Topical Soluble Tumor Necrosis Factor Receptor Type I Suppresses Ocular Chemokine Gene Expression and Rejection of Allogeneic Corneal Transplants

Abstract

Objective To determine the effect of topical soluble tumor necrosis factor receptor type I (sTNFR-I) on survival of murine orthotopic corneal transplants and on ocular chemokine gene expression after corneal transplantation. Methods BALB/c mice (N = 50) were used as recipients of multiple minor H–disparate corneal transplants from B10.D2 donors. After orthotopic corneal transplantation, mice were randomized in a masked fashion to receive either topical sTNFR-I or vehicle 3 times daily, and all grafts were evaluated for signs of rejection and neovascularization by slitlamp biomicroscopy for 8 weeks. Ocular chemokine gene expression in sTNFR-I– and vehicle only–treated groups was determined using a multiprobe ribonuclease protection assay. Results Hosts treated with topical sTNFR-I experienced significantly enhanced corneal allograft survival compared with animals treated with vehicle alone (P = .01). Moreover, postoperative messenger RNA levels of RANTES and macrophage inflammatory protein-1β in sTNFR-I–treated eyes were substantially suppressed compared with vehicle-treated eyes. Vehicle-treated eyes bearing rejected allografts expressed higher levels of messenger RNA for both chemokines than control eyes bearing accepted allografts. Conclusions Topical treatment with sTNFR-I promotes the acceptance of allogeneic corneal transplants and inhibits gene expression of 2 chemokines (RANTES and macrophage inflammatory protein-1β) associated with corneal graft rejection. Clinical Relevance Our findings support the feasibility of a topical anticytokine strategy as a means of reducing corneal allograft rejection without resorting to the use of potentially toxic immunosuppressive drugs.