FTY720 in corneal concordant xenotransplantation.
BACKGROUND
: Currently, there are no effective treatments for the control of corneal xenograft rejection. We evaluated the efficacy and mode of action of a novel immunosuppressant, FTY720, in a model of corneal xenograft transplantation.


METHODS
: Rat-to-mouse corneal xenografts were performed and the effects of treatment with daily intraperitoneal injections of FTY720 (0.5 or 3.0 mg/kg/day) or saline from 2 days pretransplantation were assessed clinically. Immunohistochemical studies of the grafts and flow cytometry of the draining lymph node subpopulations were performed at the time of clinical rejection.


RESULTS
: Treatment with FTY720 delayed the onset of corneal rejection, from 8 days postgraft in saline-treated mice to 12.0 +/- 0.89 days for low-dose FTY720 treatment and 15.6 +/- 3.1 days for high-dose FTY720 treatment (both P<0.001). Histologically, FTY-treated animals had a markedly reduced inflammatory response in the anterior chamber and cornea after replacement of the xenograft epithelium with normal healthy host epithelium. In contrast, saline-treated xenografts had persisting corneal epithelial defects and ulceration. In the draining lymph nodes, FTY720 not only inhibited the increase in the cell number observed in saline-treated recipients of xenografts, but also reduced the expression of activation markers on B cells (MHC class II and CD86).


CONCLUSIONS
: FTY720 treatment significantly delayed rejection and decreased its severity in a dose-dependent manner in a rat-to-mouse model of corneal xenotransplantation. Since corneal xenograft rejection is mediated not by natural antibodies or CD8+ T cells directly, but by CD4+ T cells, the data from these experiments imply that FTY720 mediated its effect via CD4+ T cells.
Sedláková
Klára
K
Department of Ophthalmology, University of Aberdeen, Aberdeen, UK.
Muckersie
Elizabeth
E
Robertson
Marie
M
Filipec
Martin
M
Forrester
John V
JV
D000818:Animals; D016039:Corneal Transplantation / Q000276:immunology*; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives; D014183:Transplantation, Heterologous / Q000276:immunology*
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine