T cells expressing CCR4 provide resistance to coxsackievirus B5-induced pancreatitis

Scientific Reports ◽

10.1038/s41598-019-51311-9 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Marcela C. S. Françozo ◽

Frederico R. C. Costa ◽

Isabel C. Guerra-Gomes ◽

João S. Silva ◽

Renata Sesti-Costa

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

T Lymphocyte ◽

Immune Cell ◽

Lymphocyte Activation ◽

Cellular Migration ◽

T Lymphocyte Activation ◽

Pancreatic Lymph Nodes ◽

Ifn Γ ◽

Immune Cell Migration

Abstract Type B coxsackieviruses (CVB) are enteroviruses responsible for a common infectious myocarditis and pancreatitis. DCs and regulatory T cells (Tregs) are key players in controlling virus replication and regulating the immune response and tissue damage, respectively. However, the mechanisms underlying cellular migration to target tissues remain unclear. In the present study, we found that CVB5 infection induced CCL17 production and controlled the migration of CCR4+ DCs and CCR4+ Tregs to the pancreatic lymph nodes (pLN). CVB5 infection of CCR4−/− mice reduced the migration of the CD8α+ DC subset and reduced DC activation and production of IFN-β and IL-12. Consequently, CCR4−/− mice presented decreased IFN-γ-producing CD4+ and CD8+ T cells, an increased viral load and more severe pancreatitis. In addition, CCR4−/− mice had impaired Treg accumulation in pLN as well as increased T lymphocyte activation. Adoptive transfer of CCR4+ Tregs but not CCR4− Tregs was able to regulate T lymphocyte activation upon CVB5 infection. The present data reveal a previously unknown role for CCR4 in coordinating immune cell migration to CVB-infected tissues and in controlling subsequent pancreatitis. These new insights may contribute to the design of future therapies for acute and chronic infection of non-polio enteroviruses.

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