Use of topical FK506 in a corneal graft rejection model in Lewis rats.
OBJECTIVE
To evaluate the immunosuppressive effect of topical FK506 on allograft corneal rejection in rats.


METHODS
Lewis rats were used as recipients and Fisher rats as corneal graft donors. In Experiment 1, all rats received intraperitoneally FK506 (0.3 mg/kg per day) for 7 days to ensure equal baseline parameters. The rats then were assigned randomly to treatment with topical 0.3% FK506 or vehicle alone. In another set of experiments, rats were treated only with topical treatment. The grafts were inspected by clinical evaluation. Corneas obtained at the time of maximum rejection were used for histology and immunohistochemistry.


RESULTS
The selected combination of rat strains caused 100% graft rejection in untreated animals within 2 weeks after the penetrating keratoplasty. In the treated animals, rejection was delayed until the end of topical therapy. One third of corneal grafts remained clear until day 30. Histologic and immunohistochemical studies confirmed the clinical evaluations. Untreated rat corneas had a large number of infiltrating helper-inducer T cells, macrophages, interleukin-2 receptor-expressing cells, and Ia-antigen-expressing cells. At the same timepoint, topically treated corneas showed a limited inflammatory response characterized by a 2/3 reduction in the number of infiltrating helper and cytotoxic cells, and a five-fold decrease in the expression of class I and class II major histocompatibility antigens.


CONCLUSIONS
Topical FK506 treatment is an effective way of preventing corneal graft rejection in the Lewis rat corneal graft model. It shows promise as a drug to prevent corneal graft rejection in humans.
Hikita
N
N
Department of Ophthalmology, Kurume University School of Medicine, Japan.
Lopez
J S
JS
Chan
C C
CC
Mochizuki
M
M
Nussenblatt
R B
RB
de Smet
M D
MD
D000287:Administration, Topical; D000818:Animals; D003315:Cornea / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015948:Keratoplasty, Penetrating / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D009883:Ophthalmic Solutions; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000473:pathology; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D014184:Transplantation, Homologous
D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D015375:Receptors, Interleukin-2; D016559:Tacrolimus