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Jing Hua, William Stevenson, Takenori Inomata, Yihe Chen, Thomas H Dohlman, Hyun Soo Lee, Tina Shiang, Masahiro Omoto, Reza Dana; Elevated IL-6 and IL-23 in Dry Eye Hosts Disrupt Peripheral Induction of Tregs and Exacerbate Corneal Allograft Rejection. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3216.
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© ARVO (1962-2015); The Authors (2016-present)
Anecdotal clinical observations suggest that host dry eye disease (DED) undermines corneal graft survival. However, the underlying mechanisms are not well understood. This study investigated the survival rate and the adaptive immune response following corneal allotransplantation in DED host mice.
DED was induced in female Balb/c mice using the controlled environment chamber over two weeks. C57Bl/6 donor corneas were then grafted onto Balb/c mice with DED. Normal Balb/c hosts residing in room air (RA) served as controls. Corneal graft survival was observed over 8 weeks. Flow cytometry (FACS), LN explant culture, and T cell suppression assay were carried out 10 days following transplantation. Cytokines were assayed using ELISA. Additional DED hosts received adoptive transfer of sorted Treg or non-Treg CD4+ cells from naïve Balb/c, or treated with systemic neutralizing antibodies against IL-6, IL-23 or combined.
Significantly fewer corneal grafts survived in DED hosts (22.2%, n=9, vs. RA 50%, n=10, p=0.0084). Tregs from LN of DED hosts showed significantly lower function in the T cell suppression assay (2.6±9.6%, vs. 43.9±2.9% in RA, and 85.1±0.3% in naïve control, n=3). Secreted IL-6 and IL-23 in LN explant culture were significantly increased in DED hosts (1757±31 vs. RA 1483±32pg/ml, n=5, p=0.0007; 24±2 vs. RA 10±1pg/ml, n=5, p=0.004, respectively). Flow cytometric analysis showed a lower frequency of peripherally induced (Nrp-1-) Tregs in both LN and blood samples in DED hosts (23.8% vs. RA 29.9%, n=5). Adoptive transfer of naïve Balb/c Tregs to DED hosts increased graft survival (44.4%, n=9 vs. 10% in non-Treg transferred controls, n=10, p<0.01) with improved Nrp-1- Treg frequency (26.6%, n=5). Systemic combined neutralization of IL-6 and IL-23 demonstrated a similar survival rate (50%, n=10, p<0.01) and an improved Nrp-1- Treg frequency (27.2%, n=5) in the DED hosts.
Elevated IL-6 and IL-23 expression in DED hosts diminishes peripheral induction of Tregs following corneal transplantation, and may be a key mechanism underlying the exacerbation of allograft rejection.
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