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Published Online: 2 March 2009

Protective Effect of Intravitreal Injection of Vasoactive Intestinal Peptide–Loaded Liposomes on Experimental Autoimmune Uveoretinitis

Publication: Journal of Ocular Pharmacology and Therapeutics
Volume 25, Issue Number 1

Abstract

Purpose: The aim of this study was to investigate the effect of a single intravitreal (i.v.t.) injection of vasoactive intestinal peptide (VIP) loaded in rhodamine-conjugated liposomes (VIP-Rh-Lip) on experimental autoimmune uveoretinitis (EAU).
Methods: An i.v.t. injection of VIP-Rh-Lip, saline, VIP, or empty-(E)-Rh-Lip was performed simultaneously, either 6 or 12 days after footpad immunization with retinal S-antigen in Lewis rats. Clinical and histologic scores were determined. Immunohistochemistry and cytokine quantification by multiplex enzyme-linked immunosorbent assay were performed in ocular tissues. Systemic immune response was determined at day 20 postimmunization by measuring proliferation and cytokine secretion of cells from inguinal lymph nodes (ILNs) draining the immunization site, specific delayed-type hypersensitivity (DTH), and the serum concentration of cytokines. Ocular and systemic biodistribution of VIP-Rh-Lip was studied in normal and EAU rats by immunofluorescence.
Results: The i.v.t. injection of VIP-Rh-Lip performed during the afferent, but not the efferent, phase of the disease reduced clinical EAU and protected against retinal damage. No effect was observed after saline, E-Rh-Lip, or VIP injection. VIP-Rh-Lip and VIP were detected in intraocular macrophages and in lymphoid organs. In VIP-Rh-Lip-treated eyes, macrophages expressed transforming growth factor-beta2, low levels of major histocompatibility complex class II, and nitric oxide synthase-2. T-cells showed activated caspase-3 with the preservation of photoreceptors. Intraocular levels of interleukin (IL)-2, interferon-gamma (IFN-γ), IL-17, IL-4, GRO/KC, and CCL5 were reduced with increased IL-13. At the systemic level, treatment reduced retinal soluble autoantigen lymphocyte proliferation, decreased IL-2, and increased IL-10 in ILN cells, and diminished specific DTH and serum concentration of IL-12 and IFN-γ.
Conclusions: An i.v.t. injection of VIP-Rh-Lip, performed during the afferent stage of immune response, reduced EAU pathology through the immunomodulation of intraocular macrophages and deviant stimulation of T-cells in ILN. Thus, the encapsulation of VIP within liposomes appears as an effective strategy to deliver VIP into the eye and is an efficient means of the prevention of EAU severity.

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cover image Journal of Ocular Pharmacology and Therapeutics
Journal of Ocular Pharmacology and Therapeutics
Volume 25Issue Number 1February 2009
Pages: 9 - 22
PubMed: 19232006

History

Published online: 2 March 2009
Published ahead of print: 22 February 2009
Published in print: February 2009

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Serge Camelo
INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872, Paris, France.
Université Paris Descartes, UMR S 872, Paris, France.
Laure Lajavardi
INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872, Paris, France.
Université Paris Descartes, UMR S 872, Paris, France.
Univ Paris Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
Amélie Bochot
INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
Univ Paris Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
Brigitte Goldenberg
INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872, Paris, France.
Université Paris Descartes, UMR S 872, Paris, France.
Marie-Christine Naud
INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872, Paris, France.
Université Paris Descartes, UMR S 872, Paris, France.
Nadège Brunel
Plateforme Technologique Phénotypage du Petit Animal et Microdosages, Hôpital Saint-Antoine, Paris, France.
Bernadette Lescure
Plateforme Technologique Phénotypage du Petit Animal et Microdosages, Hôpital Saint-Antoine, Paris, France.
Christophe Klein
INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872, Paris, France.
Université Paris Descartes, UMR S 872, Paris, France.
Elias Fattal
INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
Univ Paris Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
Francine Behar-Cohen
INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872, Paris, France.
Université Paris Descartes, UMR S 872, Paris, France.
Yvonne de Kozak
INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872, Paris, France.
Université Paris Descartes, UMR S 872, Paris, France.

Notes

*Serge Camelo and Laure Lajavardi have contributed equally to this work.

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