Tumor Necrosis Factor Inhibitor Gene Expression Suppresses Lacrimal Gland Immunopathology in a Rabbit Model of Autoimmune Dacryoadenitis

Zhu, Zhi Wei; Stevenson, Douglas; Schechter, Joel; Mircheff, Austin K.; Crow, Robert W.; Atkinson, Roscoe; Ritter, Thomas; Bose, Swaraj; Trousdale, Melvin D.

doi:10.1097/00003226-200305000-00012

Cited by 33 publications

(33 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[1][2][3][31][32][33] In this study, we have assessed the consequences of replication-defective and UV-inactivated Ad on secretory compartment organization and function in the acinar epithelial cells of the lacrimal gland. Exposure of lacrimal acini to replicationdefective Ad constructs at an MOI of 5 for 16-18 h Ad modulates epithelial secretory functions Y Wang et al elicited a marked dispersal of rab3D from its normally apical enrichment (Figures 3-5), a change independent of altered rab3D expression (Figure 4) or membrane association ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

“…3 Adenovirus (Ad) vectors, leading candidates for gene therapy to the anterior portion of the eye, do not require cycling of the target cell for gene transfer, and are renowned for mediating gene transfer to nondividing cells, particularly mucosal epithelial cells, with high efficiency. [4][5][6] On the other hand, Ad is intrinsically a lytic virus and is well known to express proteins that effect alterations in a wide variety of cellular processes, including host cell cycle, protein synthesis and survival.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland

et al. 2004

View full text Add to dashboard Cite

Although adenovirus (Ad) exhibits tropism for epithelial cells, little is known about the cellular effects of adenoviral binding and internalization on epithelial functions. Here, we examine its effects on the secretory acinar epithelial cells of the lacrimal gland, responsible for stimulated release of tear proteins into ocular fluid. Exposure of reconstituted rabbit lacrimal acini to replication-defective Ad for 16-18 h under conditions that resulted in 480% transduction efficiency did not alter cytoskeletal filament or biosynthetic/endosomal membrane compartment organization. Transduction specifically altered the organization of the stimulated secretory pathway, eliciting major dispersal of rab3D immunofluorescence from apical stores normally associated with mature secretory vesicles. Biochemical studies revealed that this dispersal was not associated with altered rab3D expression nor its release from cellular membranes. Ultraviolet (UV)-inactivated Ad elicited similar dispersal of rab3D immunofluorescence. In acini exposed to replication-defective or UVinactivated Ad, carbachol-stimulated release of bulk protein and b-hexosaminidase were significantly (Pp0.05) inhibited to an extent proportional to the loss of rab3D-enriched mature secretory vesicles associated with these treatments. We propose that the altered secretory compartment organization and function caused by Ad reflects changes in the normal maturation of secretory vesicles, and that these changes are caused by exposure to the Ad capsid.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland

et al. 2004

View full text Add to dashboard Cite

show abstract

“…One of the cytokines once considered elementary to inflammation, epithelial attack, and tissue damage in the exocrine tissues in pSS is tumor necrosis factor a (TNFa), and its inhibition was linked to suppression of tissue destruction in lacrimal glands [77,78] and in immortalized human salivary gland acinar cells in vitro [79,80]. In addition, TNFa is capable of inducing apoptosis and reportedly causes redistribution of several autoantigens (such as the nuclear proteins Ro and La and the cytoplasmic protein afodrin) on the cell membrane of apoptotic cells, all consonant with a vital role in pathogenesis.…”

Section: Tnfamentioning

confidence: 99%

T Lymphocytes in Sjögren’s Syndrome: Contributors to and Regulators of Pathophysiology

Katsifis

Moutsopoulos

Wahl

2007

Clinic Rev Allerg Immunol

101

View full text Add to dashboard Cite

Sjögren's syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration and malfunction of the exocrine glands, resulting in dry mouth and eyes. This multigenic and multifunctional disease can present as primary Sjögren's syndrome or secondary to an underlying connective tissue disease. Immune activation subsequent to activation or apoptosis of glandular epithelial cells in genetically predisposed individuals may expose autoantigens, which engage self-perpetuating T cell dependent autoimmune sequelae. The cellular and molecular context of this immune response may drive proinflammatory (Th1 and Th17) and restrain inhibitory (Treg) pathways. Inability to suppress the immune response results in persistent tissue damage and compromised function of salivary and lacrimal glands. Defining the contributions of participating T cells may unravel strategies for therapeutic intervention.

show abstract

“…There has been considerable interest in the application of gene therapy to the anterior segment of the eye for applications including enhancement of corneal and conjunctival wound healing (9), correction of allograft rejection after corneal transplantation (5), and suppression of lacrimal gland autoimmunity associated with Sjögren's syndrome (61,62).…”

mentioning

confidence: 99%

“…Despite real prospects for the rational design of advanced macromolecular therapeutics for treatment of severe dry eye disorders, therapy remains a remote possibility from a drug delivery standpoint. The only methods utilized successfully in animal models for gene delivery to the lacrimal gland have used replication-defective Ad5-derived vectors, which are sufficiently immunogenic to preclude their use in clinical trials (61,62). To our knowledge, there are no reports regarding delivery of other therapeutic molecules such as proteins, peptides, or antisense oligonucleotides into the lacrimal gland.…”

mentioning

confidence: 99%

Novel Fiber-Dependent Entry Mechanism for Adenovirus Serotype 5 in LacrimalAcini

Xie

Chiang²,

Contreras³

et al. 2006

J Virol

View full text Add to dashboard Cite

The established mechanism for infection of most cells with adenovirus serotype 5 (Ad5) involves fiber capsid protein binding to coxsackievirus-adenovirus receptor (CAR) at the cell surface, followed by penton base capsid protein binding to ␣ v integrins, which triggers clathrin-mediated endocytosis of the virus. Here we determined the identity of the capsid proteins responsible for mediating Ad5 entry into the acinar epithelial cells of the lacrimal gland. Ad5 transduction of primary rabbit lacrimal acinar cells was inhibited by excess Ad5 fiber or knob (terminal region of the fiber) but not excess penton base. Investigation of the interactions of recombinant Ad5 penton base, fiber, and knob with lacrimal acini revealed that the penton base capsid protein remained surface associated, while the knob domain of the fiber capsid protein was rapidly internalized. Introduction of rabbit CAR-specific small interfering RNA (siRNA) into lacrimal acini under conditions that reduced intracellular CAR mRNA significantly inhibited Ad5 transduction, in contrast to a control (nonspecific) siRNA. Preincubation of Ad5 with excess heparin or pretreatment of acini with a heparinase cocktail each inhibited Ad5 transduction by a separate and apparently additive mechanism. Functional and imaging studies revealed that Ad5, fiber, and knob, but not penton base, stimulated macropinocytosis in acini and that inhibition of macropinocytosis significantly reduced Ad5 transduction of acini. However, inhibition of macropinocytosis did not reduce Ad5 uptake. We propose that internalization of Ad5 into lacrimal acini is through a novel fiber-dependent mechanism that includes CAR and heparan sulfate glycosaminoglycans and that the subsequent intracellular trafficking of Ad5 is enhanced by fiber-induced macropinocytosis.

show abstract

Tumor Necrosis Factor Inhibitor Gene Expression Suppresses Lacrimal Gland Immunopathology in a Rabbit Model of Autoimmune Dacryoadenitis

Cited by 33 publications

References 22 publications

Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland

Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland

T Lymphocytes in Sjögren’s Syndrome: Contributors to and Regulators of Pathophysiology

Novel Fiber-Dependent Entry Mechanism for Adenovirus Serotype 5 in LacrimalAcini

Contact Info

Product

Resources

About