The results suggest that cyclosporin A eye drops inhibited fibrosis and inflammatory cell infiltration by the suppression of Th2 cytokine production in repeatedly antigen-challenged conjunctiva without affecting the early-phase reaction.

BackgroundKnock-in mice (gp130F759) with a Y759F point mutation in gp130, a signal transducing receptor subunit shared by members of the IL-6 cytokine family, show sustained activation of STAT3, enhanced acute-phase or immune responses, and autoimmune arthritis. We conducted a detailed analysis of collagen-induced arthritis (CIA) in gp130F759 with a DBA/1J background (D/J.gp130F759).MethodsWe backcrossed gp130F759 to C57BL/6 and DBA/1J, and compared the pathologic changes, including occurrence of arthritis, in the two distinct genetic backgrounds. We analyzed CIA in D/J.gp130F759 and investigated the effects of methotrexate (MTX) on CIA.ResultsC57BL/6 background gp130F759 mice, but not D/J.gp130F759, spontaneously developed polyarthritis and glomerulonephritis. On the other hand, keratitis of the eyes only developed in D/J.gp130F759, indicating the influence of genetic background on disease development in gp130F759 mice. Resistance of the DBA/1J background against spontaneous arthritis urged us to examine CIA in D/J.gp130F759. CIA in D/J.gp130F759 was more severe, with greater bone destruction, than the control mice. After collagen immunization, splenomegaly and serum levels of rheumatoid factor and anti-DNA antibody were augmented in D/J.gp130F759. Bio-Plex analysis of serum cytokines revealed increased IL-12p40 and PDGF-BB before immunization, and increased levels of IFN-γ, IL-17, TNF-α, IL-9, and MIP-1β 8 days after the booster dose. IL-6 and PDGF-BB in D/J.gp130F759 showed distinct kinetics from the other cytokines; higher levels were observed after arthritis development. MTX partially attenuated the development of arthritis and inhibited bone destruction in D/J.gp130F759, with reduction of anti-type II collagen antibody levels, suggesting that MTX mainly affects antigen-specific immune responses in CIA.ConclusionThe Tyr-759 point mutation of the IL-6 family cytokine receptor subunit, gp130, caused autoimmune disease, and this was also influenced by the genetic background. CIA in D/J.gp130F759 is useful for evaluating drugs in a relatively short period because sustained activation of STAT3 may enhance the disease symptoms.

Cyclosporine A (CyA) is a cyclic polypeptide calcineurin inhibitor that was first purified in the 1970s by Novartis Pharma (formerly Sandoz Pharma, Switzerland) from cultures of the fungus Tolypocladium inflatum. It has long been a trusted agent for suppressing not only graft rejection after transplantation, but also immune reaction disorders often observed in autoimmune diseases. The therapeutic effects of CyA eye drops in the treatment of vernal keratoconjunctivitis (VKC), one of the most severe refractory allergic conjunctival diseases, have been described in several studies. [1][2][3] VKC involves severe allergic inflammation sufficient to cause the formation of proliferative conjunctival giant papillae, hyperemia, edema, swelling, mucous discharge and corneal damage. It has been reported that the infiltration of inflammatory cells such as mast cells, eosinophils, neutrophils, and T cells were detected in the papillae of VKC patients. [4][5][6][7][8] Therefore, in addition to immunoglobulin E (IgE)-mediated allergy induced by mast cells, a late phase reaction mediated by eosinophils and delayed-type allergy induced by T cells are thought to be involved in VKC induction.Fukushima et al. reported the inhibitory effect of CyA eye drops on eosinophil infiltration in a mouse allergic conjunctivitis model. 9) We have also reported that the instillation of CyA inhibited neutrophil infiltration into the conjunctiva in a delayed-type allergic conjunctivitis model in guinea pigs. 10)However, the efficacy of CyA eye drops in treating the symptoms in these allergic conjunctivitis models has not been previously reported. Therefore, to understand how CyA works in VKC therapy, we investigated the effects of CyA eye drops on ocular symptoms in late phase and delayed-type allergic conjunctivitis models in guinea pigs. Animals Five-week-old male guinea pigs (Hartley, Nippon SLC, Shizuoka, Japan) were housed under a 12-h light-12-h dark cycle (07:00-19:00 h), with room temperature maintained at 23Ϯ3°C and humidity at 50Ϯ20%. Food and water were given ad libitum. All experiments were performed in accordance with the Association for Research in Vision and Ophthalmology statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Santen Institutional Animal Care and Use Committee. MATERIALS AND METHODS ReagentsInduction of Late Phase Reaction in the Allergic Conjunctivitis Model Allergic conjunctivitis was induced using the method of Sengoku et al.,11) with some modification. OVA solution (40 mg/ml dissolved in saline) was emulsified with an equal volume of FCA. Then, 1 ml of the mixture was intraperitoneally injected into guinea pigs on days 0 and 7. Twenty-four days after the first immunization, 10 ml of 15% OVA solution was applied topically to the right eye to elicit an allergic reaction. Inhibitory Effects of Cyclosporine A Eye Drops on Symptoms in Late Phase and Delayed-Type Reactions in Allergic Conjunctivitis ModelsDaisuke SHII,* Shizu NAKAGAWA, Miwa YOSHIMI, Osamu KATSUTA, Tomoko ODA, and Masat...

A unique conjunctive stricture was observed in the eye of a male 17-week-old Japanese White rabbit (Kbl:JW). The conjunctival membrane had proliferated centripetally and covered a large portion of the cornea. However, the membrane did not adhere to the cornea. Histopathologically, the inner epithelium of the conjunctival membrane appeared flattened, while the outer epithelium had become stratified and squamous. Goblet cells were observed on both sides of the epithelium. The lamina propria consisted of well-developed, vascularized collagen fiber. Myxoid change was seen near the tip of the membrane. In animals, these conjunctival membranes have been reported in a few dwarf rabbits, dogs and horses and have had various different terms applied to them due to their unknown etiology. Based on the conventions of human ophthalmology, such lesions should be regarded as pseudopterygia. Therefore, the present case was diagnosed as involving a pseudopterygium. The centripetal proliferation of the conjunctival membrane may be a characteristic finding in animal cases. Our goal is to encourage accumulation of such cases by researchers and practitioners working in the field of toxicology. (J Toxicol Pathol 2008; 21: 239-241)

Spontaneous nephroblastoma is an uncommon tumor in laboratory rabbits. We recently encountered this tumor, and we describe its histological characteristics in this report. A male 3-year-old Japanese White rabbit (JW/kbs), maintained as a stock animal, suddenly showed poor condition and was found dead a few days later. At necropsy, a large mass was found that extended from one side of the renal pelvis. The cut surface of the mass was dark red in color and velvety to the touch. The kidney on the contralateral side was normal. Microscopically, the tumor mass consisted of biphasic components, which consisted of epithelial (tubular and glomerular) and blastemal (nodular) elements. No sarcomatous proliferation was observed. In addition, some of the tubules were lined by cells with a large amount of eosinophilic cytoplasm. The cells were confirmed as oncocytes by immunohistochemical and electron microscopic examinations. The present case was therefore diagnosed as a nephroblastoma with oncocytic differentiation.