ABSTRACT
IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice spontaneously develop autoimmune arthritis. We demonstrate here that T cells are required for the induction of arthritis; T cell-deficient IL-1Ra(-/-) mice did not develop arthritis, and transfer of IL-1Ra(-/-) T cells induced arthritis in nu/nu mice. Development of arthritis was also markedly suppressed by TNF-alpha deficiency. We found that TNF-alpha induced OX40 expression on T cells and blocking the interaction between either CD40 and its ligand or OX40 and its ligand suppressed development of arthritis. These findings suggest that IL-1 receptor antagonist deficiency in T cells disrupts homeostasis of the immune system and that TNF-alpha plays an important role in activating T cells through induction of OX40.
Subject(s)
Antirheumatic Agents , Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/immunology , Sialoglycoproteins , Tumor Necrosis Factor-alpha/immunology , Animals , Antirheumatic Agents/immunology , CD40 Antigens/immunology , Cell Transplantation , Cytokines/metabolism , Interleukin 1 Receptor Antagonist Protein , Joints/metabolism , Joints/pathology , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Nude , Mice, SCID , Receptors, OX40 , Receptors, Tumor Necrosis Factor/metabolism , Sialoglycoproteins/genetics , Sialoglycoproteins/immunology , T-Lymphocytes/cytology , T-Lymphocytes/metabolismABSTRACT
PURPOSE: To establish a rat model of neurotrophic keratopathy and to examine the effects of the combination of substance P (SP) and insulin-like growth factor (IGF)-1 on corneal epithelial barrier function and wound healing in this model. METHODS: Corneal denervation was achieved by thermocoagulation of the ophthalmic branch of the trigeminal nerve. A modified Schirmer test was performed without topical anesthesia. Corneal epithelial barrier function was assessed by measurement of fluorescein permeability with an anterior fluorophotometer. Epithelial wound healing was evaluated by measurement of the area of the defect at various times after removal of the entire epithelium. Eye drops containing both 1 mM SP and IGF-1 (1 micro g/mL) were administered six times daily. RESULTS: The Schirmer test result in eyes subjected to trigeminal denervation was lower than that in control eyes. The fluorescein permeability of the corneal epithelium of denervated eyes was increased relative to that of control eyes. Furthermore, trigeminal denervation induced a delay in corneal epithelial wound healing. Application of eye drops containing SP and IGF-1 to denervated corneas restored the fluorescein permeability of the corneal epithelium to control levels and abolished the delay in epithelial wound healing. CONCLUSIONS: A rat model of neurotrophic keratopathy, characterized by reduced tear secretion, loss of corneal sensation, impaired epithelial barrier function, and delayed epithelial wound healing, was established by trigeminal denervation. Treatment with both SP and IGF-1 improved corneal epithelial barrier function and stimulated corneal epithelial wound healing in this model.
