Effective treatment of a mouse model of Sjögren's syndrome with eyedrop administration of anti‐CD4 monoclonal antibody

Hayashi, Yuji; Ishimaru, Naozumi; Arakaki, Rieko; Tsukumo, Shin-ichi; Fukui, Hitomi; Kishihara, Kenji; Shiota, Hiroshi; Yasutomo, Koji; Hayashi, Yoshio

doi:10.1002/art.20472

Cited by 16 publications

(10 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Analysis of Id3-deficient mice has demonstrated that aberrant T cells are sufficient for SS disease (5). Supporting a major role for CD4 ϩ T cells, eye drops containing anti-CD4 antibodies have been shown to reduce ocular symptoms in a different mouse model (20). Our analysis of r1⌬T͞r2n tends to support the conclusion that T cell-intrinsic defects can trigger SS-like disease.…”

Section: Discussionsupporting

confidence: 66%

Sjögren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase

Oak

Deane

Kharas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Sjögren's syndrome (SS) is an autoimmune disease that is characterized by infiltration of exocrine tissues, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Here, we show that mice with T cell-specific loss of class IA phosphoinositide 3-kinase function develop organ-specific autoimmunity that resembles the human disease SS. Most mutant mice aged 3–8 months develop corneal opacity and eye lesions due to irritation and constant scratching. These mice display cardinal signs of primary SS such as marked lymphocytic infiltration of the lacrimal glands, antinuclear antibodies in the serum, and elevated titer of anti-SS-A antibody, in the absence of kidney pathology. Immunofluorescence studies show the presence of numerous CD4 + T cells with a smaller number of CD8 + T cells and B cells in the lacrimal glands. CD4 + T cells from these mice exhibit aberrant differentiation in vitro . These results indicate that aberrant T cells with impaired class IA phosphoinositide 3-kinase signaling can lead to organ-specific autoimmunity. In addition, the mouse model described here represents a tool to study the pathogenesis and treatment of SS.

show abstract

Section: Discussionsupporting

confidence: 66%

Sjögren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase

Oak

Deane

Kharas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…For instance, one of the promising agents is the anti-CD4 monoclonal antibody that was found to suppress the local activation of CD4+ T cells reducing the expansion of pathologic CD4+ T cells against α-fodrin in a mouse model of SS. 99 There are also a few studies suggesting that systemic linoleic and gamma-linolenic acids, and omega-6 essential fatty acids may reduce the underlying ocular infl ammation and in turn improve the signs and symptoms of ocular discomfort in KCS. 100,101 The possible mechanisms, benefi ts and risks of the abovementioned agents are summarized in Table 1.…”

Section: Novel Therapeutic Agentsmentioning

confidence: 99%

The role of inflammation and antiinflammation therapies in keratoconjunctivitis sicca

Gümüş

Cavanagh

2008

OPTH

View full text Add to dashboard Cite

Purpose: To review and integrate recent advances in identifying the role of infl ammation in the pathogenesis of dry eye conditions and the biological rationale and practical clinical aspects of newer, antiinfl ammatory theories. Methods: A comprehensive literature survey. Results and conclusion: Keratoconjunctivitis Sicca (KCS) is a multifactorial and complex disorder in which ocular surface infl ammations play a central role. Identifi cation of specifi c CD4-T-Cell pathways and the recent recognition of targeting of alpha-fodrin suggest a case for novel new therapeutic aspects such as anti-CD4 monoclonal antibodies, systemic linoleic and gamma-linolenic acids, and omega-6 essential fatty acids. Replacement of tear volume with nonpreserved wetting agents and standard typical antiinfl ammatory corticosteroid and/or cyclosporine A continues to be central current conventional therapy for KCS. Keywords: dry eye, keratoconjunctivitis sicca, antiinfl ammatory therapy Dry eye disease or keratoconjunctivitis sicca (KCS) is a common disorder which refers to a spectrum of ocular surface diseases with multiple etiologies.1 KCS is associated with symptoms of ocular discomfort such as burning, sense of dryness, foreign body sensation, ocular pain, and is sometimes associated with photophobia, blurred vision, visual fatigue, and sight-threatening corneal complications in severe cases. 2,3Epidemiologic studies have stated that more than 6% of the population complains of dry eye symptoms, and this ratio increases to 15% over the age of 65. [4][5][6] Most of the studies have also found an increasing prevalence with aging and greater prevalence among women due to the hormonal status. 4,6,7 Pathogenesis of KCS has not been completely clarified. Even though KCS has been thought of classically and basically as a condition of tear deficiency, whether caused by decreased lacrimation or excessive evaporation, it is a complex disorder. Many clinicopathological entities involving tear film, lacrimal glands, eyelids, and a wide spectrum of ocular surface cells, including epithelial, inflammatory, immune, and goblet cells may play a role in its pathogenesis. 2,8Over the past years, as a result of numerous studies, new concepts of pathogenesis have shown that KCS seems to be caused by infl ammation mediated by T-cell lymphocytes. [9][10][11] This fi nding has also been augmented by the studies investigating the role of antiinfl ammatory therapies. For instance, the treatment of KCS gained a new dimension with the approval of topical 0.05% cyclosporine A (Restasis) (Allergan, Inc., package insert for Restasis) by the US Food and Drug Administration. Consequently, because of the increasing importance of the role of infl ammation and the use of cyclosporine eye drops, the goal of this review article is to provide the readers with an overview of Clinical Ophthalmology downloaded from https://www.dovepress.com/ by 35.167.132.9 on 10-May-2018 For personal use only.Powered by TCPDF (www.tcpdf.org)

show abstract

“…51 Similarly, topical application of an anti-CD4 monoclonal antibody to the eye also suppressed the local activation of CD4+ T cells rather than deleting them, which reduced the expansion of pathological CD4+ T cells against a-fodrin. 50 Ciclosporin A Although ciclosporin is not strictly considered to be a biological agent, we have included it here because this small fungal peptide acts by inhibiting nuclear translocation of the transcription factor NF-AT (nuclear factor of activated T cells). This leads to reduced transcription of several cytokine genes, including IL2, IL3 and IL4, and TNFa.…”

Section: Anti-cd4 Antibodymentioning

confidence: 99%

Experience with experimental biological treatment and local gene therapy in Sjogren's syndrome: implications for exocrine pathogenesis and treatment

Lodde

Baum²,

Tak³

et al. 2006

Annals of the Rheumatic Diseases

View full text Add to dashboard Cite

Effective treatment of a mouse model of Sjögren's syndrome with eyedrop administration of anti‐CD4 monoclonal antibody

Cited by 16 publications

References 37 publications

Sjögren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase

Sjögren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase

The role of inflammation and antiinflammation therapies in keratoconjunctivitis sicca

Experience with experimental biological treatment and local gene therapy in Sjogren's syndrome: implications for exocrine pathogenesis and treatment

Contact Info

Product

Resources

About