Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2012

Open Access 01-02-2012 | Research article

Local delivery of AAV2-CTLA4IgG decreases sialadenitis and improves gland function in the C57BL/6.NOD-Aec1Aec2mouse model of Sjögren's syndrome

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

Published in: Arthritis Research & Therapy | Issue 1/2012

Login to get access

Abstract

Introduction

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a key negative costimulatory molecule that displays a wide range of anti-inflammatory properties and is currently approved to treat rheumatoid arthritis as a recombinant fusion protein (CTLA4IgG). To better understand the role of CTLA4IgG in primary Sjögren's syndrome (pSS), we generated a recombinant adeno-associated virus vector serotype 2 (AAV2) expressing a chimera of mouse CTLA-4 fused with a human immunoglobulin (AAV2-CTLA4IgG) and observed the effect of this molecule in C57BL/6.NOD-Aec1Aec2 mice, an animal model of pSS.

Methods

A recombinant adeno-associated virus-2 (AAV-2) vector was constructed encoding a CTLA4IgG fusion protein. The AAV2-CTLA4IgG vector and an AAV2 control vector encoding beta galactosidase (LacZ) were administered by retrograde cannulation of the submandibular glands of C57BL/6.NOD-Aec1Aec2 mice. Protein expression was measured by ELISA and salivary glands were assessed for inflammation and activity.

Results

Recombinant CTLA4IgG blocked B7 expression on macrophages in vitro. In vivo, localized expression of CTLA4IgG in the salivary glands of C57BL/6.NOD-Aec1Aec2 mice inhibited 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 control mice. In addition a decrease in several proinflammatory cytokines and an increase in transforming growth factor beta-1 (TGF-β1) expression were also observed.

Conclusions

These data suggest expression of CTLA4IgG in the salivary gland can decrease the inflammation and improve the xerostomia reported in these mice.
Appendix
Available only for authorised users
Literature
1.
Fox E, Khaliq AA, Sarwar M, Strickland GT: Chloroquine-resistant Plasmodium falciparum: now in Pakistani Punjab. Lancet. 1985, 1: 1432-1435.CrossRefPubMed
2.
Voulgarelis M, Tzioufas AG: Pathogenetic mechanisms in the initiation and perpetuation of Sjogren's syndrome. Nat Rev Rheumatol. 2010, 6: 529-537. 10.1038/nrrheum.2010.118.CrossRefPubMed
3.
Xanthou G, Tapinos NI, Polihronis M, Nezis IP, Margaritis LH, Moutsopoulos HM: CD4 cytotoxic and dendritic cells in the immunopathologic lesion of Sjogren's syndrome. Clin Exp Immunol. 1999, 118: 154-163. 10.1046/j.1365-2249.1999.01037.x.PubMedCentralCrossRefPubMed
4.
Skopouli FN, Fox PC, Galanopoulou V, Atkinson JC, Jaffe ES, Moutsopoulos HM: T cell subpopulations in the labial minor salivary gland histopathologic lesion of Sjogren's syndrome. J Rheumatol. 1991, 18: 210-214.PubMed
5.
Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M: Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005, 353: 1114-1123. 10.1056/NEJMoa050524.CrossRefPubMed
6.
Bombardieri M, Barone F, Pittoni V, Alessandri C, Conigliaro P, Blades MC, Priori R, McInnes IB, Valesini G, Pitzalis C: Increased circulating levels and salivary gland expression of interleukin-18 in patients with Sjogren's syndrome: relationship with autoantibody production and lymphoid organization of the periductal inflammatory infiltrate. Arthritis Res Ther. 2004, 6: R447-456. 10.1186/ar1209.PubMedCentralCrossRefPubMed
7.
Vosters JL, Landek-Salgado MA, Yin H, Swaim WD, Kimura H, Tak PP, Caturegli P, Chiorini JA: Interleukin-12 induces salivary gland dysfunction in transgenic mice, providing a new model of Sjogren's syndrome. Arthritis Rheum. 2009, 60: 3633-3641. 10.1002/art.24980.PubMedCentralCrossRefPubMed
8.
Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB: Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjogren's syndrome: findings in humans and mice. Arthritis Rheum. 2008, 58: 734-743. 10.1002/art.23214.PubMedCentralCrossRefPubMed
9.
Wu AJ, Chen ZJ, Baum BJ, Ambudkar IS: Interferon-gamma induces persistent depletion of internal Ca2+ stores in a human salivary gland cell line. Am J Physiol. 1996, 270: C514-521.PubMed
10.
Nguyen CQ, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB: Pathogenic effect of interleukin-17A in induction of Sjogren's syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther. 2010, 12: R220-10.1186/ar3207.PubMedCentralCrossRefPubMed
11.
Leung S, Liu X, Fang L, Chen X, Guo T, Zhang J: The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease. Cell Mol Immunol. 2010, 7: 182-189. 10.1038/cmi.2010.22.PubMedCentralCrossRefPubMed
12.
Li X, Li X, Qian L, Wang G, Zhang H, Wang X, Chen K, Zhai Z, Li Q, Wang Y, Harris DC: T regulatory cells are markedly diminished in diseased salivary glands of patients with primary Sjogren's syndrome. J Rheum. 2007, 34: 2438-2445.PubMed
13.
McCartney-Francis NL, Mizel DE, Redman RS, Frazier-Jessen M, Panek RB, Kulkarni AB, Ward JM, McCarthy JB, Wahl SM: Autoimmune Sjogren's-like lesions in salivary glands of TGF-beta1-deficient mice are inhibited by adhesion-blocking peptides. J Immunol. 1996, 157: 1306-1312.PubMed
14.
Perkins D, Wang Z, Donovan C, He H, Mark D, Guan G, Wang Y, Walunas T, Bluestone J, Listman J, Finn PW: Regulation of CTLA-4 expression during T cell activation. J Immunol. 1996, 156: 4154-4159.PubMed
15.
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S: Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000, 192: 303-310. 10.1084/jem.192.2.303.PubMedCentralCrossRefPubMed
16.
Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T: Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006, 212: 8-27. 10.1111/j.0105-2896.2006.00427.x.CrossRefPubMed
17.
Matsumura R, Umemiya K, Goto T, Nakazawa T, Kagami M, Tomioka H, Tanabe E, Sugiyama T, Sueishi M: Glandular and extraglandular expression of costimulatory molecules in patients with Sjogren's syndrome. Ann Rheum Dis. 2001, 60: 473-482. 10.1136/ard.60.5.473.PubMedCentralCrossRefPubMed
18.
Downie-Doyle S, Bayat N, Rischmueller M, Lester S: Influence of CTLA4 haplotypes on susceptibility and some extraglandular manifestations in primary Sjogren's syndrome. Arthritis Rheum. 2006, 54: 2434-2440. 10.1002/art.22004.CrossRefPubMed
19.
Moreland L, Bate G, Kirkpatrick P: Abatacept. Nat Rev Drug Discov. 2006, 5: 185-186. 10.1038/nrd1989.CrossRefPubMed
20.
Izawa A, Sano K, Takehara M, Inobe M, Suzuki J, Imamura H, Takahashi M, Ikeda U, Isobe M, Uede T: Cre/loxP-mediated CTLA4IgG gene transfer induces clinically relevant immunosuppression via on-off gene recombination in vivo. Cardiovasc Res. 2006, 69: 289-297. 10.1016/j.cardiores.2005.07.021.CrossRefPubMed
21.
Cutolo M, Soldano S, Montagna P, Sulli A, Seriolo B, Villaggio B, Triolo P, Clerico P, Felli L, Brizzolara R: CTLA4-Ig interacts with cultured synovial macrophages from rheumatoid arthritis patients and downregulates cytokine production. Arthritis Res Ther. 2009, 11: R176-10.1186/ar2865.PubMedCentralCrossRefPubMed
22.
Kok MR, Yamano S, Lodde BM, Wang J, Couwenhoven RI, Yakar S, Voutetakis A, Leroith D, Schmidt M, Afione S, Pillemer SR, Tsutsui MT, Tak PP, Chiorini JA, Baum BJ: Local adeno-associated virus-mediated interleukin 10 gene transfer has disease-modifying effects in a murine model of Sjogren's syndrome. Hum Gene Ther. 2003, 14: 1605-1618. 10.1089/104303403322542257.CrossRefPubMed
23.
Kaludov N, Brown KE, Walters RW, Zabner J, Chiorini JA: Adeno-associated virus serotype 4 (AAV4) and AAV5 both require sialic acid binding for hemagglutination and efficient transduction but differ in sialic acid linkage specificity. J Virol. 2001, 75: 6884-6893. 10.1128/JVI.75.15.6884-6893.2001.PubMedCentralCrossRefPubMed
24.
Kanaya K, Tsuchida Y, Inobe M, Murakami M, Hirose T, Kon S, Kawaguchi S, Wada T, Yamashita T, Ishii S, Uede T: Combined gene therapy with adenovirus vectors containing CTLA4Ig and CD40Ig prolongs survival of composite tissue allografts in rat model. Transplantation. 2003, 75: 275-281. 10.1097/01.TP.0000046966.35399.75.CrossRefPubMed
25.
Grimm D, Kern A, Rittner K, Kleinschmidt JA: Novel tools for production and purification of recombinant adenoassociated virus vectors. Hum Gene Ther. 1998, 18: 2745-2760.CrossRef
26.
Cha S, Nagashima H, Brown VB, Peck AB, Humphreys-Beher MG: Two NOD Idd-associated intervals contribute synergistically to the development of autoimmune exocrinopathy (Sjogren's syndrome) on a healthy murine background. Arthritis Rheum. 2002, 46: 1390-1398. 10.1002/art.10258.CrossRefPubMed
27.
Katano H, Kok MR, Cotrim AP, Yamano S, Schmidt M, Afione S, Baum BJ, Chiorini JA: Enhanced transduction of mouse salivary glands with AAV5-based vectors. Gene Ther. 2006, 13: 594-601. 10.1038/sj.gt.3302691.CrossRefPubMed
28.
Yin H, Vistica BP, Chan CC, Strominger JL, Gery I: Inhibition of experimental autoimmune uveitis by amino acid copolymers. J Neuroimmunol. 2009, 215: 43-48. 10.1016/j.jneuroim.2009.08.002.PubMedCentralCrossRefPubMed
29.
Nguyen CQ, Sharma A, Lee BH, She JX, McIndoe RA, Peck AB: Differential gene expression in the salivary gland during development and onset of xerostomia in Sjogren's syndrome-like disease of the C57BL/6.NOD-Aec1Aec2 mouse. Arthritis Res Ther. 2009, 11: R56-10.1186/ar2676.PubMedCentralCrossRefPubMed
30.
Whittingham S, Naselli G, McNeilage LJ, Coppel RL, Sturgess AD: Serological diagnosis of primary Sjogren's syndrome by means of human recombinant La (SS-B) as nuclear antigen. Lancet. 1987, 2: 1-3.PubMed
31.
Greenspan JS, Daniels TE, Talal N, Sylvester RA: The histopathology of Sjogren's syndrome in labial salivary gland biopsies. Oral Surg Oral Med Oral Pathol. 1974, 37: 217-229. 10.1016/0030-4220(74)90417-4.CrossRefPubMed
32.
Cotrim AP, Baum BJ: Gene therapy: some history, applications, problems, and prospects. Toxicol Pathol. 2008, 36: 97-103. 10.1177/0192623307309925.CrossRefPubMed
33.
Voutetakis A, Kok MR, Zheng C, Bossis I, Wang J, Cotrim AP, Marracino N, Goldsmith CM, Chiorini JA, Loh YP, Nieman LK, Baum BJ: Reengineered salivary glands are stable endogenous bioreactors for systemic gene therapeutics. Proc Natl Acad Sci USA. 2004, 101: 3053-3058. 10.1073/pnas.0400136101.PubMedCentralCrossRefPubMed
34.
Tsunawaki S, Nakamura S, Ohyama Y, Sasaki M, Ikebe-Hiroki A, Hiraki A, Kadena T, Kawamura E, Kumamaru W, Shinohara M, Shirasuna K: Possible function of salivary gland epithelial cells as nonprofessional antigen-presenting cells in the development of Sjogren's syndrome. J Rheumatol. 2002, 29: 1884-1896.PubMed
35.
Howe KL, Reardon C, Wang A, Nazli A, McKay DM: Transforming growth factor-beta regulation of epithelial tight junction proteins enhances barrier function and blocks enterohemorrhagic Escherichia coli O157:H7-induced increased permeability. Am J Pathol. 2005, 167: 1587-1597. 10.1016/S0002-9440(10)61243-6.PubMedCentralCrossRefPubMed
36.
Metadata
Title
Local delivery of AAV2-CTLA4IgG decreases sialadenitis and improves gland function in the C57BL/6.NOD-Aec1Aec2mouse model of Sjögren's syndrome
Authors
Hongen Yin
Cuong Q Nguyen
Yuval Samuni
Toshimitsu Uede
Ammon B Peck
John A Chiorini
Publication date
01-02-2012
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2012
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar3753

Other articles of this Issue 1/2012

Arthritis Research & Therapy 1/2012 Go to the issue

Research article

Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis

Editorial

Inhibiting citrullination in rheumatoid arthritis: taking fuel from the fire

Research article

Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis

Research article

Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group

Research article

Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies

Research article

Effect of in uteroexposure to diethylstilbestrol on lumbar and femoral bone, articular cartilage, and the intervertebral disc in male and female adult mice progeny with and without swimming exercise
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits