Corneal Transplant Rejection Research Articles

Inhibiting corneal transplantation rejection via lymphatic vessel ligation in a novel murine model

The lymphatic system is a crucial contributor to allograft rejection after corneal transplantation. However, no surgical procedures for the central pathway where conjunctival lymphatic vessels converge have been investigated. Therefore, we aimed to establish a murine model of lymphatic vessel ligation and evaluate its inhibitory effect on corneal allograft rejection. A tracer was used to visualise lymphatic vessels, and complications were evaluated. A surgical technique was developed to block the lymphatic vessels. Corneas from C57BL/6 mice were transplanted into BALB/c mice divided into two groups—one with and one without lymphatic vessel ligation, to evaluate their effects on allograft rejection. Graft opacity scores were evaluated for 8 weeks, and immunohistochemistry was used to quantify angiogenesis and lymphangiogenesis. 20% trypan blue used as a tracer showed clear inflow with no complications. The two sutures and cyanoacrylate glue combination demonstrated a blocking effect after 25 days and was thus used for lymphatic ligation. Three and nine out of fourteen eyes showed rejection at 8 weeks post-surgery in the lymphatic vessel ligation and control groups, respectively. Furthermore, neovascularisation and lymphangiogenesis significantly decreased in the lymphatic vessel ligation group. Overall, we present a novel therapeutic strategy for corneal transplantation.

A chimeric anti-vascularization immunomodulator prevents high-risk corneal transplantation rejection via ex vivo gene therapy

Corneal blindness affects greater than 5 million individuals, with over 180,000 corneal transplantations (CTs) performed annually. Inhigh-risk CTs, almost all grafts are rejected within 10 years. Herein, adeno-associated virus (AAV) ex vivo gene therapy was investigated to establish immune tolerance in the corneal allograft to prevent high-risk CT rejection. Our previous work has demonstrated that HLA-G contributes to ocular immune privilege by inhibiting both immune cells and neovascularization; however, homodimerization is a rate-limiting step for optimal HLA-G function. Therefore, a chimeric protein termed single chain immunomodulator (sclM), was engineered to mimic the native activity of the secreted HLA-G dimer complex and eliminate the need for homodimerization. In a murine corneal burn model, AAV8-sclM significantly reduced corneal vascularization and fibrosis. Next, ex vivo AAV8-scIM gene delivery to corneal allografts was evaluated in a high-risk CT rejection rabbit model. All sclM treated corneas were well tolerated and transparent after 42 days while 83% of vehicle treated corneas were rejected. Histologically, AAV-scIM treated corneas were devoid of immune cell infiltration, vascularization, with minimal fibrosis at the host-graft interface. The data collectively demonstrate that sclM gene therapy prevents corneal neovascularization, reduces trauma-induced corneal fibrosis, and prevents allogeneic CT rejection in a high-risk large animal model.

Corneal Transplant Rejection Following Durvalumab Therapy in a Patient With NSCLC: A Case Report.

We report the case of corneal transplant rejection in a 77-year-old male receiving durvalumab as consolidative therapy for stage IIIB non-small cell lung cancer (NSCLC). Following successful chemoradiation and initiation of durvalumab, the patient underwent a right corneal transplant for corneal dystrophy. Six months after an initially stable post-transplant course, he developed progressive visual decline culminating in graft failure 1 year later despite treatment with prednisone eye drops. This case adds to the limited evidence implicating immune checkpoint inhibitors (ICIs) in corneal graft rejection, emphasizing the need for multidisciplinary evaluation and close monitoring of corneal transplant recipients undergoing ICI therapy.

Combination Nanomedicine Strategy for Preventing High-Risk Corneal Transplantation Rejection.

High-risk (HR) corneal transplantation presents a formidable challenge, with over 50% of grafts experiencing rejection despite intensive postoperative care involving frequent topical eyedrop administration up to every 2 h, gradually tapering over 6-12 months, and ongoing maintenance dosing. While clinical evidence underscores the potential benefits of inhibiting postoperative angiogenesis, effective antiangiogenesis therapy remains elusive in this context. Here, we engineered controlled-release nanomedicine formulations comprising immunosuppressants (nanoparticles) and antiangiogenesis drugs (nanowafer) and demonstrated that these formulations can prevent HR corneal transplantation rejection for at least 6 months in a clinically relevant rat model. Unlike untreated corneal grafts, which universally faced rejection within 2 weeks postsurgery, a single subconjunctival injection of the long-acting immunosuppressant nanoparticle alone effectively averted graft rejection for 6 months, achieving a graft survival rate of ∼70%. Notably, the combination of an immunosuppressant nanoparticle and an anti-VEGF nanowafer yielded significantly better efficacy with a graft survival rate of >85%. The significantly enhanced efficacy demonstrated that a combination nanomedicine strategy incorporating immunosuppressants and antiangiogenesis drugs can greatly enhance the ocular drug delivery and benefit the outcome of HR corneal transplantation with increased survival rate, ensuring patient compliance and mitigating dosing frequency and toxicity concerns.

The ocular immunological alterations in the process of high-risk corneal transplantation rejection

PurposeThis study aims to reveal the immunopathogenesis of the high-risk corneal transplantation using a comparative proteomic approach. MethodsThe immunological properties of ocular tissues (including corneal grafts, aqueous humour, and iris-ciliary body) were analysed using a high-risk rabbit corneal transplantation model employing a comparative proteomic approach. ResultsThe corneal grafts revealed a dramatic increase in the immune response both at the early (postoperative day 7) and rejection stages, along with the appearance of transplantation stress-induced cellular senescence in the early stage. The aqueous humour (AH) displayed persistent pathological alterations, indicated by the significant enrichment of complement and coagulation cascades pathway in the early stage and interleukin (IL)-17 signalling pathway in the rejection stage. More surprisingly, the pronounced elevation of immune response was also observed in the iris-ciliary body (I-CB) tissues at the early and rejection stages. The enriched immune-related pathways were associated with antigen processing and presentation, complement and coagulation cascades, and IL-17 signalling pathway. Furthermore, proteomic analysis revealed that the implantation of Cyclosporine A drug delivery system (CsA-DDS) into the anterior chamber obviously mitigated corneal transplantation rejection by inhibiting immunoreaction both in the corneal grafts and I-CB tissues. ConclusionThe results highlighted the involvement of intraocular immunity both in the grafts and I-CB tissues during corneal transplantation rejection, further suggesting the anterior chamber as an optimal drug-delivery site for its treatment.

CORNEAL TRANSPLANTATION

Corneal transplantation is an ophthalmic surgery that aims to restore vision in patients with corneal diseases. Advances in transplantation techniques and in the treatment of rejection have improved the results of this procedure, making it more effective and safer. This paper seeks to analyze the latest developments in transplantation techniques and treatments for rejection in corneal transplantation, highlighting not only scientific advances, but also the emotional and social aspects involved in this procedure, providing a comprehensive overview of the latest innovations in the field of corneal transplantation, highlighting improvements in surgical techniques and post-operative treatments, which are helping to transform the lives of thousands of patients around the world. This is a bibliographical review, using qualitative premises, with the PubMed, Scopus, Web of Science and Scielo databases. The health descriptors “corneal transplantation”, “corneal graft rejection” and “penetrating keratoplasty” were used to better refine the research. Corneal transplantation is indicated for various conditions, such as keratoconus, corneal dystrophies, corneal opacities, among others. The most common transplant techniques include complete (penetrating) corneal transplantation, anterior lamellar transplantation and endothelial transplantation (DSAEK/ DMEK). In recent years, there have been significant advances in lamellar transplantation techniques, which allow specific layers of the cornea to be replaced while preserving the healthy layers. This has resulted in better success rates and faster visual recovery compared to penetrating transplantation. Treatment of corneal graft rejection includes the use of topical and systemic corticosteroids, immunosuppressants and anti-inflammatory agents. New approaches, such as biological and immunomodulatory therapies, are also being investigated to improve results in cases of refractory graft rejection. In conclusion, corneal transplantation remains an important option for restoring vision in patients with corneal diseases. Updates in transplantation techniques and advances in the treatment of rejection have improved the results of this procedure, providing patients with a better quality of life and faster and more effective visual recovery.

Cyclic guanosine monophosphate-adenosine monophosphate synthetase/stimulator of interferon genes signaling aggravated corneal allograft rejection through neutrophil extracellular traps

The activation of innate immunity following transplantation has been identified as a crucial factor in allograft inflammation and rejection. However, the role of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling-mediated innate immunity in the pathogenesis of allograft rejection remains unclear. Utilizing a well-established murine model of corneal transplantation, we demonstrated increased expression of cGAS and STING in rejected-corneal allografts compared with syngeneic (Syn) and normal (Nor) corneas, along with significant activation of the cGAS/STING pathway, as evidenced by the enhanced phosphorylation of TANK-binding kinase 1and interferon regulatory factor 3. Pharmacological and genetic inhibition of cGAS/STING signaling markedly delayed corneal transplantation rejection, resulting in prolonged survival time and reduced inflammatory infiltration. Furthermore, we observed an increase in the formation of neutrophil extracellular traps (NETs) in rejected allografts, and the inhibition of NET formation through targeting peptidylarginine deiminase 4 and DNase I treatment significantly alleviated immune rejection and reduced cGAS/STING signaling activity. Conversely, subconjunctival injection of NETs accelerated corneal transplantation rejection and enhanced the activation of the cGAS/STING pathway. Collectively, these findings demonstrate that NETs contribute to the exacerbation of allograft rejection via cGAS/STING signaling, highlighting the targeting of the NETs/cGAS/STING signaling pathway as a potential strategy for prolonging allograft survival.

Risk of Corneal Transplant Rejection Following COVID-19 Vaccination: A Systematic Review and Meta-analysis.

The COVID-19 pandemic has initiated an unparalleled global vaccination campaign, raising concerns about the vaccine's effects on various health conditions, including the risk of corneal transplant rejection. This systematic review aimed to identify the relationship between COVID-19 vaccination and rejection of corneal transplant, filling a significant gap in the existing medical literature. A literature search was performed across multiple databases up to February 12, 2024, to identify studies evaluating the risk of corneal transplant rejection post-COVID-19 vaccination. Eligible studies were original research that reported outcomes of corneal graft rejection following vaccination. Nested Knowledge web software facilitated screening and data extraction. The Newcastle-Ottawa Scale was employed for quality assessment. A meta-analysis was conducted to calculate the aggregated relative risk (RR) utilizing R software version 4.3. Six studies were included in the qualitative synthesis, with four meeting the criteria for meta-analysis. These studies varied in geographic location, surgical techniques, and types of vaccines used. The pooled RR for corneal transplant rejection following COVID-19 vaccination was 0.816 (95% CI 0.178-1.453), indicating no significant risk of rejection. No statistical heterogeneity was observed among the studies (I2 = 0%). This review and meta-analysis found no significant evidence that COVID-19 vaccination increases the risk of corneal graft rejection. However, the current evidence is insufficient to conclusively determine the vaccine's safety for corneal transplant recipients. These findings underscore the need for additional research to confirm these preliminary results and investigate the long-term effects of COVID-19 vaccination on corneal transplants, aiming to provide evidence-based guidance to healthcare providers and patients.

Rho-kinase inhibitor alleviates CD4+T cell mediated corneal graft rejection by modulating its STAT3 and STAT5 activation

Penetrating keratoplasty remains the most common treatment to restore vision for corneal diseases. Immune rejection after corneal transplantation is one of the major causes of graft failure. In recent years, Rho-associated protein kinase (ROCK) inhibitors have been found to be associated with the activation of the STATs pathway and are widely studied in autoimmune diseases. Therefore, it may be possible that the ROCK inhibitors also participate in the local and systemic immune regulation in corneal transplantation through activation of the STATs pathway and affect the CD4+ T cell differentiation. This study aimed to explore the role of ROCK-STATs pathway in the occurrence of immune rejection in corneal transplantation by applying Y27632, a ROCK inhibitor, to the recipient mice and peripheral CD4+ T cells. We found that Y27632 significantly up-regulated the phosphorylation level of STAT5 in both spleen and lymph nodes, down-regulated the phosphorylation level of STAT3 in the CD4+ T cells in the spleen. It also increased the proportion of CD4+CD25+Foxp3+Helios+ Tregs while decreased CD4+IL17A+ -Th17 cells. Moreover, Y27632 also reduced the proportion of dendritic cells in both spleen and lymph nodes, as well as the expression level of CD86 on their surfaces in the spleen, while the proportion of macrophages was not affected. The expression levels of ROCK1, ROCK2, CD11c and IL-17A mRNA were also found to be low in the graft tissue while the expression of Helios was upregulated. Rho-kinase inhibitor can modulate the balance of Tregs/Th17 by regulating the phosphorylation levels of both STAT3 and STAT5, thereby inhibiting the occurrence of immune rejection in allogeneic corneal transplantation.

Corneal Transplant Rejection Postvaccination Among Medicare Beneficiaries.

The purpose of this study was to describe the incidence of corneal graft rejection after COVID and influenza vaccination. Patients 65 years or older undergoing penetrating keratoplasty or endothelial keratoplasty any time between 2016 and 2021 followed by COVID or influenza vaccination in 2021 among the 100% Medicare Fee-For-Service database were included. Demographic and ocular history characteristics of patients with (cases) and without graft rejection (controls) were compared using the χ 2 test. After COVID (n = 31,398) and influenza (n = 24,290) vaccination, 0.45% (n = 140) and 0.17% (n = 41) patients developed rejection within 90 days, respectively. There was no difference in the rate of graft rejection within 90 days relative to 90 to 180 days after vaccination after both COVID (90 days: 0.45% vs. 180 days: 0.61%, P = 0.37) and influenza (90 days: 0.17% vs. 180 days: 0.29%, P = 0.11) vaccines. For COVID vaccination, patients who underwent penetrating keratoplasty (n = 51, 0.97%; vs. endothelial keratoplasty = 89; 0.34%, P < 0.001), history of rejection up to 1 year before vaccination (n = 13; 1.30% vs. no history = 127, 0.42%; P < 0.001), and having an ocular comorbidity (n = 110, 0.54% vs. no ocular comorbidity = 30, 0.27%; P = 0.001) had higher rates of graft rejections, and most rejections were after 1 year postkeratoplasty (87.14%, n = 122). The incidence of graft rejection postvaccination is low compared with the overall rates of rejection in the published literature. Most post-COVID vaccination graft rejections were after 1 year postkeratoplasty when corticosteroids are expected to have been tapered to lower doses. Surgeons may counsel patients regarding graft rejection symptoms, but overall low rates may not warrant pretreatment in low-risk keratoplasty patients.

Serum Extracellular Vesicle Protein Profiling for Prediction of Corneal Transplant Rejection.

Corneal transplantation is the most common transplant procedure worldwide. Despite immune and angiogenic privilege of the cornea, 50% to 70% of corneal transplants fail in high-risk recipients, primarily because of immune rejection. Therefore, it is crucial to identify predictive biomarkers of rejection to improve transplant survival. In search for predictive biomarkers, we performed proteomics analysis of serum extracellular vesicles (EVs) in a fully major histocompatibility complex-mismatched (C57BL/6-to-BALB/c) murine corneal transplantation model, wherein 50% of transplants undergo rejection by day 28 following transplantation. Our time course study revealed a decrease in the number of serum EVs on day 1, followed by a gradual increase by day 7. A comparative analysis of proteomics profiles of EVs from transplant recipients with rejection (rejectors) and without rejection (nonrejectors) found a distinct enrichment of histocompatibility 2, Q region locus 2, which is a part of major histocompatibility complex-class I of donor C57BL/6 mice, in day 7 EVs of rejectors, compared with nonrejectors, syngeneic controls, or naïve mice. In contrast, serum amyloid A2, a protein induced in response to injury, was increased in day 7 EVs of nonrejectors. Our findings offer noninvasive EV-based potential biomarkers for predicting corneal allograft rejection or tolerance.

Effector T Cells Promote Fibrosis in Corneal Transplantation Failure.

To evaluate whether fibrosis contributes to corneal transplant failure and to determine whether effector CD4+ T cells, the key immune cells in corneal transplant rejection, play a direct role in fibrosis formation. Allogeneic corneal transplantation was performed in mice. Graft opacity was evaluated by slit-lamp biomicroscopy, and fibrosis was assessed by in vivo confocal microscopy. Expression of alpha-smooth muscle actin (α-SMA) in both accepted and failed grafts was assessed by real-time PCR and immunohistochemistry. Frequencies of graft-infiltrating CD4+ T cells, neutrophils, and macrophages were assessed using flow cytometry. In vitro, MK/T-1 corneal fibroblasts were co-cultured with activated CD4+CD25- effector T cells isolated from corneal transplant recipient mice, and α-SMA expression was quantified by real-time PCR and ELISA. Neutralizing antibody was used to evaluate the role of interferon gamma (IFN-γ) in promoting α-SMA expression. The majority of failed grafts demonstrated clinical signs of fibrosis which became most evident at week 6 after corneal transplantation. Failed grafts showed higher expression of α-SMA as compared to accepted grafts. Flow cytometry analysis showed a significant increase in CD4+ T cells in failed grafts compared to accepted grafts. Co-culture of activated CD4+CD25- effector T cells with corneal fibroblasts led to an increase in α-SMA expression by fibroblasts. Inhibition of IFN-γ in culture significantly suppressed this increase in α-SMA expression as compared to immunoglobulin G control. Fibrosis contributes to graft opacity in corneal transplant failure and is mediated at least in part by effector CD4+ T cells via IFN-γ.

Rejection of corneal transplant after administration of SARS-CoV-2 messenger RNA vaccine

Rejection of corneal transplant after administration of SARS-CoV-2 messenger RNA vaccine

Granular polyrotaxane microgels as injectable hydrogels for corneal tissue regeneration.

Corneal diseases, a leading cause of global vision impairment, present challenges in treatment due to corneal tissue donor scarcity and transplant rejection. Hydrogel biomaterials in the form of corneal implants for tissue regeneration, while promising, have faced obstacles related to cellular and tissue integration. This study develops and investigates the potential of granular polyrotaxane (GPR) hydrogels as a scaffold for corneal keratocyte growth and transparent tissue generation. Employing host-guest driven supramolecular interactions, we developed injectable, cytocompatible hydrogels. By optimizing cyclodextrin (CD) concentrations in thiol-ene crosslinked PEG microgels, we observed improved mechanical properties and thermoresponsiveness while preserving injectability. These microgels, adaptable for precise defect filling, 3D printing or tissue culture facilitate enhanced cellular integration with corneal keratocytes and exhibit tissue-like structures in culture. Our findings demonstrate the promise of GPR hydrogels as a minimally invasive avenue for corneal tissue regeneration. These results have the potential to address transplantation challenges, enhance clinical outcomes, and restore vision.

1164. Risk of corneal transplant rejection and vaccination: a case-control study from a large, integrated health care system in Southern California

Abstract Background Vaccination is recommended for prevention of infectious diseases. For individuals with a history of corneal transplantation, however, there are concerns that vaccination may trigger allograft rejection through elevated immune activity. The association between vaccination and graft rejection remains unclear. Methods We conducted a nested case-control study to evaluate the association between graft rejection and vaccination in corneal transplant recipients at Kaiser Permanente Southern California (KPSC) between January 2008 and August 2022. We identified all KPSC members who received a corneal transplant during the study period, with no history of prior transplant or rejection. Cases were those who experienced a graft rejection during the study period and eligible controls were those who had not experienced a rejection at the time of a given case. Controls were randomly selected via risk-set sampling and matched in a 3:1 ratio to cases on age, sex, and transplant date (±12 weeks). Index date was the date of rejection for cases. For controls, index date was determined by adding the number of days between transplant and rejection of the matched case to the control’s transplant date. We performed multivariable conditional logistic regression to compare the odds of vaccination (all types) in the 12 weeks prior to the index date in cases and controls, while adjusting for potential confounders. Results Our study included 601 corneal transplant recipients with rejection (cases), and 1,803 matched controls. The overall cohort was 48% female and 47% white, with a mean age of 66 years (s.d. 17) (Table 1). A total of 136 (23%) cases and 373 (21%) controls received vaccination within 12 weeks of the index date (adjusted odds ratio 1.17, 95% CI: 0.91, 1.50) (Table 2).Table 1.Characteristics of corneal transplant recipients who experienced graft rejection (cases) and who did not experience graft rejection (controls), Kaiser Permanente Southern California, 01/01/2008 - 08/31/2022. a Defined in the 12 months prior to index date unless otherwise indicated b Defined in the 12 weeks prior to index date c HIV/AIDS, leukemia, lymphoma, congenital immunodeficiencies, asplenia/hypospenia, or organ transplant at any time prior to index date, or immunosuppressant medication used during 12 weeks prior to index date d Includes dexamethasone, fluorometholone, loteprednol, difluprednate, prednisolone, methylprednisolone, and prednisone.Table 2.Vaccination among corneal transplant recipients who experienced graft rejection (cases) and who did not experience graft rejection (controls), Kaiser Permanente Southern California, 01/01/2008 - 08/31/2022. a Adjusted for race/ethnicity, Charlson comorbidity score, immunocompromised status, corneal transplant type, oral/ocular steroids received 12 weeks prior to index date (yes/no), non-index vaccinations received 12 weeks prior to index date (yes/no), and medical center and area. Conclusion We did not find evidence of an elevated risk of graft rejection associated with vaccination given in the 12 weeks prior to the index date. Although our study is the largest study examining the association between corneal transplant rejection and vaccination to our knowledge, this study may be underpowered to detect a minimal increase in risk. Our findings provide support for completion of recommended vaccinations for patients who are planning or have received a corneal transplant. Disclosures Jennifer H. Ku, PhD MPH, GlaxoSmithKline: Grant/Research Support|Moderna: Grant/Research Support Julia Tubert, MPH, Moderna: Grant/Research Support|Pfizer: Grant/Research Support Yi Luo, PhD, GlaxoSmithKline: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support Kevin L. Winthrop, MD, MPH, AN2: Advisor/Consultant|AN2: Grant/Research Support|Insmed: Advisor/Consultant|Insmed: Grant/Research Support|Insmed: This study was funded by Insmed Inc.|Paratek: Advisor/Consultant|Paratek: Grant/Research Support|Red Hill Biopharma: Advisor/Consultant|Red Hill Biopharma: Board Member|Red Hill Biopharma: Grant/Research Support|Renovion: Advisor/Consultant|Renovion: Grant/Research Support|Spero: Advisor/Consultant|Spero: Grant/Research Support Divya Srikumaran, MD, Alcon: Advisor/Consultant|Claris Biotherpeautics: Grant/Research Support Ana Florea, PhD MPH, Gilead: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support Hung Fu Tseng, PhD MPH, GSK: Grant/Research Support|Moderna: Grant/Research Support

Human mesenchymal stem cells derived from adipose tissue showed a more robust effect than those from the umbilical cord in promoting corneal graft survival by suppressing lymphangiogenesis

BackgroundMesenchymal stem cells (MSCs) have shown promising potential in allograft survival. However, few reports have focused on comparing the immunosuppressive capacity of MSCs from different sources and administered via different routes in inhibiting transplant rejection. Moreover, virtually nothing is known about the role of MSCs in the regulation of graft neovascularization and lymphangiogenesis. In this study, we compared the efficacy of human adipose MSCs (hAD-MSCs) and human umbilical cord MSCs (hUC-MSCs) in vitro and in corneal transplantation models to explore the underlying molecular mechanisms and provide a powerful strategy for future clinical applications.MethodshAD-MSCs and hUC-MSCs were generated, and their self-renewal and multi-differentiation abilities were evaluated. The inhibitory effect of human MSCs (hMSCs) was examined by T-cell proliferation assays with or without transwell in vitro. Two MSCs from different sources were separately adoptively transferred in mice corneal transplantation (5 × 105 or 1 × 106/mouse) via topical subconjunctival or intravenous (IV) routes. Allograft survival was evaluated every other day, and angiogenesis and lymphomagenesis were quantitatively analyzed by immunofluorescence staining. The RNA expression profiles of hMSCs were revealed by RNA sequencing (RNA-seq) and verified by quantitative real-time PCR (qRT‒PCR), western blotting or ELISA. The function of the differentially expressed gene FAS was verified by a T-cell apoptosis assay.ResultshAD-MSCs induced stronger immunosuppression in vitro than hUC-MSCs. The inhibitory effect of hUC-MSCs but not hAD-MSCs was mediated by cell–cell contact-dependent mechanisms. Systemic administration of a lower dose of hAD-MSCs showed better performance in prolonging corneal allograft survival than hUC-MSCs, while subconjunctival administration of hMSCs was safer and further prolonged corneal allograft survival. Both types of hMSCs could inhibit corneal neovascularization, while hAD-MSCs showed greater superiority in suppressing graft lymphangiogenesis. RNA-seq analysis and confirmation experiments revealed the superior performance of hAD-MSCs in allografts based on the lower expression of vascular endothelial growth factor C (VEGF-C) and higher expression of FAS.ConclusionsThe remarkable inhibitory effects on angiogenesis/lymphangiogenesis and immunological transplantation effects support the development of hAD-MSCs as a cell therapy against corneal transplant rejection. Topical administration of hMSCs was a safer and more effective route for application than systemic administration.

Immune tolerance induced in the anterior chamber ameliorates corneal transplant rejection

The relevance of regulatory T cells (Tregs) in induction of tolerance against corneal allografts has been well established. However, whether Tregs can be induced in the anterior chamber and suppress local alloimmune response after corneal transplantation is largely unknown. In the current study we report that not only can alloantigen specific Tregs be generated in the anterior chamber during corneal transplantation, they also play important roles in suppressing allograft rejection. Allograft rejected mice exhibit reduced Treg induction in the anterior chamber and the ability of aqueous humor and corneal endothelial cells from allograft rejected mice to induce Tregs is compromised. Further analysis revealed that the expression of immune-tolerance-related molecules is significantly decreased. Finally, we demonstrate that increasing Treg cells specifically in the anterior chamber can effectively suppress allograft rejection and exhibits better efficacy in promoting corneal allograft survival than systemic administration of Treg cells. Our current study may provide new ideas for the prevention and treatment of corneal transplant rejection.

Examining the Influence of COVID-19 Infection and Pandemic Restrictions on the Risk of Corneal Transplant Rejection or Failure: A Multicenter Study

ABSTRACT Purpose The purpose of this study was to evaluate two aims. The first was whether patients with a history of keratoplasty who developed COVID-19 were at a higher risk of corneal graft rejection or failure. The second was examining whether patients who underwent a new keratoplasty during the first 2 years of the pandemic from 2020–2022 were at a higher risk of the same outcomes compared to those undergoing keratoplasty from 2017–2019 before the pandemic. Methods A multicenter research network, TriNetX, was used to query for keratoplasty patients with or without a COVID-19 between January 2020 and July 2022. Additionally, the database was also queried to identify new keratoplasties performed from January 2020-July 2022 and compare it to keratoplasties performed during a similar pre-pandemic interval between 2017–2019. 1:1 Propensity Score Matching was utilized to adjust for confounders. Graft complication of either a rejection or failure was assessed within 120 day follow-up using the Cox proportional hazard model and survival analysis. Results A total of 21,991 patients with any keratoplasty history were identified from January 2020-July 2022, of which 8.8% were diagnosed with COVID-19. Matching revealed two balanced cohorts of 1,927 patients where no significant difference in risk of corneal graft rejection or failure among groups ((aHR [95% CI] = 0.76 [0.43,1.34]; p = .244)). Comparing first-time keratoplasties performed in a pandemic period of January 2020-July 2022 to a corresponding pre-pandemic interval from 2017–2019 also similarly revealed no differences in graft rejection or failure in matched analysis (aHR = 0.937[0.75, 1.17], p = .339). Conclusions This study found no significant increase in the risk of graft rejection or failure in patients with a prior keratoplasty history following COVID-19 diagnosis nor in any patients who had a new keratoplasty done during 2020–2022 when compared to a similar pre-pandemic interval.

Ocular surface complications following biological therapy for cancer.

Novel and highly effective biological agents developed to treat cancer over the past two decades have also been linked to multiple adverse outcomes, including unanticipated consequences for the cornea. This review provides an overview of adverse corneal complications of biological agents currently in use for the treatment of cancer. Epidermal growth factor receptor inhibitors and immune checkpoint inhibitors are the two classes of biological agents most frequently associated with corneal adverse events. Dry eye, Stevens-Johnson syndrome, and corneal transplant rejection have all been reported following the use of immune checkpoint inhibitors. The management of these adverse events requires close collaboration between ophthalmologists, dermatologists, and oncologists. This review focuses in depth on the epidemiology, pathophysiology, and management of ocular surface complications of biological therapies against cancer.

Conventional type I migratory CD103+ dendritic cells are required for corneal allograft survival

Corneal transplant rejection primarily occurs because of the T helper 1 (Th1) effector cell-mediated immune response of the host towards allogeneic tissue. The evidence suggests that type 1 migratory conventional CD103+ dendritic cells (CD103+DC1) acquire an immunosuppressive phenotype in the tumor environment; however, the involvement of CD103+DC1 in allograft survival continues to be an elusive question of great clinical significance in tissue transplantation. In this study, we assess the role of CD103+DC1 in suppressing Th1 alloreactivity against transplanted corneal allografts. The immunosuppressive function of CD103+DC1 has been extensively studied in non-transplantation settings. We found that host CD103+DC1 infiltrates the corneal graft and migrates to the draining lymph nodes to suppress alloreactive CD4+ Th1 cells via the programmed death-ligand 1 axis. The systemic depletion of CD103+ DC1 in allograft recipients leads to amplified Th1 activation, impaired Treg function, and increased rate of allograft rejection. Although allograft recipient Rag1 null mice reconstituted with naïve CD4+CD25- T cells efficiently generated peripheral Treg cells (pTreg), the CD103+DC1-depleted mice failed to generate pTreg. Furthermore, adoptive transfer of pTreg failed to rescue allografts in CD103+DC1-depleted recipients from rejection. These data demonstrate the critical role of CD103+DC1 in regulating host alloimmune responses.