Evaluation of experimental autoimmune uveitis in mice treated with FTY720.
OBJECTIVE
FTY720 (fingolimod) is an immunomodulatory drug capable of preventing T-cell migration to inflammatory sites by binding to and subsequently downregulating the expression of sphingosine-1 phosphate receptor 1 (S1P(1)) leading in turn to T-cell retention in lymphoid organs. Additional effects of FTY720 by increasing functional activity of regulatory T cells have recently been demonstrated, raising the conversion of conventional T cells into regulatory T cells and affecting the sequestration of regulatory T cells in normal mice. In this study, the action of FTY720 in the ocular autoimmune model in mice was investigated.


METHODS
Mice were immunized with 161-180 peptide and pertussis toxin and were treated with 1 mg/kg/d FTY720 by gavage (7-21 days postimmunization [dpi]) or left untreated. Spleen cells, harvested 21 dpi, were cultured and assayed for cytokine production. Draining lymph node, spleen, and eye cells 21 dpi were assayed for quantification of T-cell populations. Disease severity was evaluated by histologic examination of the enucleated eyes at 21 and 49 dpi. In addition, anti-IRBP antibodies were analyzed by ELISA.


RESULTS
FTY720 was effective in suppressing the experimental autoimmune uveitis score. Although there was a reduction in the number of eye-infiltrating cells, FTY did not prevent Treg accumulation at this site. FTY720 leads to a significant increase of CD4(+)IFN-gamma(+) and CD4(+)Foxp3(+) cell percentages in lymph nodes, suggesting that this site could be the source of Treg cells found in the eye.


CONCLUSIONS
The data showed that treatment in vivo with FTY720 was able to suppress EAU in mice. These results are indicative of the possible therapeutic use of FTY720 in ocular autoimmune processes.
Commodaro
Alessandra Gonçalves
AG
Vision Institute, Universidade Federal de São Paulo, São Paulo, Brazil.
Peron
Jean Pierre S
JP
Lopes
Camila Takao
CT
Arslanian
Christina
C
Belfort
Rubens
R
Rizzo
Luiz Vicente
LV
Bueno
Valquiria
V
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000276:immunology; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007441:Intubation, Gastrointestinal; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology; D011409:Propylene Glycols / Q000008:administration & dosage*; D012177:Retinol-Binding Proteins / Q000276:immunology; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015866:Uveitis, Posterior / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial
D016207:Cytokines; D005136:Eye Proteins; D000068876:Fingolimod Hydrochloride; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D010446:Peptide Fragments; D011409:Propylene Glycols; D012177:Retinol-Binding Proteins; D013110:Sphingosine; D000099214:Retinol-Binding Proteins, Interstitial