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A New Concept in Keratoconus

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A New Concept in Keratoconus Gonadotropins: A new concept in keratoconus AuthorBlock: Dimitrios Karamichos1, Brayden Barrientez1, Sarah E. Nicholas1, Symon Ma1, Lyly Van1, Sashia Bak-Nielsen2, Jesper Hjortdal2 1Ophthalmology, OUHSC, Dean McGee Eye Institute, Oklahoma City, Oklahoma, United States; 2Aarhus University, , Denmark; DisclosureBlock: Dimitrios Karamichos, University of Oklahoma Health Sciences Center Code P (Patent), Brayden Barrientez, None; Sarah E. Nicholas, None; Symon Ma, None; Lyly Van, None; Sashia Bak-Nielsen, None; Jesper Hjortdal, None; Purpose Keratoconus (KC) is the most common ectatic corneal disease with significant visual acuity burden. Despite recent advancements, KC pathobiology remains unclear. In recent years, our focus has been on unravelling the role of sex hormones in KC. The current study presents evidence, for the first time, that sex hormone imbalances in KC initiated from the anterior pituitary and the secretion of gonadotropins.Methods The purpose of this study was to investigate the role of gonadotropins in KC. We recruited 86 KC patients (63 male, 23 female), and 45 healthy controls (22 male, 23 female). Plasma samples were collected and analyzed using enzyme-linked immunosorbent assay. Corneal stromal cells from KC and healthy controls and human epithelial corneal cells were also investigated for gonadotropin-related markers.Results Our findings showed a significantly lower LH/FSH ratio in KCs when compared to healthy controls, in both males and females. The lowest LH/FSH ratio was seen in KC-Females at the 15-29y/o and ≥46y/o age groups and was directly correlated with increased KC severity. Stromal cells from both healthy and KC expressed LH, LHR, and FSHR, but not FSH. Corneal epithelial cells only expressed FSHR.Conclusions Our study is the first to demonstrate the role of LH/FSH in KCs and expands the list of organs known to express gonadotropins to include the human cornea. Our findings suggest an intriguing mechanism for the onset and/or progression of KC.Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details. Corneal nerve ablation abolishes ocular immune privilege through a SP-mediated down-regulation of CD103 and interferon gamma receptor expression on T regulatory cells. AuthorBlock: Jerry Y. Niederkorn1, Sudha neelam1 1Ophthalmology, Univ Texas Southwestern Med Ctr, Dallas, Texas, United States; DisclosureBlock: Jerry Y. Niederkorn, None; Sudha neelam, None; Purpose Severing corneal nerves during orthotopic corneal transplantation elicits the elaboration of the neuropeptide substance P (SP), which induces the generation of CD11c+ contrasuppressor (CS) cells. CS cells disable T regulatory cells (Tregs) that are induced when antigens enter the anterior chamber, either by direct injection or by orthotopic corneal transplantation. This study examined the crucial cell surface molecules on T regulatory cells that are adversely affected by CS cells that are generated by severing corneal nerves.Methods CS cells were induced by severing corneal nerves with a 2.0 mm trephine in the corneal epithelium of BALB/c mice. Anterior chamber-associated immune deviation (ACAID) CD8+ Tregs were generated by injecting ovalbumin into the anterior chamber (AC). We analyzed the effects of CS cells and SP on the expression and function of two cell surface molecules (CD103 and the receptor of interferon-gamma; IFN-γR), that are crucial for the induction and function of ACAID T regs. CS cells were co-cultured with ACAID Tregs and the expression of CD103 and IFN-γR was analyzed by flow cytometry. Transwell cultures were used to determine if the effect of CS cells on CD103 and IFN-γR expression was contact- dependent.Results Severing corneal nerves resulted in a 66% reduction in the expression of CD103 and a 70% reduction in the interferon-gamma receptor (IFN-γR) on CD8+ ACAID Tregs isolated from the spleens of trephined mice. These effects could be mimicked in vitro by co-culturing CD8+ ACAID T regs with either CS cells or with SP. Down regulation of CD103 and IFN-γR on ACAID Tregs by CS cells was found to be contact-dependent.Conclusions Severing corneal nerves resulted in a 66% reduction in the expression of CD103 and a 70% reduction in the interferon-gamma receptor (IFN-γR) on CD8+ ACAID Tregs isolated from the spleens of trephined mice. These effects could be mimicked in vitro by co-culturing CD8+ ACAID T regs with either CS cells or with SP. Down regulation of CD103 and IFN-γR on ACAID Tregs by CS cells was found to be contact-dependent.Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details. The effect of the diabetic state in donors on resident corneal immune cells and graft survival AuthorBlock: Hayate Nakagawa1, Tomas Blanco1, Sonia Anchouche1, Rohan Bir Singh1, Hamid Alemi1, Jia Yin1, Reza Dana1 1Schepens Eye Research Institute of Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States; DisclosureBlock: Hayate Nakagawa, None; Tomas Blanco, None; Sonia Anchouche, None; Rohan Bir Singh, None; Hamid Alemi, None; Jia Yin, None; Reza Dana, None; Purpose The diabetic state promotes infiltration and maturation of antigen presenting cells (APC) in the cornea. The effect of these corneal APCs on outcomes of corneal transplantation is yet to be elucidated. In this study, we investigate the effect of altered immune milieu in corneas from diabetic donors transplanted to normal recipients, using a validated murine model of corneal allotransplantation.Methods Type I diabetes mellitus was induced in C57BL/6 mice by injecting 50mg/kg streptozocin (STZ) for 5 days. The altered glycemic state was confirmed by a self-monitoring glucometer. On day 25, mice with blood glucose levels of 300mg/dL were considered diabetic. The corneas from diabetic mice were harvested and grafted onto normal BALB/c recipient mice, or used for flow cytometry analysis. Recipient mice were followed up for 8 weeks using slit-lamp biomicroscopy. Two weeks after the transplantation, both cornea and draining lymph node of recipient mice were analyzed using flow cytometry.Results A significantly higher frequency of CD11b+ cells (82±2.5%, p=0.0009) and higher expression of MHC- II (fold increase p=0.048) were observed in corneas from diabetic donors compared to normal mice. The allograft rejection was faster in recipients of diabetic donor corneas compared to recipients with normal donors. CD11b+ cells frequency (2.58±0.2%;p=0.014) as well as their maturation markers such as MHC-II (p=0.006), CD80 (p=0.007) and CD86 (p=0.03), were significantly increased in recipients corneas with diabetic donors compared to recipients with normal donors. The frequency of CD11b+APCs (0.9±0.06%; p=0.047) and IFNγ+ T-cells (2±0.18%; p=0.005) were significantly higher in dLNs of mice receiving grafts from diabetic donors compared to recipients with normal donors. Conversely, the frequency of FoxP3+ Tregs (13.3±0.2%; p=0.012), and their expression of IL-10 (p=0.07) and TGFβ1 (p=0.0085) were significantly reduced in mice receiving grafts from diabetic donors compared to recipients with normal donors.Conclusions Our data suggest that type I diabetes mellitus induces maturation of resident corneal immune cells and; consequently, diabetic donor corneas may precipitate graft immune rejection in recipient mice.Layman Abstract (optional): Provide a 50-200 word description of your work that non- scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details. PRE-ACTIVATED MESENCHYMAL STROMAL CELLS INDUCE REGULATORY IMMUNE POPULATIONS IN VIVO AND PROLONG CORNEAL ALLOGRAFT SURVIVAL AuthorBlock: Thomas Ritter1, Oliver Treacy2,1, Xizhe Chen1, Nick Murphy1, Paul Lohan1, Md Nahidul Islam1, Ellen Donohoe1, Matthew Griffin1, Luke Watson3, Steven McLoughlin1, Grace O'Malley2, Kevin Lynch2,1, Aideen Ryan2 1Medicine, Nt'l Univ of Ireland, Galway, Galway, Ireland; 2Discipline of Pharmacology and Therapeutics, National University of Ireland Galway, Galway, Ireland; 3Orbsen Therapeutics, Galway, Ireland; DisclosureBlock: Thomas Ritter, None; Oliver Treacy, None; Xizhe Chen, None; Nick Murphy, None; Paul Lohan, None; Md Nahidul Islam, None; Ellen Donohoe, None; Matthew Griffin, None; Luke Watson, None; Steven McLoughlin, None; Grace O'Malley, None; Kevin Lynch, None; Aideen Ryan, None; Purpose To investigate a novel licensing strategy to significantly improve the immunosuppressive capacity of MSCs in vitro and their therapeutic efficacy in vivo in a fully allogeneic murine corneal transplant model.Methods Murine mesenchymal stromal cells (Balb/c) were pre-conditioned with TGF-β1 (TGF-β MSC) and tested for immunomodulatory properties in vitro in T cell co-culture assays. Moroever we tested if TGF-β MSC had an enhanced ability to prolong rejection free survival in a fully allogeneic mouse cornea transplant model (C57BL/6 to Balb/c). Immune cell populations were analysed in the draining lymph nodes, spleens and lungs of TGF-β MSC treated mice. Finally, contact-dependent and contact- independent signalling mechanisms of TGF-β MSC were investigated to identify the mechanism of action of enhanced immunomodulation.Results Pre-conditioning of murine MSC with TGF-β1 (TGF-β MSC) significantly improved their ability to modulate innate and adaptive immune cells in vitro and in vivo. We found that TGF-β MSCs significantly suppressed the proliferation of stimulated CD3+CD4+ and CD3+CD8+ T lymphocytes while significantly increasing the numbers of CD3+CD4+FoxP3+ regulatory T lymphocytes (Tregs) following co-culture assays. We tested if TGF-β MSC had an enhanced ability to prolong rejection free survival in a fully allogeneic mouse cornea transplant model (C57BL/6 to Balb/c). TGF-β MSC treated mice presented with a rejection free survival rate of 70% (n=13) compared to 25% (n=14) in the non- activated MSC treatment group.
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