Administration of a peptide inhibitor of alpha4-integrin inhibits the development of experimental autoimmune uveitis.
OBJECTIVE
Recruitment of 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. alpha4 Integrins and their receptors play an important role during homing of cells to the inflammatory site. In the present study, the effect of alpha4-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 interphotoreceptor retinoid-binding protein (IRBP)-specific uveitogenic T cells. Animals were treated with an active peptide inhibitor (alpha4-api) or a peptide control at different time points after induction of disease. EAU was evaluated by histology 21 to 49 days after immunization. Antigen-specific cell proliferation was evaluated by thymidine incorporation. Cytokine synthesis in culture supernatants and anti-IRBP-specific serum IgG1 and IgG2a were evaluated by ELISA. Delayed-type hypersensitivity was evaluated by ear challenge 2 days before the termination of the experiment.


RESULTS
Treatment with alpha4-api had a significant ameliorating effect on EAU. The anti-IRBP antibody response and cellular proliferation were not affected by the treatment, whereas delayed-type hypersensitivity was significantly diminished. Cytokine synthesis was not changed by treatment, except for a decrease in IL-10 levels.


CONCLUSIONS
The results show that small-molecule inhibitors of alpha4-integrins can act therapeutically in EAU, possibly by interfering with cell adhesion events involved in the development of the disease.
Martín
Andrea P
AP
Department of Immunology, Biomedical Sciences Institute, University of São Paulo, Brazil.
de Moraes
Luciana Vieira
LV
Tadokoro
Carlos E
CE
Commodaro
Alessandra G
AG
Urrets-Zavalia
Enrique
E
Rabinovich
Gabriel A
GA
Urrets-Zavalia
Julio
J
Rizzo
Luiz V
LV
Serra
Horacio M
HM
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D007074:Immunoglobulin G / Q000097:blood; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation; D051379:Mice; D009842:Oligopeptides / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000276:immunology; D012177:Retinol-Binding Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015866:Uveitis, Posterior / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial
D016207:Cytokines; D005136:Eye Proteins; D007074:Immunoglobulin G; D039041:Integrin alpha4beta1; D009842:Oligopeptides; D010446:Peptide Fragments; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C108486:phenylacetyl-leucyl-aspartyl-phenylalanyl-prolineamide