Effects of cytotoxic T lymphocyte antigen 4 (CTLA4) signaling andlocally applied steroid on retinal dysfunction by recoverin,cancer-associated retinopathy antigen

[摘要] Purpose: To assess the cytotoxic T lymphocyte antigen 4 (CTLA4)pathway in the recoverin peptide (R64; AYAQHVFRSF) mouse model ofcancer-associated retinopathy (CAR) and to assess the protective effectsof subconjunctival triamcinalone injections in this model.Methods: To study the role of the CTLA4 pathway on the R64-inducedmouse model of CAR, BALB/c mice were immunized with R64. The mice werefurther intraperitoneally treated with anti-CTLA4 antibody to getstronger immunoreaction. The development of CAR was evaluated byelectroretinogram (ERG) examinations 21 days after treatment. Acytotoxicity assay was employed to detect induction of R64-specificcytotoxic T lymphocytes (CTLs). Immunoblotting to assess the developmentof anti-recoverin antibody and a T cell proliferation assay to determinethe activity of lymphocytes against R64 were examined in twoexperimental groups, anti-CTLA4 antibody treated and untreated mice.Tostudy the protective effect of subconjunctival triamcinalone in thismodel, mice immunized with R64 peptide and anti-CTLA4 antibody wereeither treated with 50 mg/kg/body weight of triamcinalone or phosphatebuffered saline (PBS). These mice were assayed using ERG andhistological examination 35 days after the first R64 immunization.Results: When mice were challenged with R64 peptide and anti-CTLA4antibody, R64 peptide-specific CTLs were induced and decreased b-waveamplitudes were observed in ERG. Conversely, no CAR symptoms weredetected in mice not treated with anti-CTLA4 antibody. Anti-CTLA4antibody treatment did not give any significant differences in T cellproliferation and humoral reaction against recoverin. Subconjunctivaltriamcinalone treated mice show a trend toward improved survival ofouter nuclear layer cell bodies, but did not show significantimprovement of ERG amplitudes compared to the untreated mice.Conclusions: Inhibition of the CTLA4 pathway is essential for thedevelopment of recoverin-induced murine CAR, suggesting thatstrengthening negative T cell signaling through CTLA4 may lessen theretinal degenerations in CAR-affected subjects. The positive effects ofattenuation of the CTLA4 pathway must be weighed against a potentialnegative effect on survival since this pathway may also provide naturalimmunotherapy against the underlying malignancy. Subconjunctivalinjections of triamcinalone may have beneficial effects on the integrityof the outer nuclear layer (ONL) of the retina in the CAR model,although there was no significant effect on the ERG recordings.

[学科分类] 生物化学/生物物理