ADMINISTRATION OF A PEPTIDE INHIBITOR OF ALPHA4-INTEGRIN INHIBITS THE DEVELOPMENT OF EXPERIMENTAL AUTOIMMUNE UVEITIS

ANDREA P. MARTIN,; LUCIANA V. DE MORAES,; CARLOS E. TADOKORO,; ALESSANDRA G. COMMODARO,; ENRIQUE URRETS-ZAVALIA,; GABRIEL A. RABINOVICH,; JULIO URRETS-ZAVALIA,; LUIS V. RIZZO,; HORACIO M. SERRA

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE

Association for Research in Vision and Ophthalmology

Lugar: Rockville, MD, USA; Año: 2005 vol. 46 p. 2056 - 2063

0146-0404

PURPOSE: The cascade of events leading to the recruitment of autoreactive lymphocytes into the retina and to the vitreous during the development of Experimental Autoimmune Uveitis (EAU) is governed by factors such as the state of activation of inflammatory cells and the repertoire of adhesion molecules expressed by the local vascular endothelia. It has been shown that a-4 integrins and their receptors play an important role during the homing of cells to the inflammatory site. In the present study, the effect of alpha.4 integrin inhibitor on the development of EAU was investigated. METHODS: EAU was induced either by immunizing B10.RIII mice with the 161-180 peptide or by adoptive transfer of 106 IRBP-specific uveitogenic of T cells. Animals were treated with active peptide inhibitor (a4-api) or an inactive peptide control (control) during the afferent (days 2, 4, 6) or efferent phase (days 14, 16, 18) of the immune response. EAU was evaluated by histology and scores were attributed according eye damage. The immune response was evaluated by antigen-specific cell proliferation of draining lymph nodes and the production of cytokines in the supernantants of cell cultures. Anti-IRBP specific IgG1 and IgG2a isotype production were determined by ELISA in the serum of mice. DTH responses were evaluated in the pinna of the ear 2 days before the termination of the experiment. RESULTS: Treatment with the inhibitor completely prevented both clinical signs and cellular infiltration in actively and passively induced EAU. It is noteworthy that the anti-IRBP antibody response and cellular proliferation were not affected by the treatment, whereas delayed-type hypersensitivity was significantly diminished. We observed an increase of IL-10 levels, whereas the secretion of IL-12, IL-18 and IFN-g was not different from the control. CONCLUSIONS: Our results show that small-molecule inhibitors of a4 integrins can act therapeutically in EAU possibly by interfering with cell adhesion events involved in the development of the disease.