FTY720 prolongs clear corneal allograft survival with a differential effect on different lymphocyte populations

Abstract

Background: FTY720 is a potent immunomodulator with unique effects on lymphocyte homing and has recently proved to be safe and effective in renal transplantation in man. The authors investigated the potency of FTY720 in inhibiting allograft rejection in the rat model of orthotopic allogeneic penetrating keratoplasty. Methods: Penetrating keratoplasties were performed using Fisher rats as donors and Lewis rats as recipients or donors: group 1 (n = 10), allogeneic control; group 2 (n = 10), Lewis/Lewis syngeneic control; group 3 (n = 9), mycophenolate mofetile (MMF) 40 mg/kg; group 4 (n = 10), FTY720 1.2 mg/kg; group 5 (n = 8), FTY720 0.3 mg/kg. Four animals from each group were sacrificed for immunohistological evaluation on day 14. Medication in the therapy groups was given for 18 days. Results: The mean (SD) rejection free graft survival time was 11.3 (0.8) days for the allogeneic control (group 1), 24.6 (2.5) days for group 3 (MMF), 44.5 (5.7) days for group 4 (FTY720 1.2 mg/kg), and 35.3 (5.7) days for group 5 (FTY720 0.3 mg/kg) (p,0.05). The allogeneic control showed a dense infiltration with CD4+, CD8+, CD161+ (NK-cells), CD25+ (IL2 receptor), and macrophages. In the therapy groups the density of infiltrating CD4+, CD8+, CD161+ (NK-cells), and CD25+ (IL2 receptor) cells was notably reduced compared with the allogeneic control (p,0.05). In group 5 however, the reduction of infiltration by CD4+ cells was higher than the reduction of infiltration by CD8+ (p,0.05) and CD161+ (NK) cells. Discussion: Oral immunosuppression with FTY720 significantly prolongs corneal allograft survival in this transplant model. The results suggest that FTY720 has a different effect on certain lymphocyte populations. CD4+ cells seem to be more affected than CD8+ cells and NK-cells.

Fingolimod (FTY720) as an Acute Rescue Therapy for Intraocular Inflammatory Disease

“…Fingolimod has been successful in preventing inflammation in numerous systems, 22,29,30 including relapsingremitting multiple sclerosis, 23 ocular inflammation, 24 limiting inflammation, and infiltration following transplantation, [31][32][33] and as a rescue therapy following cardiac transfer, dramatically extending allograft survival 34 (and as a single dose, limiting adverse events that may accrue with chronic therapy 35 ). We wished to test the efficacy of short-term treatment with fingolimod in EAU.…”

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

“…The role of Tregs in malaria infection remains controversial (58), and therefore the impact of S1P on this cell type during infection requires further investigation. Despite FTY720 mainly affecting T cells (15), an effect on B and NK cells cannot be excluded (59). NK cells have been implicated as potent IFNγ producers during malaria infection (60) and the reduced inflammation observed in FTY720-treated animals ( Figure 4B) may result partially from an effect of FTY720 on NK cells.…”

Proliferative Expansion and Acquisition of Effector Activity by Memory CD4+ T Cells in the Lungs following Pulmonary Virus Infection

“…Although FTY720 is believed to act preferentially on S1PRs displayed by lymphocytes (with the CD4 ϩ T cell exhibiting the greatest sensitivity to the drug) (15,16), other potential CD4 ϩ T cell-independent effects of the drug such as suppression of RSV replication in the lungs and/or inhibition of viral Ag delivery to the PBLN through the inhibition of dendritic cell migration (17) might occur. This would also result in impaired viral Ag recognition by T cells (in the lung-draining PBLN), which could account for the observed inhibition of the memory CD4 ϩ T cell response in the lungs.…”