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Morio Ueno, Munetoyo Toda, Asako Hiraga, Naomi Tobita, Hiroko Nakagawa, Chie Sotozono, Noriko Koizumi, Kazuko Asada, Junji Hamuro, Shigeru Kinoshita; Analysis of cytokines in serum and aqueous humor in patients with bullous keratopath. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4018.
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© ARVO (1962-2015); The Authors (2016-present)
We are developing novel regenerative medicine for bullous keratopathy (BK) using cultivated human corneal endothelial cells (cHCECs). Although transplanted cells hold promise for treating BK by ‘seeding’ corneal endothelium, the regenerative ability of the cells is influenced by the host microenvironment. Here we examined cytokines in aqueous humor (AH) and serum of BK patients for future elucidation of the contribution of the microenvironment for improvement of the surgical outcome
Serum samples were obtained from BK patients before and after undergoing cell therapy. AH samples were obtained at the start of the surgical procedure from BK patients undergoing cell therapy or DSAEK. Bio-Plex® Multiplex Immunoassay (BIO-RAD Laboratories) was used to measure the concentrations of 48 cytokines and 4 adipokines.
IL-1ra, IL-12, IL-17, IP-10, MCP-1, IFN-γ, G-CSF, GM-CSF, MIP-1β, Eotaxin, RANTES, TNF-α, PDGF-bb, b-FGF, and VEGF were detected in all serum samples. Concentrations of IL-12, IL-17, IP-10, G-CSF, MIP-1β, RANTES, PDGF-bb, and VEGF were particularly higher than the historical serum data of subjects without BK. Variation in serum cytokine levels was found among BK patients before cell infusion. Three distinct patterns of periodical changes of serum cytokines were observed after cell therapy. Examination of cytokines in cHCEC-conditioned medium (CM) as a source of systemic cytokines in serum showed that cytokine profiles of the CM differed from those of the serum, and that the CM from the culture of cHCECs with phase transitions such as fibrosis contained elevated levels of senescence-associated secretory phenotypes (SASPs). IL-6, IL-8, IP-10, MCP-1, and GM-CSF were elevated in the CM of phase-transitioned cHCECs and in all AH samples, while VEGF was elevated in most of the samples. Interestingly, SASPs driving cHCECs into senescence were elevated in the BK-patient AH samples. Relative AH cytokine levels varied among the BK patients, indicating the presence of variations among them and the relevance of the pathological conditions of the microenvironment in which the cells will be seeded.
A variety of cytokines including SASPs exist in the AH of BK patients. The cytokine profiles are candidate markers to stratify BK patients. Modification of the cytokine profiles can possibly improve the prognosis of corneal regenerative medicine for BK.
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