Person: Dana, Reza
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Dana
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Reza
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Dana, Reza
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Publication Systemic Immunomodulatory Strategies in High-risk Corneal Transplantation(Medknow Publications & Media Pvt Ltd, 2017) Abud, Tulio B.; Di Zazzo, Antonio; Kheirkhah, Ahmad; Dana, RezaThe cornea is the most commonly transplanted tissue in the body. Although corneal grafts generally have high success rates, transplantation onto inflamed and vascularized host beds, or so-called high-risk corneal transplantation, has a high rate of graft rejection. The management of this high-risk corneal transplantation is challenging and involves numerous measures. One of the key measures to prevent graft rejection in these cases is the use of systemic immunosuppressive agents. In this article, we will review the systemic immunosuppressive agents most commonly used for high-risk corneal transplantation, which include corticosteroids, cysclosporine A, tacrolimus, mycophenolate mofetil, and rapamycin. Benefits, risks, and published data on the use of these medications for high-risk corneal transplantation will be detailed. We will also summarize novel immunoregulatory approaches that may be used to prevent graft rejection in high-risk corneal transplantation.Publication T Cell–Derived Granulocyte-Macrophage Colony-Stimulating Factor Contributes to Dry Eye Disease Pathogenesis by Promoting CD11b+ Myeloid Cell Maturation and Migration(The Association for Research in Vision and Ophthalmology, 2017) Dohlman, Thomas H.; Ding, Julia; Dana, Reza; Chauhan, SunilPurpose Growing evidence suggests that granulocyte-macrophage colony-stimulating factor (GM-CSF) contributes to T helper 17 (Th17) cell–associated immunoinflammatory diseases. The purpose of this study was to evaluate the effect of T cell–derived GM-CSF on CD11b+ myeloid cell function in dry eye disease (DED). Methods: In a murine model of DED, quantitative real-time PCR and ELISA were used to measure GM-CSF expression at the ocular surface, and flow cytometry was used to enumerate GM-CSF producing Th17 cells. A granulocyte-macrophage colony-stimulating factor neutralizing antibody was used topically in vivo and in an in vitro culture system to evaluate the role of GM-CSF in recruiting and maturing CD11b+ cells. Clinical disease severity was evaluated after topical administration of GM-CSF neutralizing antibody. Results: In dry eye disease, GM-CSF is significantly upregulated at the ocular surface and the frequency of GM-CSF producing Th17 cells is significantly increased in the draining lymph nodes. In vitro neutralization of GM-CSF from CD4+ T cells derived from DED mice suppresses major histocompatibility complex II expression by CD11b+ cells and CD11b+ cell migration. Topical neutralization of GM-CSF in a murine model of DED suppresses CD11b+ maturation and migration, as well as Th17 cell induction, yielding a reduction in clinical signs of disease. Conclusions: T helper 17 cell–derived GM-CSF contributes to DED pathogenesis by promoting CD11b+ cell activation and migration to the ocular surface.Publication Influence of Aging on the Polar and Neutral Lipid Profiles in Human Meibomian Gland Secretions(American Medical Association (AMA), 2006) Sullivan, Benjamin D.; Evans, James E.; Dana, Reza; Sullivan, DavidObjective To determine whether aging is associated with significant alterations in the polar and neutral lipid profiles in human meibomian gland secretions. Methods Meibomian gland secretions were collected from both eyes of younger and older men and women. Samples were processed for high-performance liquid chromatography or mass spectrometry and for the analysis of associated spectra of fragment ions. Subjects also underwent slitlamp evaluations of the eyelid. Results Aging is associated with numerous significant alterations in the lipid profiles of human meibomian gland secretions. Analysis of polar and neutral lipid patterns identified ions that were significantly different in secretions of younger vs older men and women, as well as ions that varied significantly only between men and women. Correlation coefficients within, but not between, groups were high. Aging was accompanied by increased opacity of meibomian gland secretions and by eyelid and eyelid margin changes. Conclusion Aging is associated with significant sex-related alterations in the polar and neutral lipid profiles of human meibomian gland secretions. Clinical Relevance The observed changes may contribute to the age-related increase in the prevalence of dry eye syndromes.Publication Modulation of Integrin α4β1 (VLA-4) in Dry Eye Disease(American Medical Association (AMA), 2008) Ecoiffier, Tatiana; Dana, Reza; El Annan, Jaafar; Rashid, Saadia; Schaumberg, Debra A.Objective To study the effect of topical application of very late antigen 4 (VLA-4) small-molecule antagonist (anti–VLA-4 sm) in a mouse model of dry eye disease. Methods Anti–VLA-4 sm (or control vehicle) was applied topically to mice placed in a controlled-environment chamber. Corneal fluorescein staining and conjunctival T-cell enumeration were performed in the different treatment groups. Real-time polymerase chain reaction was used to quantify expression of inflammatory cytokines in the cornea and conjunctiva. Results Dry eye syndrome induced increased corneal fluorescein staining, corneal and conjunctival tumor necrosis factor α messenger RNA expression, and T-cell infiltration into the conjunctiva. Very late antigen 4 blockade significantly decreased corneal fluorescein staining compared with the untreated dry eye disease and control vehicle–treated groups (P < .001 and P = .02, respectively). In addition, VLA-4 blockade was associated with a significant decrease in conjunctival T-cell numbers (P < .001 vs control vehicle–treated group) and tumor necrosis factor-α transcript levels in the cornea (P = .04 vs control vehicle–treated group) and conjunctiva (P = .048 vs control vehicle–treated group). Conclusion Application of topical anti–VLA-4 sm led to a significant decrease in dry eye signs and suppression of inflammatory changes at the cellular and molecular levels. Clinical Relevance Topical blockade of VLA-4 may be a novel therapeutic approach to treat the clinical signs and inflammatory changes accompanying dry eye disease.Publication Amelioration of Murine Dry Eye Disease by Topical Antagonist to Chemokine Receptor 2(American Medical Association (AMA), 2009) Goyal, Sunali; Chauhan, Sunil; Zhang, Qiang; Dana, RezaObjective To determine the effect of a topical antagonist to the chemokine receptor 2 (CCR2) in a murine model of dry eye disease. Methods The effects of a topical CCR2 antagonist and a vehicle control treatment were studied in murine dry eyes. A controlled environment chamber induced dry eye by exposing mice to high-flow desiccated air. Corneal fluorescein staining and enumeration of corneal CD11b+ and conjunctival CD3+ T cells were performed in the different groups. Real-time polymerase chain reaction was performed to quantify expression of different inflammatory cytokine transcripts in the cornea and conjunctiva. Results Eyes receiving the formulation containing CCR2 antagonist showed a significant decrease in corneal fluorescein staining and decreased infiltration of corneal CD11b+ cells and conjunctival T cells compared with the vehicle-treated and untreated dry eye groups. The CCR2 antagonist also significantly decreased messenger RNA expression levels of interleukins 1α and 1β in the cornea, and tumor necrosis factor α and interleukin 1β in the conjunctiva. Conclusion Topical application of CCR2 antagonist is associated with significant improvement in dry eye disease and is reflected by a decrease in inflammation at the clinical, molecular, and cellular levels. Clinical Relevance Topical application of CCR2 antagonist may hold promise as a therapeutic modality in dry eye disease.Publication Role of CCR7 in Facilitating Direct Allosensitization and Regulatory T-Cell Function in High-Risk Corneal Transplantation(Association for Research in Vision and Ophthalmology (ARVO), 2010) Jin, Yiping; Chauhan, Sunil; Saban, Daniel R.; Dana, RezaPurpose. Chemokine receptor 7 (CCR7) is a key homing molecule for immune cell trafficking, including corneal antigen-presenting cell (APC) migration from the inflamed cornea to draining lymph nodes (LNs). Here, the authors investigated the effect of CCR7-facilitated donor APC trafficking on allosensitization, regulatory T-cell (Treg) function, and graft survival in corneal transplantation. Methods. CCR7−/− or wild-type (WT) allogeneic corneal grafts were transplanted onto the neovascularized high-risk recipient beds. Two weeks later, the frequency of directly alloprimed host T cells was measured by the IFN-γ ELISPOT assay. Treg function was tested by a coculture suppression assay and an IFN-γ ELISPOT assay. Kaplan-Meier analysis was performed to evaluate graft survival. Results. The recipients of CCR7−/− grafts had fewer migrated donor APCs and lower frequency of IFN-γ–producing T cells in the draining LNs. However, there was no statistically significant difference in transplant survival between recipients of CCR7−/− and those of WT grafts. Tregs from the CCR7−/− graft recipient group showed reduced regulatory potential for the suppression of proliferation of naive T cells and direct alloprimed T cells and expressed lower Foxp3 levels. In vitro studies confirmed that mature CCR7+ major histocompatibility complex class II+ CD86+ graft-derived dendritic cells were critical for Treg function. Conclusions. Not only is CCR7-mediated donor-derived APC trafficking to the draining LNs important in the initiation of host T-cell priming, it is crucial for Treg-mediated tolerance.Publication The International Workshop on Meibomian Gland Dysfunction: Report of the Clinical Trials Subcommittee(Association for Research in Vision and Ophthalmology (ARVO), 2011) Asbell, Penny A.; Stapleton, Fiona J.; Wickström, Kerstin; Akpek, Esen K.; Aragona, Pasquale; Dana, Reza; Lemp, Michael A.; Nichols, Kelly K.Diagnostic tests of meibomian gland dysfunction (MGD) and of MGD-related disorders are based on the demonstration of abnormal anatomy and physiology of the glands and the detection of specific pathologic events. For this reason, this subcommittee report is divided into two sections. In part I, those aspects of meibomian anatomy and physiology that are relevant to currently available tests are described; a fuller account of the anatomy and physiology is provided in the report of the Anatomy Subcommittee of this workshop. In part II, each test and its performance is described in detail. In part III, the practical application of selected tests is summarized and recommendations for future approaches are made. Additional recommendations and a summary of pertinent literature and concepts are presented in Appendices 1 to 17.Publication Blockade of Prolymphangiogenic Vascular Endothelial Growth Factor C in Dry Eye Disease(American Medical Association (AMA), 2012) Goyal, Sunali; Chauhan, Sunil; Dana, RezaObjective To determine if blocking prolymphangiogenic factors like VEGF-C would suppress alloimmunity in dry eye disease (DED) using a murine model. Methods The effects of intraperitoneal injections of 400 μg of anti-VEGF-C antibody (treated group) and intraperitoneal normal saline (untreated group) were studied in murine dry eyes induced by exposing mice to high-flow desiccated air in the Controlled Environment Chamber (CEC). Growth of lymphatic vessels and infiltration of macrophages was evaluated by immunohistochemistry using CD31 (pan-endothelial marker), LYVE -1(lymphatic endothelial marker) and CD11b (monocytes/macrophages marker). Real time PCR was performed to quantify expression of different inflammatory cytokine transcripts in the conjunctiva and lymph nodes, and vascular endothelial growth factors and their receptors (VEGF-A, C, D/R2, R3) in the cornea. Results Blocking VEGF-C led to significant reduction in lymphatic caliber (P=0.025) and lymphatic area (P=0.006) in the corneas of DED mice. In addition to significantly decreasing (P=0.005) CD11b+ cells, anti-VEGF-C treatment significantly decreased transcript levels of VEGF-C (P=0.002), VEGF-D (P=0.014) and VEGFR-3 (P=0.023) in the corneas of treated group. Significant decrease in expression of inflammatory cytokines in the conjunctiva (IL1-α, P= 0.003; IL1-β, P= 0.025 and IL-6, P= 0.005) and lymph nodes (IFN-γ, P= 0.008; and IL-17, P= 0.003) was also seen with anti-VEGF-C treatment. Conclusions Treatment with anti-VEGF-C led to significant improvement in DED reflected by decrease in inflammation at the clinical, molecular, and cellular levels.Publication Trigeminal stereotactic electrolysis induces dry eye in mice(Wiley-Blackwell, 2012) Ferrari, Giulio; Ueno, Hiroki; Bignami, Fabio; Rama, Paolo; Dana, RezaPublication Topical Ranibizumab as a Treatment of Corneal Neovascularization(Ovid Technologies (Wolters Kluwer Health), 2013) Ferrari, Giulio; Dastjerdi, Mohammad H.; Okanobo, Andre; Cheng, Sheng-Fu; Amparo, Francisco; Nallasamy, Nambi; Dana, RezaPurpose To examine the effect of topical ranibizumab on clinically stable corneal neovascularization (NV). Methods This was a prospective, open-label, monocentric, uncontrolled, non-comparative study. Ten eyes of 9 patients with corneal NV received topical ranibizumab (1%) 4 times a day for 3 weeks with a follow-up of 16 weeks. The main corneal neovascularization outcome measures were: neovascular area (NA), the area occupied by the corneal neovessels; vessel caliber (VC), the mean diameter of the corneal neovessels; and invasion area (IA), the fraction of the total cornea area covered by the vessels. This study was conducted at the Massachusetts Eye and Ear Infirmary, Boston, MA, USA. Results Statistically significant decreases in NA (55.3%, P<0.001), which lasted through 16 weeks, and VC (59%, P<0.001), which continued to improve up to week 16, were observed after treatment. No significant decrease was observed in IA (12.3%, P=0.49). There was no statistically significant change in visual acuity or intraocular pressure. No adverse events ascribed to the treatment were noted. Conclusions Topical application of ranibizumab is effective in reducing the severity of corneal NV in the context of established corneal NV, mostly through decrease in VC rather than IA.