Comparison of topical interleukin-1 vs tumor necrosis factor-alpha blockade with corticosteroid therapy on murine corneal inflammation, neovascularization, and transplant survival (an American Ophthalmological Society thesis).
OBJECTIVE
Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) play critical roles in mediating corneal inflammation. In this study, topical blockade of IL-1 and TNF-alpha, alone or in combination, was compared to conventional corticosteroid anti-inflammatory therapy in suppressing infiltration of the cornea by antigen-presenting Langerhans cells (LCs) and in promoting corneal transplant survival in a mouse model of keratoplasty.


METHODS
Study drugs included topical 2% IL-1 receptor antagonist (IL-1Ra), 1.5% soluble TNF-alpha receptor (sTNFR), and 1% prednisolone phosphate (Pred), all formulated in hyaluronic acid vehicle. Fifty eyes of BALB/c mice were used for LC studies where the numbers of LCs were determined 1 week after electrocautery to the corneal surface or transplantation of C57BL/6 corneas. Additionally, 65 BALB/c mice received corneal allografts and were randomized to receive one of the following for 8 weeks: (1) IL-1Ra, (2) sTNFR, (3) Pred, (4) combined IL-1Ra and Pred, or (5) vehicle alone.


RESULTS
Mean suppression of LC infiltration after electrocautery or transplantation was 67% and 71%, respectively, for IL-1Ra, 40% and 62% for sTNFR, 70% and 72% for sTNFR+IL-1Ra, and 77% and 78% for Pred alone. Rejection rates were 15% for IL-1Ra (P = .01), 38% for sTNFR (P = .1), 17% for Pred (P = .02), and 7% for combined IL-1Ra+Pred (P = .002) as compared to 69% for the vehicle-treated group. IL-1Ra and Pred, but not sTNFR, significantly inhibited post-transplantation neovascularization.


CONCLUSIONS
Topical IL-1Ra and prednisolone are comparable in their capacity to promote graft survival. sTNFR therapy, though effective, has much lower efficacy as compared to IL-1Ra or Pred. Combination IL-1Ra and steroid therapy offers only minimal added efficacy over either agent used alone.
Dana
Reza
R
Laboratory of Immunology, Schepens Eye Research Institute, and the Cornea Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, USA.
D000287:Administration, Topical; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000818:Animals; D003316:Corneal Diseases / Q000188:drug therapy*; D016039:Corneal Transplantation / Q000502:physiology*; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation / Q000517:prevention & control; D007375:Interleukin-1 / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D023421:Models, Animal; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000305:Adrenal Cortex Hormones; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha