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Biodegradable scaffolds play an important adjunct role in transplantation of retinal progenitor cells (RPCs) to the subretinal space. Poly(ε-Caprolactone) (PCL) scaffolds with different modifications were subretinally implanted in 28 porcine eyes and evaluated by multifocal electroretinography (mfERG) and histology after 6 weeks of observation. PCL Short Nanowire, PCL Electrospun, and PCL Smooth scaffolds were well tolerated in the subretinal space in pigs and caused no inflammation and limited tissue disruption. PCL Short Nanowire had an average rate of preserved overlying outer retina 17% higher than PCL Electrospun and 25% higher than PCL Smooth. Furthermore, PCL Short Nanowire was found to have the most suitable degree of stiffness for surgical delivery to the subretinal space. The membrane-induced photoreceptor damage could be shown on mfERG, but the reductions in P1 amplitude were only significant for the PCL Smooth. We conclude that of the tested scaffolds, PCL Short Nanowire is the best candidate for subretinal implantation.

Purpose: The purpose of this study was to evaluate the impact of vitrectomy and posterior hyaloid (PH) peeling on color alteration of optic nerve head (ONH) and retina as a surrogate biomarker of induced perfusion changes., Methods: Masked morphometric and colorimetric analyses were conducted on preoperative (<1 month) and postoperative (<18 months) color fundus photographs of 54 patients undergoing vitrectomy, either with (44) or without (10) PH peeling and 31 years of age and gender-matched control eyes. Images were calibrated according to the hue and saturation values of the parapapillary venous blood column. Chromatic spectra of the retinal pigment epithelium and choroid were subtracted to avoid color aberrations. Red, green, and blue (RGB) bit values over the ONH and retina were plotted within the constructed RGB color space to analyze vitrectomy-induced color shift. Vitrectomy-induced parapapillary vein caliber changes were also computed morphometrically., Results: A significant post-vitrectomy red hue shift was noted on the ONH (37.1 degrees ± 10.9 degrees vs. 4.1 degrees ± 17.7 degrees, P < 0.001), which indicates a 2.8-fold increase in blood perfusion compared to control (2.6 ± 1.9 vs. 0.9 ± 1.8, P < 0.001). A significant post-vitrectomy increase in the retinal vein diameter was also noticed (6.8 ± 6.4% vs. 0.1 ± 0.3%, P < 0.001), which was more pronounced with PH peeling (7.9 ± 6.6% vs. 3.1 ± 4.2%, P = 0.002)., Conclusions: Vitrectomy and PH peeling increase ONH and retinal blood flow. Colorimetric and morphometric analyses offer valuable insights for future artificial intelligence and deep learning applications in this field., Translational Relevance: The methodology described herein can easily be applied in different clinical settings and may enlighten the beneficial effects of vitrectomy in several retinal vascular diseases.

Purpose: Short chain fatty acids (SCFAs) produced by gut microbiota are known to play primary roles in gut homeostasis by immunomodulation partially through G-protein coupled receptors (GPR) 43. Using mouse models of TLR ligand induced keratitis, we investigated whether SCFAs and GPR43 play any regulatory roles in the pathogenesis of inflammatory responses in the eye., Methods: Both human and mouse eyes were labeled with a specific antibody for GPR43 and imaged by a laser scanning confocal microscope. Corneal cups from naïve C57BL/6J (B6) and GPR43 knockout (KO) mice were stimulated with TLR ligands in the presence or absence of sodium butyrate overnight and then processed for RT-PCR assay for expression of GPR43 and cytokines. Keratitis was induced by Poly I:C in wild type (WT) B6, GPR43KO and chimeric mice and the disease severity was evaluated by the corneal fluorescein staining test, and infiltrating cell staining and calculating in corneal whole mount., Results: GPR43 is expressed in both human and mouse eyes and the expression is bidirectionally regulated by TLR ligands and butyrate. Butyrate significantly inhibited inflammation caused by several TLR ligands such as Poly I:C, Flagellin, and CpG-ODN (TLR-3, 5 and 9 agonists, respectively) in WT, but not GPR43KO, mice. Butyrate inhibition of TLR-induced keratitis is mediated by the GPR43 expressed in tissue but not hematopoietic, cells., Conclusions: This is the first report to demonstrate of the protective effect of SCFAs on microbial keratitis, and the dynamic expression and anti-inflammatory function of GPR43 in the eye. SCFAs can modulate inflammation and immunity in the eye through GPR43., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow 13 C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Autoimmune diseases caused by T cells can arise from either T-helper 1 (Th1) or T-helper 17 (Th17)-type pathogenic T cells. However, it is unclear whether these two T-cell subsets are influenced by distinct pathogenic factors and whether treatments that are effective for Th1 responses also work for Th17 responses. To compare these two pathogenic responses, we conducted a systematic analysis in a mouse model of experimental autoimmune uveitis (EAU) to identify the factors that promote or inhibit each response and to determine their responses to various treatments. Our study found that the two types of pathogenic responses differ significantly in their pathological progressions and susceptibility to treatments. Specifically, we observed that extracellular adenosine is a crucial pathogenic molecule involved in the pathogenicity of inflammation and T-cell reactivity and that reciprocal interaction between adenosine and gamma delta (γδ) T cells plays a significant role in amplifying Th17 responses in the development of autoimmune diseases. The potential effect of targeting adenosine or adenosine receptors is analyzed regarding whether such targeting constitutes an effective approach to modulating both γδ T-cell responses and the pathogenic Th17 responses in autoimmune diseases.

Purpose: The purpose of this study was to quantify retinal hydration (RH) levels with optical coherence tomography (OCT) and determine the extent of cellular damage resulting from intraretinal fluid alterations., Methods: We took 6.0 mm sections of the human sensory retina that were excised from 18 fresh (<24 hours) donor eyes. They were either exposed to various osmotic stresses between 90 and 305 mOsm or dehydrated under a laminar flow hood. Change in tissue weight was used to calculate the retinal water content (RWC). Image analyses were conducted on OCT between 0 and 180 minutes to assess retinal thickness (RT) and "optically empty areas" (OEAs) representing intraretinal fluid. Correlations were sought among RWC, OEA, RWC, and RT. The effect of RH on retinal cell viability (RCV) was assessed with the Live-Dead Assay., Results: RH demonstrated a stronger correlation with the OEA than plain RT measurements (r = 0.99, P < 0.001). RH-RCV interaction fits well to a bell-shaped curve. A significant proportion of retinal cells (>80%) remained viable despite the change in RH ranging between 0.87 and 1.42 times. This "safe zone" was found to be associated with a 22% increase in OEA (r = 0.99, P < 0.01)., Conclusions: OCT has been demonstrated as a valuable tool for assessing RH and can be used for intraretinal fluid content analysis. RH is a better indicator of RCV compared with RT. Computing RH may improve the determination of functional outcome of intravitreal pharmacotherapeutics used for diabetic macular edema and exudative age-related macular degeneration., Translational Relevance: We link basic research and clinical care by assessing retinal hydration's impact on retinal fluid dynamics, macular edema, and cell viability.

Age-related macular degeneration (AMD) is a progressive degenerative disease of the central retina and the leading cause of severe loss of central vision in people over age 50. Patients gradually lose central visual acuity, compromising their ability to read, write, drive, and recognize faces, all of which greatly impact daily life activities. Quality of life is significantly affected in these patients, and there are worse levels of depression as a result. AMD is a complex, multifactorial disease in which age and genetics, as well as environmental factors, all play a role in its development and progression. The mechanism by which these risk factors interact and converge towards AMD are not fully understood, and therefore, drug discovery is challenging, with no successful therapeutic attempt to prevent the development of this disease. In this review, we describe the pathophysiology of AMD and review the role of complement, which is a major risk factor in the development of AMD.

Background: Retained surgical items (RSIs) are rare but serious events associated with significant morbidity and costs. We assessed the effectiveness of radiofrequency (RF) detection technology and Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) in reducing the incidence of RSIs., Study Design: All RSIs reported to the New York Patient Occurrence Reporting and Tracking System at five large urban teaching hospitals from 2007 to 2017 were analyzed. In 2012, TeamSTEPPS training was provided to all perioperative staff at each site, and use of RF detection became required in all procedures. The incidence of events before and after the interventions were compared using odds ratios., Results: A total of 997,237 operative procedures were analyzed. After the interventions, the incidence of RSIs decreased from 11.66 to 5.80 events per 100,000 operations (odds ratio [OR] [95% CI] = 0.50 [0.32 to 0.78]). The frequency of RSIs involving RF-detectable items decreased from 5.21 to 1.35 events per 100,000 operations (OR [95% CI] = 0.26 [0.11 to 0.60]). The difference in RSIs involving non-RF-detectable surgical items was not statistically significant., Conclusions: The incidence of RSIs was significantly lower during the time period after implementing RF detection technology and after TeamSTEPPS training, primarily driven by a decrease in retained RF-detectable items. RF detection technology may be worth pursuing for hospitals looking to decrease RSI frequency. The benefit of TeamSTEPPS training alone may not result in a reduction of RSIs., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Resection of many congenital lung lesions is commonly performed under single-lung ventilation, which helps collapse the lung being manipulated and enables a thoracoscopic approach in most cases. We set out to determine whether lung isolation achieved by either main stem intubation or usage of a bronchial blocker was associated with superior clinical outcomes. Materials and Methods: A retrospective review of all patients aged <2 years undergoing elective pulmonary lobectomy for congenital lung malformations at a tertiary-care pediatric hospital from 2011 through 2020 was performed. Demographic data, diagnosis type, type of lung isolation method employed, and perioperative outcomes were recorded. Continuous variables were analyzed with Student's t -tests, whereas categorical variables were analyzed with Fisher's exact tests and chi-square tests. Results: Thirty-two patients were analyzed-17 were managed with a bronchial blocker while 15 underwent main stem intubation. The most common diagnoses were congenital pulmonary airway malformations (53.1%) and intralobar bronchopulmonary sequestrations (34.4%). Patients managed with main stem intubation were slightly younger ( P  = .06) than those for which a bronchial blocker was used. Thirty-one (96.9%) resections were initiated thoracoscopically. Main stem intubation was associated with shorter operative times ( P  = .01), shorter anesthetic times ( P  = .02), and less blood loss ( P  = .04). No differences in length of stay ( P  = .64), conversation to thoracotomy ( P  = .35), intraoperative complications ( P  = .23), or postoperative complications ( P  = .49) were observed. Conclusion: Lung isolation through main stem intubation, when compared with bronchial blockers, is associated with shorter operative time, shorter anesthetic exposure, and diminished blood loss in pediatric patients undergoing lobectomy for congenital lung anomalies.

The extracellular level of adenosine increases greatly during inflammation, which modulates immune responses. We have previously reported that adenosine enhances Th17 responses while it suppresses Th1 responses. This study examined whether response of DC to adenosine contributes to the biased effect of adenosine and determined whether adenosine and TLR ligands have counteractive or synergistic effects on DC function. Our results show that adenosine is actively involved in both in vitro and in vivo activation of pathogenic T cells by DCs; however, under adenosine effect DCs' capability of promoting Th1 versus Th17 responses are dissociated. Moreover, activation of A2ARs on DCs inhibits Th1 responses whereas activation of A2BRs on DC enhances Th17 responses. An intriguing observation was that TLR engagement switches the adenosine receptor from A2ARs to A2BRs usage of bone marrow-derived dendritic cells (BMDCs) and adenosine binding to BMDCs via A2BR converts adenosine's anti-to proinflammatory effect. The dual effects of adenosine and TLR ligand on BMDCs synergistically enhances the Th17 responses whereas the dual effect on Th1 responses is antagonistic. The results imply that Th17 responses will gain dominance when inflammatory environment accumulates both TLR ligands and adenosine and the underlying mechanisms include that TLR ligand exposure has a unique effect switching adenosine receptor usage of DCs from A2ARs to A2BRs, via which Th17 responses are promoted. Our observation should improve our understanding on the balance of Th1 and Th17 responses in the pathogenesis of autoimmune and other related diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Splenectomy, still a commonly performed treatment for splenic injury in trauma patients, has been shown to have a high rate of complications. The purpose of this study was to identify predictors, including race and insurance status, associated with adverse outcomes post-splenectomy in trauma patients. We discuss possible explanations and methods for reducing these disparities., Methods: The American College of Surgeons - Trauma Quality Improvement Program (ACS-TQIP) participant user database was queried from 2010 to 2015 and patients who underwent total splenectomy were identified. All mechanisms of injury, including both blunt and penetrating trauma, were included. Patients with advance directives limiting care or aged under 18 were excluded. Propensity score matching was used to control for age, preexisting medical conditions, and the severity of the traumatic injury. A chi-squared test was used to find significant associations between available predictors and outcomes for this cross-sectional study., Results: The post-splenectomy mortality rate was 9.2% (n = 1047), 8.0% (n = 918) of patients had three or more complications, and 20.3% (n = 2315) had major complications. A primary race of white (OR 0.7, 95% Confidence Interval (CI) 0.6-0.9, p < 0.01) and private insurance (OR 0.5, 95%CI 0.4-0.6, p < 0.01) were associated with lower risks of mortality A primary race of neither Black nor white (OR 1.3, 95%CI 1.03-1.7, p = 0.03) and a lack of health insurance ("self-pay") (OR 1.6, 95%CI 1.3-1.9, p < 0.01) were both correlated with mortality. When limited to hospitals of 600+ beds, there were no associations between race and mortality., Conclusion: The post-splenectomy mortality rate after trauma remains high. In U.S. trauma centers, a primary race of Black and payment status of "self-pay" are associated with adverse outcomes after splenectomy following a traumatic injury. These disparities are reduced when limiting analysis to larger hospitals. Efforts to reduce disparities in outcomes among trauma patients requiring a splenectomy should focus on improving resource availability and quality in smaller hospitals., Competing Interests: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (© 2022 The Authors.)

γδ T cells are important immunoregulatory cells in experimental autoimmune uveitis (EAU), and the activation status of γδ T cells determines their disease-enhancing or inhibitory effects. Because γδ T cells can be activated via various pathways, we questioned whether the nature of their activation might impact their function. In this study, we show that γδ T cells activated under different inflammatory conditions differ greatly in their functions. Whereas anti-CD3 treatment activated both IFN-γ + and IL-17 + γδ T cells, cytokines preferentially activated IL-17 + γδ T cells. γδ T cells continued to express high levels of surface CD73 after exposure to inflammatory cytokines, but they downregulated surface CD73 after exposure to dendritic cells. Although both CD73 high and CD73 low cells have a disease-enhancing effect, the CD73 low γδ T cells are less inhibitory. We also show that polarized activation not only applies to αβ T cells and myeloid cells, but also to γδ T cells. After activation under Th17-polarizing conditions, γδ T cells predominantly expressed IL-17 (gdT17), but after activation under Th1 polarizing conditions (gdT1) they mainly expressed IFN-γ. The pro-Th17 activity of γδ T cells was associated with gdT17, but not gdT1. Our results demonstrate that the functional activity of γδ T cells is strikingly modulated by their activation level, as well as the pathway through which they were activated., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Pro- and ant-inflammatory effects of IFN-γ have been repeatedly found in various immune responses, including cancer and autoimmune diseases. In a previous study we showed that the timing of treatment determines the effect of adenosine-based immunotherapy. In this study we examined the role of IFN-γ in pathogenic Th17 responses in experimental autoimmune uveitis (EAU). We observed that IFN-γ has a bidirectional effect on Th17 responses, when tested both in vitro and in vivo . Anti-IFN-γ antibody inhibits Th17 responses when applied in the initial phase of the immune response; however, it enhances the Th17 response if administered in a later phase of EAU. In the current study we showed that IFN-γ is an important immunomodulatory molecule in γδ T cell activation, as well as in Th17 responses. These results should advance our understanding of the regulation of Th17 responses in autoimmunity., Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. It is a leading cause of visual disability, with an incidence of ~1 in 7000 persons. Although most RP is nonsyndromic, 20%-30% of patients with RP also have an associated nonocular condition. The gene mutations responsible for RP occur overwhelmingly in rod photoreceptors. Visual loss frequently begins with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors. Although the visual disability from rod dysfunction is significant, it is the subsequent loss of central vision later in life due to cone degeneration that is catastrophic. Until recently, the reason for cone dysfunction in RP was unknown. However, it is now recognized that cones degenerate, losing outer segment (OS) synthesis and inner segment (IS) disassembly because of glucose starvation following rod demise. Rod OS phagocytosis by the apical microvilli of retinal pigment epithelium is necessary to transport glucose from the choriocapillaris to the subretinal space. Although cones lose OS with the onset of rod degeneration in RP, regardless of the gene mutation in rods, cone nuclei remain viable for years (i.e. enter cone dormancy) so that therapies aimed at reversing glucose starvation can prevent and/or recover cone function and central vision., Competing Interests: The authors declare that there are no conflicts of interest in this paper., (Copyright: © 2021 Taiwan Journal of Ophthalmology.)

Background: Exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including autoimmune development. The role of circulating exosomes in the development of autoimmune uveitis is unknown. In this study, using the rat model of experimental autoimmune uveitis, which has clinical and histological features of pan uveitis in man, we evaluated the immunoregulatory function of circulating exosomes., Methods: Experimental autoimmune uveitis was induced in Lewis rats either immunised with interphotoreceptor retinoid-binding protein R16 peptides or injected with activated R16-specific T cells. The disease incidence and severity were examined by indirect fundoscopy and flow cytometry. Circulating exosomes were isolated from peripheral blood of naïve and Day 14 R16 immunised Lewis rats. The effect of exosomes on specific T cells was evaluated by R16-specific T cell proliferation, cytokine production and recurrent uveitis induction., Results: Circulating exosomes derived from active immunised uveitis rats selectively inhibited immune responses of R16-specific T cells in vitro. Vaccination of naïve rats with these exosomes reduced the incidence of recurrent uveitis in an antigen-specific manner. Antigen-specific uveitogenic T cells reduced IFN-γ production and increased IL-10 after vaccination., Conclusions: Circulating exosomes in autoimmune uveitis have the potential to be a novel treatment for recurrent autoimmune uveitis., (© 2021 Royal Australian and New Zealand College of Ophthalmologists.)

Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RP) is the most common cause of RP in North America. There is no proven cure for the disease, and multiple approaches are being studied. Gene therapy is an evolving field in medicine and ophthalmology. In this review, we will go over the basic concept of gene therapy and the different types of gene therapy that are currently being studied to treat this disease., Competing Interests: The authors declare that there are no conflicts of interests of this paper., (Copyright: © 2021 Taiwan Journal of Ophthalmology.)

Adenosine is an important regulatory molecule of the immune response. We have previously reported that treatment of experimental autoimmune uveitis (EAU)-prone mice with an adenosine-degrading enzyme (adenosine deaminase) prohibited EAU development by inhibiting Th17 pathogenic T cell responses. To further validate that the targeting of adenosine or adenosine receptors effectively modulates Th17 responses, we investigated the effect of adenosine receptor antagonists. In this study, we show that the A2AR antagonist SCH 58261 (SCH) effectively modulates aberrant Th17 responses in induced EAU. However, timing of the treatment is important. Whereas SCH inhibits EAU when administered during the active disease stage, it did not do so if administered during quiescent disease stages, thus implying that the existing immune status influences the therapeutic effect. Mechanistic studies showed that inhibition of γδ T cell activation is crucially involved in adenosine-based treatment. Adenosine is an important costimulator of γδ T cell activation, which is essential for promoting Th17 responses. During ongoing disease stages, adenosine synergizes with existing high levels of cytokines, leading to augmented γδ T cell activation and Th17 responses, but in quiescent disease stages, when existing cytokine levels are low, adenosine does not enhance γδ T cell activation. Our results demonstrated that blockade of the synergistic effect between adenosine and inflammatory cytokines at active disease stages can ameliorate high-degree γδ T cell activation and, thus, suppress Th17 pathogenic T cell responses., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Our previous studies demonstrated that γδ T cells have a strong regulatory effect on Th17 autoimmune responses in experimental autoimmune uveitis (EAU). In the current study, we show that reciprocal interactions between mouse γδ T cells and dendritic cells (DCs) played a major role in γδ regulation of Th17 responses. Mouse bone marrow-derived dendritic cells (BMDCs) acquired an increased ability to enhance Th17 autoimmune responses after exposure to γδ T cells; meanwhile, after exposure, a significant portion of the BMDCs expressed CD73 - a molecule that is fundamental in the conversion of immunostimulatory ATP into immunosuppressive adenosine. Functional studies showed that CD73 + BMDCs were uniquely effective in stimulating the Th17 responses, as compared to CD73 - BMDCs; and activated γδ T cells are much more effective than non-activated γδ T cells at inducing CD73 + BMDCs. As a result, activated γδ T cells acquired greater Th17-enhancing activity. Treatment of BMDCs with the CD73-specific antagonist APCP abolished the enhancing effect of the BMDCs. γδ T cells more effectively induced CD73 + BMDCs from the BMDCs that were pre-exposed to TLR ligands, and the response was further augmented by adenosine. Moreover, BMDCs acquired increased ability to stimulate γδ activation after pre-exposure to TLR ligands and adenosine. Our results demonstrated that both extra-cellular adenosine and TLR ligands are critical factors in augmented Th17 responses in this autoimmune disease, and the reciprocal interactions between γδ T cells and DCs play a major role in promoting Th17 responses., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cannabidiol (CBD) exhibits anti-inflammatory and neuroprotective properties and is suggested to be effective in the pre-clinical and clinical treatment of illnesses of the central nervous system (CNS). Two major types of CNS glial cells, astrocytes and microglia, play critical roles in the development and pathogenesis of CNS diseases. However, the mechanisms by which CBD plays an anti-inflammatory and neuroprotective role for these glial cells have not been fully elucidated. In this study, we examined the effects of CBD on the inflammatory response of mouse primary astrocytes and microglia. We also investigated whether the effect of CBD on cytokine release is mediated by the G protein coupled receptor 3 (GPR3), which was recently identified as a novel receptor for CBD. Our results showed that CBD inhibited inflammatory responses of astrocytes and microglia stimulated with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand in vitro and in vivo. In addition, CBD reduced the phosphorylation of STAT3 and NF-κB signaling pathways in LPS-stimulated astrocytes. However, the inhibitory effect of CBD on pro-inflammatory cytokine production was independent of GPR3 expression in both types of glial cells. Thus, although CBD is effective in ameliorating the activation of astrocytes and microglia, its mechanism of action still requires further study. Our data support the concept that CBD may have therapeutic potential for neurological disorders that involve neuroinflammation., Competing Interests: No authors have competing interests.

Short chain fatty acids (SCFAs) are produced by gut microbiota as fermentation products of digestion-resistant oligosaccharides and fibers. Their primary roles are functioning as major energy sources for colon cells and assisting in gut homeostasis by immunomodulation. Recent evidence suggests that they affect various organs both at cellular and molecular levels, and regulate functions in distance sites including gene expression, cell proliferation, cell differentiation, apoptosis and inflammation. In this study, we examined whether SCFAs are present in the mouse eye and whether SCFAs affect inflammatory responses of the eye and retinal astrocytes (RACs). We observed that intra-peritoneal injected SCFAs were detected in the eye and reduced intraocular inflammation induced by lipopolysaccharide (LPS). Moreover, SCFAs displayed two disparate effects on LPS-stimulated RACs - namely, cytokine and chemokine production was reduced, but the ability to activate T cells was enhanced. Our results support the existence of gut-eye cross talk and suggest that SCFAs can cross the blood-eye-barrier via the systemic circulation. If applied at high concentrations, SCFAs may reduce inflammation and impact cellular functions in the intraocular milieu., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Posterior ocular trauma and the subsequent fibrotic retinal complication termed proliferative vitreoretinopathy (PVR) are leading causes of blindness in children and young adults. A previous study suggested that changes occurring within the first month post-trauma can lead to development of PVR later. The aim of this study was to examine the effect of dasatinib, a tyrosine kinase inhibitor clinically used to treat chronic myeloid leukemia, on fibrotic changes occurring within the first month following ocular trauma., Methods: A previously established swine ocular trauma model that mimics both contusion and penetrating injuries was used. Dasatinib was administered on days 4 and 18 post-trauma via intravitreal injection of either bolus solution or suspension of a sustained release system incorporated in biodegradable poly (lactic-co-glycolic acid) (PLGA) nanoparticles. Animals were followed up to day 32, and the development of traction full-thickness fold in the posterior retina was assessed., Results: A full-thickness retinal fold extending from the wound site developed in 3 out of 4 control eyes injected with PLGA nanoparticles alone at 1 month. Administration of dasatinib solution had little preventative effect with 6 out of 7 eyes developing a fold. In contrast, dasatinib-incorporated PLGA nanoparticle injection significantly reduced the incidence of fold to 1 out of 10 eyes., Conclusions: Injection of dasatinib-incorporated PLGA significantly reduced early fibrotic retinal changes which eventually lead to PVR following posterior ocular trauma. Thus, our sustained dasatinib release system can potentially be used to both prevent and/or broaden the surgical treatment window for PVR.

Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can "cloak" the vector from inducing unwanted immune responses in multiple, but not all, models. This "coupled immunomodulation" strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Various pathological conditions are accompanied by release of adenosine triphosphate (ATP) from the intracellular to the extracellular compartment, where it degrades into adenosine and modulates immune responses. Previous studies concluded that both ATP and its degradation product adenosine are important immune-regulatory molecules; ATP acted as a danger signal that promotes immune responses, but adenosine's effect was inhibitory. We show that adenosine receptor ligation plays an important role in balancing Th1 and Th17 pathogenic T cell responses in experimental autoimmune uveitis (EAU). While its effect on Th1 responses is inhibitory, its effect on Th17 responses is enhancing, thereby impacting the balance between Th1 and Th17 responses. Mechanistic studies showed that this effect is mediated via several immune cells, among which γδ T cell activation and dendritic cell differentiation are prominent; adenosine- and γδ-mediated immunoregulation synergistically impact each other's effect. Adenosine receptor ligation augments the activation of γδ T cells, which is an important promoter for Th17 responses and has a strong effect on dendritic cell (DC) differentiation, tipping the balance from generation of DCs that stimulate Th1 responses to those that stimulate Th17 responses. The knowledge acquired in this study should improve our understanding of the immune-regulatory effect of extracellular ATP-adenosine metabolism and improve treatment for autoimmune diseases caused by both Th1-and Th17-type pathogenic T cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Chronic endoplasmic reticulum stress resulting from misfolding of the visual pigment rhodopsin (RHO) can lead to loss of rod photoreceptors, which initiates retinitis pigmentosa, characterized initially by diminished nighttime and peripheral vision. Cone photoreceptors depend on rods for glucose transport, which the neurons use for assembly of visual pigment-rich structures; as such, loss of rods also leads to a secondary loss of cone function, diminishing high-resolution color vision utilized for tasks including reading, driving, and facial recognition. If dysfunctional rods could be maintained to continue to serve this secondary cone preservation function, it might benefit patients with retinitis pigmentosa, but the mechanisms by which rods are removed are not fully established. Using pigs expressing mutant RHO, we find that induction of a danger-associated molecular pattern (DAMP) "eat me" signal on the surface of mutant rods is correlated with targeting the live cells for (PrCR) by retinal myeloid cells. Glucocorticoid therapy leads to replacement of this DAMP with a "don't eat me" immune checkpoint on the rod surface and inhibition of PrCR. Surviving rods then continue to promote glucose transport to cones, maintaining their viability., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Previous studies have shown that CD73 is pivotal in the conversion of pro-inflammatory adenosine triphosphate into anti-inflammatory adenosine and that immune cells of the same type that express different levels of CD73 are functionally distinct. In this study we show that adenosine enhances the Th17 promoting effect of dendritic cells (DCs), and DCs expressing CD73 critically augment Th17 responses. Bone marrow dendritic cells (BMDCs) do not constantly express CD73; however, a significant portion of the BMDCs expressed CD73 after exposure to Toll-like receptor ligand, leading to stronger Th17 responses by converting adenosine monophosphate to adenosine. We show that the CD73 + BMDCs play a critical role in cascading Th17 responses, and CD73 + BMDCs are functionally augmented after treatment with Toll-like receptor ligand. Splenic antigen presenting cells (DCs) of CD73 -/- mouse have a poor Th17-stimulating effect, even after exposure to lipopolysaccharide (LPS) or γδ T cells, indicating that induction of CD73 + DCs is critically involved in augmented Th17 responses. We conclude that CD73 + DCs critically trigger cascading Th17 responses, and the activated Th17 cells that express CD73 further augment Th17 responses, leading to cascading exacerbation. Hence, disabling the CD73 function of DCs should block this cascading response and mitigate Th17 responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Ko, Shao, Kaplan and Sun.)

Angiogenesis is required for tissue repair; but abnormal angiogenesis or neovascularization (NV) causes diseases in the eye. The avascular status in the cornea is a prerequisite for corneal clarity and thought to be maintained by the equilibrium between proangiogenic and antiangiogenic factors that controls proliferation and migration of vascular endothelial cells (ECs) sprouting from the pericorneal plexus. VEGF is the most important intrinsic factor for angiogenesis; anti-VEGF therapies are available for treating ocular NV. However, the effectiveness of the therapies is limited because of VEGF-independent mechanism(s). We show that Zeb1 is an important factor promoting vascular EC proliferation and corneal NV; and a couple of small molecule inhibitors can evict Ctbp from the Zeb1-Ctbp complex, thereby reducing EC Zeb1 expression, proliferation, and corneal NV. We conclude that Zeb1-regulation of angiogenesis is independent of Vegf and that the ZEB1-CtBP inhibitors can be of potential therapeutic significance in treating corneal NV.

Nuclear YAP1 plays a critical role in regulation of stem cell proliferation, tissue regeneration, and organ size in many types of epithelia. Due to rapid turnover of most epithelial cell types, the cytoplasmic function of YAP1 in epithelial cells has not been well studied. The retinal pigment epithelium (RPE) is a highly polarized epithelial cell type maintained at a senescence state, and offers an ideal cell model to study the active role of YAP1 in maintenance of the adult epithelial phenotype. Here, we show that the cytoplasmic function of YAP1 is essential to maintain adult RPE differentiation. Knockout of Yap1 in the adult mouse RPE caused cell depolarization and tight junction breakdown, and led to inhibition of RPE65 expression, diminishment of RPE pigments, and retraction of microvilli and basal infoldings. These changes in RPE further prompted the loss of adjacent photoreceptor outer segments and photoreceptor death, which eventually led to decline of visual function in older mice between 6 and 12 months of age. Furthermore, nuclear β-catenin and its activity were significantly increased in mutant RPE. These results suggest that YAP1 plays an important role in active inhibition of Wnt/β-catenin signaling, and is essential for downregulation of β-catenin nuclear activity and prevention of dedifferentiation of adult RPE., (© 2020 Federation of American Societies for Experimental Biology.)

Purpose: This work was motivated by the goals of demonstrating methods to fabricate and implant large numbers of penetrating arrays into the retina and the feasibility of extraction., Methods: Arrays of inactive, three-dimensional (3D) SU-8 structures were microfabricated onto 13-µm polyimide substrates. Standard vitreoretinal surgical techniques were used with an ab externo approach for subretinal implantation of arrays in 12 mini-pigs. In the first three surgeries, different post-geometries were explored, while a preferred design (128-µm tall, 30-µm diameter, 200-µm spacing) was used for the remaining nine implantations. Two arrays were extracted. Funduscopy, optical coherence tomography (OCT) and immunohistochemistry of the retinae were performed. The unoperated eyes and tissue far from implantation served as controls. A thirteenth pig was implanted with a planar array., Results: Ten implant surgeries had no significant complication, and two arrays were successfully extracted. One retinal tear occurred after implantation due to too long posts in an early surgery. In "successful" cases, OCT showed close apposition of the arrays to the retina and integration of the posts, the tops of which were positioned at the junction of the inner plexiform and ganglion cells, without significant gliosis., Conclusions: These results provide a proof-of-concept that relatively large numbers of 3D posts can be implanted into, and extracted from, the retina of mini-pigs. Our surgical numbers were relatively small, especially for the extractions, and our conclusions must be viewed with that limitation. Our methods are applicable for human surgeries., Translational Relevance: This study provides results of implantation and extraction of relatively large numbers of 3D posts from the retina of minipig eyes. If similar technology were used in humans, a 3D array of this type should lower perceptual thresholds, provide safer long-term stimulation, and perhaps provide better perceptual outcomes., Competing Interests: Disclosure: J. Chen, Bionic Eye Technologies, Inc. (I); V. Poulaki, None; S.-J. Kim, None; W.D. Eldred, None; S. Kane, None; M. Gingerich, Bionic Eye Technologies, Inc. (I,E,P); D.B. Shire, Bionic Eye Technologies, Inc. (I,E,P); R. Jensen, None; G. DeWalt, None; H.J. Kaplan, None; J.F. Rizzo III, Bionic Eye Technologies, Inc. (I,C,P,S), (Copyright 2020 The Authors.)

Background: Retinal degeneration is a leading cause of blindness in the world; its etiology is complex and involves genetic defects and stress-associated aging. In addition to gene therapies for known genetically defective retinal degeneration, cellular therapies have been widely explored for restoring vision in both preclinical animal models and clinical trials. Stem cells of distinct tissue sources and their derived lineages have been tested for treating retinal degeneration; most of them were reported to be effective to some extent in restoring/improving deteriorated vision. Whether this visual improvement is due to a functional integration of grafted cells to substitute for lost retinal neurons in recipients or due to their neuroprotective and neurotrophic effects to retain recipient functional neurons, or both, is still under debate., Methods: We compared the results of subretinal transplantation of various somatic cell types, such as stem cells and differentiated cells, into Rho P23H/+ mice, a retinal degeneration model for human retinitis pigmentosa (RP) by evaluating their optokinetic response (OKR) and retinal histology. We identified some paracrine factors in the media that cultured cells secreted by western blotting (WB) and functionally evaluated the vascular endothelial growth factor Vegfa for its potential neurotrophic and neuroprotective effects on the neuroretina of model animals by intravitreal injection of VEGF antibody., Results: We found that live cells, regardless of whether they were stem cells or differentiated cell types, had a positive effect on improving degenerating retinas after subretinal transplantation; the efficacy depended on their survival duration in the host tissue. A few paracrine factors were identified in cell culture media; Vegfa was the most relevant neurotrophic and neuroprotective factor identified by our experiments to extend neuron survival duration in vivo., Conclusions: Cellular therapy-produced benefits for remediating retinal degeneration are mostly, if not completely, due to a paracrine effect of implanted cells on the remaining host retinal neurons.

Background: The retinal pigment epithelium (RPE) has the potential to regenerate the entire neuroretina upon retinal injury in amphibians. In contrast, this regenerative capacity has been lost in mammals. The reprogramming of differentiated somatic cells into induced pluripotent stem cells (iPSCs) by viral transduction of exogenous stem cell factors has triggered a revolution in regenerative medicine. However, the risks of potential mutation(s) caused by random viral vector insertion in host genomes and tumor formation in recipients hamper its clinical application. One alternative is to immortalize adult stem cells with limited potential or to partially reprogram differentiated somatic cells into progenitor-like cells through non-integration protocols., Methods: Sphere-induced RPE stem cells (iRPESCs) were generated from adult mouse RPE cells. Their stem cell functionality was studied in a mouse model of retinal degeneration. The molecular mechanism underlying the sphere-induced reprogramming was investigated using microarray and loss-of-function approaches., Findings: We provide evidence that our sphere-induced reprogramming protocol can immortalize and transform mouse RPE cells into iRPESCs with dual potential to differentiate into cells that express either RPE or photoreceptor markers both in vitro and in vivo. When subretinally transplanted into mice with retinal degeneration, iRPESCs can integrate to the RPE and neuroretina, thereby delaying retinal degeneration in the model animals. Our molecular analyses indicate that the Hippo signaling pathway is important in iRPESC reprogramming., Interpretation: The Hippo factor Yap1 is activated in the nuclei of cells at the borders of spheres. The factors Zeb1 and P300 downstream of the Hippo pathway are shown to bind to the promoters of the stemness genes Oct4, Klf4 and Sox2, thereby likely transactivate them to reprogram RPE cells into iRPESCs. FUND: National Natural Science Foundation of China and the National Institute of Health USA., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose : To investigate the link between treatment with CTLA-4 and PD-1 checkpoint blockade inhibitors and the development of noninfectious uveitis. Methods : A survey was distributed to uveitis specialists to identify patients who developed uveitis while receiving either PD-1 inhibitors pembrolizumab and nivolumab; PD-L1 inhibitors atezolizumab, avelumab, and durvalumab; or the CTLA-4 inhibitor ipilimumab. Results : Fifteen patients from seven institutions were identified. The most common cancer diagnosis (13/15) was malignant melanoma. Fourteen patients had a new uveitis diagnosis following checkpoint blockade administration (six anterior uveitis, six panuveitis, one posterior uveitis, one anterior/intermediate combined); one patient developed optic neuritis. Uveitis was diagnosed within 6 months after drug initiation for 11/12 patients (median 63 days). Corticosteroid treatment was effective for most patients, although two patients had permanent loss of vision. Conclusions : Patients on checkpoint inhibitor therapy should be educated to seek care if they develop ocular symptoms, and prompt referral to specialists should be incorporated into oncology protocols.

Purpose: To evaluate different methods of studying cone photoreceptor structure in wild-type (WT) and transgenic pigs carrying the human rhodopsin P23H mutant gene (TgP23H)., Methods: For in vivo imaging, pigs were anesthetized with tiletamine-zolazepam and isoflurane and given lidocaine-bupivacaine retrobulbar injections. Stay sutures and a custom head mount were used to hold and steer the head for adaptive optics scanning light ophthalmoscopy (AOSLO). Six WT and TgP23H littermates were imaged at postnatal day 30 (P30), P90, and P180 with AOSLO and optical coherence tomography (OCT), and two additional sets of littermates were imaged at P3 and P15 with OCT only. AOSLO imaging and correlative differential interference contrast microscopy were performed on a P240 WT pig and on WT and TgP23H littermates at P30 and P180., Results: AOSLO cone density generally underestimates histology density (mean difference ± SD = 24.8% ± 21.4%). The intensity of the outer retinal hyperreflective OCT band attributed to photoreceptors is attenuated in TgP23H pigs at all ages. In contrast, AOSLO images show cones that retain inner and outer segments through P180. At retinal locations outside the visual streak, TgP23H pigs show a heterogeneous degenerating cone mosaic by using two criteria: variable contrast on a split detector AOSLO and high reflectivity on a confocal AOSLO., Conclusions: AOSLO reveals that the cone mosaic is similar to ex vivo histology. Its use as a noninvasive tool will enable observation of morphologic changes that arise in the cone mosaic of TgP23H pigs over time., Translational Relevance: Pigs are widely used for translational studies, and the ability to noninvasively assess cellular changes in the cone mosaic will facilitate more detailed investigations of new retinal disease models as well as outcomes of potential therapies., (Copyright 2019 The Authors.)

Retinitis pigmentosa (RP) initiates with diminished rod photoreceptor function, causing peripheral and night-time vision loss. However, subsequent loss of cone function and high-resolution daylight and color vision is most debilitating. Visual pigment-rich photoreceptor outer segments (OS) undergo phagocytosis by the retinal pigment epithelium (RPE), and the RPE also acts as a blood-outer retinal barrier transporting nutrients, including glucose, to photoreceptors. We provide evidence that contact between externalized phosphatidylserine (PS) on OS tips and apical RPE receptors activates Akt, linking phagocytosis with glucose transport to photoreceptors for new OS synthesis. As abundant mutant rod OS tips shorten in RP, Akt activation is lost, and onset of glucose metabolism in the RPE and diminished glucose transport combine to cause photoreceptor starvation and accompanying retinal metabolome changes. Subretinal injection of OS tip mimetics displaying PS restores Akt activation, glucose transport, and cone function in end-stage RP after rods are lost., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Th17-type autoreactive T cells contribute to pathogenicity in autoimmune diseases, including autoimmune uveitis. However, the mechanisms of regulation of Th17 cell activities remain unsolved and are likely to be tissue- and disease specific. In this review, we have summarized our studies from the murine model of experimental autoimmune uveitis (EAU). The resultsdemonstrate that γδ T cells have a regulatory effect on Th17 response. The regulatory effects of γδ T cells depend on their action state. Activated γδ T cells express significantly high levels of adenosine receptor A2 (A2AR) but low CD73. Both molecules are crucially involved in adenosine generation, thus modifying T cell responses. While the increased expression of A2AR-allows activated γδ T cells to bind adenosine more effectively than other immune cells, the decreased CD73 restricts their ability to convert AMP to adenosine. Adenosine affects Th1 and Th17 autoimmune responses differently. Its activation of γδ T cells shifts the Th1/Th17 balance towards the Th17 autoreactivity., (Copyright © 2018. Published by Elsevier Inc.)

The purpose of this study was to evaluate focal damage in the retinal pigment epithelium (RPE) layer in serous retinal pigment epithelium detachment (PED) with multi-contrast optical coherence tomography (OCT), which is capable of simultaneous measurement of OCT angiography, polarization-sensitive OCT and standard OCT images. We evaluated 37 eyes with age-related macular degeneration that had serous PED. Focal RPE damage was indicated by hyper-transmission beneath the RPE-Bruch's membrane band in standard OCT images. Distribution of RPE melanin was calculated using the dataset from multi-contrast OCT. Twenty-four points with hyper-transmission were detected in 21 of the 37 eyes. Standard OCT images failed to show disruption of the RPE-Bruch's membrane band at 5 of the 24 hyper-transmission points. Conversely, multi-contrast OCT images clearly showed melanin defects in the RPE-Bruch's membrane band at all points. Areas of melanin defects with disruption of the RPE-Bruch's membrane band were significantly larger than those without disruption. The volume of intraretinal hyper-reflective foci was significantly larger in eyes with hyper-transmission than that in eyes without hyper-transmission. Multi-contrast OCT is more sensitive than standard OCT for displaying changes at the RPE-Bruch's membrane band when there are small areas of RPE damage.

Purpose : To compare genetic testing for microbes in infectious endophthalmitis or uveitis to culture. Methods : This was a retrospective, single-center case series that enrolled patients with clinically suspected endophthalmitis or uveitis of unknown etiology. Aqueous humor or vitreous was collected and sent for routine cultures and genetic testing. Results : In total, 46 patients were enrolled. Genetic testing was positive in 32/46 (70%) cases and culture 6/46 cases (13%). Five of 16 uveitis cases had a final clinical diagnosis of infectious uveitis, and polymerase chain reaction (PCR) was positive in 4/5 cases (80%), versus 0% for culture. In uveitis cases, PCR was 80% sensitive and 82% specific, and culture had 0% sensitivity. The overall sensitivity and specificity of PCR for all cases were 85% and 67%, respectively, compared with 17% and 100% for culture. Conclusion : Genetic assays are inexpensive ($25/case) and more sensitive than culture for identifying intraocular pathogens in endophthalmitis and uveitis.

[This corrects the article DOI: 10.1371/journal.pone.0199601.].

The domestic swine eye resembles the human eye both anatomically and physiologically. Xenotransplantation of the swine cornea to humans in need of full keratoplasty shows promise as a potential therapeutic strategy to restore vision in individuals with advanced corneal disease, especially those residing in developing nations. That said, we characterized the morphology of corneas from miniature swine, which are smaller in size, easier to handle, and more cost-effective compared to domestic swine. Eyes (N = 15) were harvested from miniature swine from different age groups: 1 month (N = 3), 2 month (N = 3), 4 month (N = 3), 8 month (N = 3), as well as 24 month old adult domestic swine (N = 3). They were immediately submerged in fixative and processed for histological examination at the light and transmission electron microscopic level. Gross anatomic measurements of the cornea were significantly less (P value ≤ 0.05) in miniature swine versus domestic swine. Corneal strata exhibited morphological characteristics similar to the domestic swine cornea. Adult miniature swine corneas show similar overall corneal thickness at 8 months of age versus domestic swine. Miniature swine exhibit similar corneal morphology with the domestic pig and humans, with the exception of Bowman's layer, which is absent in pigs. Therefore, miniature pigs may be a useful resource of corneal tissue for humans in need of full keratoplasty, as well as serve as a large eye model for ophthalmology residents to develop surgical skills and for development and testing of ocular therapeutic strategies that translate to humans. Anat Rec, 301:1955-1967, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

A local immune response has been implicated in the pathogenesis of age-related macular degeneration (AMD), but it is unclear if systemic immunosuppressive/immunomodulatory therapy (IMT) protects against the onset and/or progression of AMD. We performed a retrospective cohort study using a Cox proportional hazards model of two cohorts. Cohort 1 included patients with stage V chronic kidney disease (CKD) status post kidney transplantation, on at least one IMT agent, and older than 50. Cohort 2 included patients with stage IV or V CKD who had not undergone kidney transplantation, were not on IMT, and were older than 50. The main outcomes were hazard ratios of a new diagnosis of dry AMD, wet AMD, or conversion from dry to wet. There were 10,813 patients in cohort 1, and 217,081 patients in cohort 2. After controlling for sex and age, there was no significant difference in the hazard of developing a new diagnosis of dry AMD (HR = 0.95, 95% CI 0.87-1.05, p = 0.32), developing a new diagnosis of wet AMD without any prior diagnosis of dry AMD (HR = 0.85, 95% CI 0.66-1.08, p = 0.18), or converting from dry to wet AMD (HR 1.24, 95% CI 0.94-1.62, p = 0.12). For patients over 70 on mycophenolate mofetil, there was a reduced hazard of converting from dry to wet AMD (HR = 0.92, 95% CI = 0.85-0.99, p = 0.02). In contrast, everolimus had an increased hazard of dry AMD (HR = 2.14, 95% CI 1.24-3.69, p < 0.01). Most systemic IMT does not affect the risk of onset or progression of AMD in patients with CKD. However, mycophenolate mofetil may confer some degree of protection against the conversion of dry AMD to wet AMD, suggesting that modulation of the immune response may prevent progression of the disease., Competing Interests: The authors have declared that no competing interests exist