Local delivery of AAV2-CTLA4IgG decreases sialadenitis and improves gland function in the C57BL/6.NOD-Aec1Aec2 mouse model of Sjögren's syndrome

Yin, Hongen; Nguyen, Cuong Q.; Samuni, Yuval; Uede, Toshimitsu; Peck, Ammon B.; Chiorini, John A.

doi:10.1186/ar3753

Cited by 31 publications

(41 citation statements)

References 30 publications

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“…Research has shown SjS patients’ salivary gland epithelial cells express antigen-presenting molecules MHC class I and II, as well as, express CD86 and ICAM-1 co-stimulatory molecules [3, 33-36]. Of note,localized delivery of CTLA-4-Ig recombinant fusion protein tothe salivary gland epithelial cellsof B6DC mice prevented disease progression [41],indicating that costimulation from salivary gland epithelial cells arequirement for SjS progression. Expression of CD86 is well documented to be highly expressed in salivary gland epithelial cells of SjS patients [33, 35, 36].…”

Section: Discussionmentioning

confidence: 99%

“…This reduction in CD80 in the salivary gland epithelial cells could impact both the ability to activate Tregs and to inhibit effector T-cells directly. Importantly, full functionality of Tregs are shown to be biased towards CD80-CTLA-4 and CD80-PD-L1 interactions [26, 27, 31, 43], while CD86-CD28 interactions are prone to be inhibitory in Tregs [24, 25, 28, 29] and may contribute to SjS progression [35, 36, 41, 44]. Therefore, in vitro and in vivo testing to identify specific functional consequences of miR-146a and the imbalance of CD86:CD80 in the salivary epithelial cells on T-cell responses are currently in progress.…”

Section: Discussionmentioning

confidence: 99%

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Dysregulated co-stimulatory molecule expression in a Sjögren’s syndrome mouse model with potential implications by microRNA-146a

Gauna

Park

Nayar

et al. 2015

Molecular Immunology

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Sjögren’s syndrome (SjS) is an autoimmune condition that primarily affects salivary and lacrimal glands, causing loss of secretion. We have previously shown that microRNA-146a (miR-146a) is over-expressed in the salivary glands and peripheral blood mononuclear cells(PBMC) of SjS-prone mice (C57BL/6.NOD-Aec1Aec2, B6DC) and in PBMC of SjS patients. The purpose of this research was to identify a target molecule of miR-146a and identify subpopulations of cells affected by altered miR-146a in the salivary glands of SjS-prone mice.In silico analyses identified costimulatory molecule CD80as a potential target of miR-146a. Luciferase assay of the human CD80 3’untranslated region demonstrated miR-146a directly inhibited CD80 protein expression as indicated by reduced luciferase reporter expression and an examination of B6DC salivary glands revealed a reduction in CD80 protein.More interestingly, the specific reduction in CD80 protein wasdetectedfrom the salivary gland epithelial cell population and in interstitial dendritic cells in the glands as well. The reduction in CD80 protein levels in salivary gland epithelial cells were negatively associated with elevated miR-146a expression.Therefore, this study provides the first indication that salivary gland epithelial cells may be critically involved in SjS progression by altering CD86:CD80protein ratioin response to miR-146a upregulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dysregulated co-stimulatory molecule expression in a Sjögren’s syndrome mouse model with potential implications by microRNA-146a

Gauna

Park

Nayar

et al. 2015

Molecular Immunology

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“…Conversely, impedance of cytotoxic T-lymphocyte antigen 4 (CTLA-4), which is a key negative co-stimulatory molecule that displays a wide range of anti-inflammatory properties, seems to offer beneficial effects [40]. The recombinant fusion protein CTLA4IgG, which consists of the extracellular portion of murine CTLA-4 and the Fc portion of human IgG1, is currently approved to treat rheumatoid arthritis and is now in clinical trials for the treatment of SS.…”

Section: Glandular Disordersmentioning

confidence: 99%

“…Theoretically, transferring the CTLA4IgG cDNA offers the possibility of local expression of this immunomodulatory protein in the salivary glands to gain continuous benefit. That hypothesis has been evaluated in mouse models and its efficacy in blocking B7 expression on macrophages in vitro also has been assessed [40]. In this study CTLA4IgG expressed locally in the salivary glands of C57BL/6.NOD-Aec1Aec2 mice (another, more specific model of SS) inhibited of the loss of salivary gland activity and decreased T and B cell infiltration, as well as dendritic cells and macrophages, in the glands, compared with findings in control mice.…”

Section: Glandular Disordersmentioning

confidence: 99%

Advances in salivary gland gene therapy – oral and systemic implications

Baum¹,

Alevizos²,

Chiorini³

et al. 2015

Expert Opinion on Biological Therapy

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Introduction Much research demonstrates the feasibility and efficacy of gene transfer to salivary glands. Recently, the first clinical trial targeting a salivary gland was completed, yielding positive safety and efficacy results. Areas covered There are two major disorders affecting salivary glands; radiation damage following treatment for head and neck cancers and Sjögren’s syndrome. Salivary gland gene transfer has also been employed in preclinical studies using transgenic secretory proteins for exocrine (upper gastrointestinal tract) and endocrine (systemic) applications. Expert opinion Salivary gland gene transfer is safe and can be beneficial in humans. Applications to treat and prevent radiation damage show considerable promise. A first-in-human clinical trial for the former was recently successfully completed. Studies on Sjögren’s syndrome suffer from an inadequate understanding of its etiology. Proof of concept in animal models has been shown for exocrine and endocrine disorders. Currently, the most promising exocrine application is for the management of obesity. Endocrine applications are limited, as it is currently impossible to predict if systemically required transgenic proteins will be efficiently secreted into the bloodstream. This results from not understanding of how secretory proteins are sorted. Future studies will likely employ ultrasound assisted and pseudotyped adenoassociated viral vector-mediated gene.

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“…Studies in the C57BL/6.NOD- Aec1Aec2 mouse model of SS have demonstrated benefits of gene therapy with adeno-associated virus (AAV2) in delivering immunomodulatory proteins either locally or systemically. Administration of CTLA4IgG via retrograde instillation of AAV2-CTLA4IgG into salivary glands led to decreased sialadenitis and increased salivary gland function [13]. Low levels of CTLA4IgG were detected in serum and a trend toward improved lacrimal gland function was noted.…”

Section: Treatmentmentioning

confidence: 99%

Childhood Sjögren syndrome

Lieberman

2013

Current Opinion in Rheumatology

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Purpose of review Sjögren syndrome (SS) is a chronic autoimmune disease affecting lacrimal and salivary glands and potentially involving extraglandular manifestations. While common in adults, the prevalence and prognosis of childhood SS is unknown, in part due to lack of child-specific diagnostic and classification criteria. This review discusses difficulties in diagnosing childhood SS and highlights recent findings in SS treatment and pathogenesis from studies in adults and animal models over the past 18 months. Recent findings Studies of rituximab show some therapeutic potential in adult SS while newer modalities including gene therapy and mesenchymal stem cell transfer are promising. The pathogenesis of SS is emerging, including roles of T and B lymphocytes, autoantibodies, interferons, and glandular epithelial cells. Specific recent notable findings in SS pathogenesis include identification of a type II interferon signature in salivary glands of SS patients, characterization of salivary gland-infiltrating T cell subsets, and characterization of anti-muscarinic acetylcholine receptor type 3 autoantibodies. Summary Childhood SS is a poorly defined and underdiagnosed autoimmune disease which requires child-specific criteria in order to study disease burden and prognosis. Studies in adults and animal models continue to elucidate new potential diagnostic and therapeutic targets, which may be relevant for childhood SS.

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Local delivery of AAV2-CTLA4IgG decreases sialadenitis and improves gland function in the C57BL/6.NOD-Aec1Aec2 mouse model of Sjögren's syndrome

Cited by 31 publications

References 30 publications

Dysregulated co-stimulatory molecule expression in a Sjögren’s syndrome mouse model with potential implications by microRNA-146a

Dysregulated co-stimulatory molecule expression in a Sjögren’s syndrome mouse model with potential implications by microRNA-146a

Advances in salivary gland gene therapy – oral and systemic implications

Childhood Sjögren syndrome

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