title: Protective effect of intravitreal injection of vasoactive intestinal peptide-loaded liposomes on experimental autoimmune uveoretinitis.
abstract: OBJECTIVE
  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-gamma), 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-gamma.
  
  
  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.
authors.affiliation: INSERM, U872 Physiopathology of Ocular Disease, Therapeutic Innovations, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Camelo
authors.forename: Laure
authors.initials: L
authors.lastname: Lajavardi
authors.forename: Amélie
authors.initials: A
authors.lastname: Bochot
authors.forename: Brigitte
authors.initials: B
authors.lastname: Goldenberg
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Naud
authors.forename: Nadège
authors.initials: N
authors.lastname: Brunel
authors.forename: Bernadette
authors.initials: B
authors.lastname: Lescure
authors.forename: Christophe
authors.initials: C
authors.lastname: Klein
authors.forename: Elias
authors.initials: E
authors.lastname: Fattal
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: de Kozak
mesh_terms: D000818:Animals; D019393:Arrestin / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D007267:Injections; D008081:Liposomes; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012173:Retinitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D012235:Rhodamines; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014605:Uveitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014822:Vitreous Body
chemical_list: D019393:Arrestin; D016207:Cytokines; D008081:Liposomes; D012235:Rhodamines; D014660:Vasoactive Intestinal Peptide