UV light-mediated corneal crosslinking as (lymph)angioregressive pretreatment to promote graft survival after subsequent high-risk corneal transplantation (CrossCornealVision): protocol for a multicenter, randomized controlled trial
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ABSTRACT:
SUBMITTER: Wiedemann J
PROVIDER: S-EPMC10916195 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Antigen-presenting cells (APCs) play an important role in transplant rejection and tolerance. In high-risk corneal transplantation, where the graft bed is inflamed and vascularized, immature APCs in the donor corneal stroma quickly mature and migrate to lymphoid tissues to sensitize host T cells. In this study, using a mouse model of corneal transplantation, we investigated whether enrichment of tolerogenic APCs (tolAPCs) in donor corneas can enhance graft survival in corneal allograft recipients with inflamed graft beds. Treatment of donor corneas with interleukin-10 (IL-10) and transforming growth factor-β1 (TGFβ1) altered the phenotype and function of tissue-residing APCs. Transplantation of these tolAPC-enriched corneas decreased frequencies of interferon gamma (IFNγ)+ effector T cells (Teffs), as well as allosensitization in the hosts, diminished graft infiltration of CD45+ and CD4+ cells, and significantly improved corneal allograft survival compared to saline-injected controls. These data provide a novel approach for tolAPC-based immunotherapy in transplantation by direct cytokine conditioning of the donor tissue.
| S-EPMC5430534 | biostudies-literature
Project description:PurposeTo 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.MethodsAllogeneic 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.ResultsThe 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.ConclusionsFibrosis contributes to graft opacity in corneal transplant failure and is mediated at least in part by effector CD4+ T cells via IFN-γ.
| S-EPMC10810018 | biostudies-literature
Project description:This review compared the clinical results of transepithelial corneal crosslinking (CXL) to epithelium-off (epi-off) CXL in progressive corneal ectasia using a metaanalysis. The Cochrane databases and Medline were searched for randomized controlled trials (RCTs). Seven RCTs involving 505 eyes that met the eligibility criteria were identified. The epi-off CXL group showed significantly better outcomes in postoperative changes in maximum keratometry (K) during 1-year observation periods. Transepithelial CXL resulted in significantly greater post-treatment central corneal thickness and best spectacle-corrected visual acuity (BSCVA). The presence of a postoperative demarcation line was significantly more frequent after epi-off CXL than that after transepithelial CXL. No statistically significant difference was found between other parameters. Although patients in the transepithelial CXL group demonstrated a greater improvement in BSCVA compared with patients in the epi-off CXL group at the 1 year follow-up, transepithelial CXL had less impact on halting progressive corneal ectasia in terms of maximum K than epi-off CXL.
| S-EPMC8561077 | biostudies-literature
Project description:Background and objectivesDonor dopamine improves initial graft function after kidney transplantation due to antioxidant properties. We investigated if a 4 µg/kg per minute continuous dopamine infusion administered after brain-death confirmation affects long-term graft survival and examined the exposure-response relationship with treatment duration.Design, setting, participants, & measurementsFive-year follow-up of 487 renal transplant patients from 60 European centers who had participated in the randomized, multicenter trial of dopamine donor pretreatment between 2004 and 2007 (ClinicalTrials.gov identifier: NCT00115115).ResultsFollow-up was complete in 99.2%. Graft survival was 72.6% versus 68.7% (P=0.34), and 83.3% versus 80.4% (P=0.42) after death-censoring in treatment and control arms according to trial assignment. Although infusion times varied substantially in the treatment arm (range 0-32.2 hours), duration of the dopamine infusion and all-cause graft failure exhibited an exposure-response relationship (hazard ratio, 0.96; 95% confidence interval [95% CI], 0.92 to 1.00, per hour). Cumulative frequency curves of graft survival and exposure time of the dopamine infusion indicated a maximum response rate at 7.10 hours (95% CI, 6.99 to 7.21), which almost coincided with the optimum infusion time for improvement of early graft function (7.05 hours; 95% CI, 6.92 to 7.18). Taking infusion time of 7.1 hours as threshold in subsequent graft survival analyses indicated a relevant benefit: Overall, 81.5% versus 68.5%; P=0.03; and 90.3% versus 80.2%; P=0.04 after death-censoring.ConclusionsWe failed to show a significant graft survival advantage on intention-to-treat. Dopamine infusion time was very short in a considerable number of donors assigned to treatment. Our finding of a significant, nonlinear exposure-response relationship disclosed a threshold value of the dopamine infusion time that may improve long-term kidney graft survival.
| S-EPMC5338714 | biostudies-literature
Project description:PurposeTo compare the results of standard corneal crosslinking (CXL) and transepithelial iontophoresis-assisted CXL after 24 months follow-up.Material and methodsCorneal crosslinking (CXL) was performed in a series of 149 eyes of 119 patients with keratoconus I-II of Amsler classification. Depending on the CXL method, patients were divided into two groups: (1) 73 eyes with standard CXL and (2) 76 eyes with transepithelial iontophoresis-assisted CXL. Depending on the group, epithelium removal or administration of riboflavin solution by iontophoresis for 10 min was performed, after which standard surface UVA irradiation (370 nm, 3 mW/cm2 ) was performed at a 5-cm distance for 30 min.ResultsA statistically significant difference in corrected distance visual acuity (CDVA) was observed between the two groups, with a better outcome in the second group after 6 months (p = 0.037); however, no significant difference was found 24 months after treatment (p = 0.829). Stabilization and regression of keratometry values were achieved in both groups, but standard CXL was more effective. The average demarcation line depth in the standard CXL group was 292 ± 14 μm after 14 days and 172 ± 16 μm in the transepithelial iontophoresis-assisted CXL group. No demarcation line was detected after 1 month and 3 months in 45% and 100% of the eyes in the second group respectively.ConclusionTransepithelial iontophoresis-assisted collagen crosslinking showed to be less effective than standard CXL after 24 months of follow-up, possibly due to a more superficial formation of corneal collagen crosslinks, however the stopping of disease progression was achieved 24 months after procedure.
| S-EPMC5111766 | biostudies-literature
Project description:Orthokeratology (Ortho-K) works to reshape cornea and is the only non-surgical way to enable vision without corrective aids. However, its effect is only temporary, and successful stabilization requires ongoing Ortho-K wear to maintain the reshaping effect. Corneal crosslinking (CXL) is a commonly-used technique in clinical practice to stabilize corneal shape in keratoconic eyes. However, whether or not CXL can stabilize corneal shape after Ortho-K in normal cornea has not been reported. Therefore, this proof-of-concept study using 2 rhesus monkeys aimed to determine the efficacy of the combined procedure. One monkey wore Ortho-K bilaterally for 24 hours, and the other from 6 pm to 8 am for 7 days. The left eyes of both monkeys underwent CXL after Ortho-K while the contralateral eye served as control. Results showed a gradual regression of corneal shape in all eyes with or without CXL. However, eyes underwent CXL regressed more slowly than the control eyes. The control eyes and the CXL treatment eye in the 7-day Ortho-K monkey regressed completely at last, while the CXL treatment eye in the 24 h Ortho-K monkey maintained a corneal flattening of -1.48 D 27 days after procedure. These findings suggest CXL can slow the regression of Ortho-K for a short duration, but cannot sustain its effect according to the current protocol.
| S-EPMC7012905 | biostudies-literature
Project description:PURPOSE:To assess the clinical efficacy of sequential intrastromal corneal ring segment (ICRS) implantation and corneal crosslinking (CXL) in corneal ectasia. METHODS:This retrospective case series included eight eyes in which both ICRS implantation and CXL had been performed. CXL was performed within 1 month after ICRS implantation. The clinical outcomes (visual acuity, refractive errors, keratometry, and topographic indices) of these patients were compared with those of patients who had undergone only ICRS implantation (eight eyes) or CXL (20 eyes). RESULTS:Greater improvement in uncorrected visual acuity was observed in the ICRS + CXL group than in the ICRS or CXL alone groups at both 6 (p = 0.008) and 12 months (p = 0.028). Refractive errors of sphere and spherical equivalent were significantly reduced in both the ICRS (p = 0.002 at 6 months, p = 0.004 at 12 months) and ICRS + CXL groups (p < 0.001 at both 6 and 12 months). Keratometric values including the maximum, minimum, and average were significantly reduced in all 3 groups at postoperative 6 and 12 months; however, the greatest reductions were observed in the ICRS + CXL group (all p < 0.001). CONCLUSIONS:ICRS implantation followed by CXL within 1 month seems to be effective, and may be superior to ICRS or CXL alone in improving visual acuity and reducing refractive errors and keratometric values.
| S-EPMC6911792 | biostudies-literature
Project description:PurposeTo determine the efficacy of local (subconjunctival and topical) bevacizumab (Avastin) treatment in patients undergoing vascularized high-risk corneal transplantation.DesignPilot, prospective, randomized, double-blind, placebo-controlled clinical trial conducted at 5 clinical centers in the United States, India, and Brazil.ParticipantsPatients aged > 18 years undergoing high-risk penetrating keratoplasty, defined as corneal neovascularization (NV) in 1 or more quadrants ≥2 mm from the limbus or extension of corneal NV to the graft-host junction in a previously failed graft.MethodsPatients were randomized to receive subconjunctival bevacizumab (2.5 mg/0.1 ml) or placebo at the time of surgery, followed by topical bevacizumab (10 mg/ml) or topical placebo, administered 4 times per day for 4 weeks.Main outcome measureThe 52-week endothelial immune rejection rate.ResultsNinety-two patients were randomized to receive bevacizumab (n = 48) or control (n = 44). The 52-week endothelial rejection rate was 10% in the bevacizumab group and 19% in the control group (P = 0.20). Post hoc, extended follow-up at the lead study site showed an endothelial rejection rate of 3% in the bevacizumab group and 38% in the control group (P = 0.003). Treatment with bevacizumab was found to have a hazard ratio of 0.15 (95% confidence interval, 0.03-0.65, P = 0.01) in a post hoc Cox regression analysis.ConclusionsIn patients undergoing vascularized high-risk corneal transplantation, there was no statistically significant difference in the rate of endothelial rejection at 1 year in the bevacizumab treatment group compared with the control group. This study may have been underpowered to detect a difference between treatment groups, and taken together, our data suggest that, in the current trial design, bevacizumab has a positive but not (yet) significant effect on endothelial rejection.
| S-EPMC10742165 | biostudies-literature
Project description:Ocular graft-versus-host disease (oGVHD) is a fast progressing, autoimmunological disease following hematopoietic stem cell transplantation, leading to severe inflammation of the eye and destruction of the lacrimal functional unit with consecutive sight-threatening consequences. The therapeutic "window of opportunity" is narrow, and current treatment options are limited and often insufficient. To achieve new insights into the pathogenesis and to develop new therapeutic approaches, clinically relevant models of oGVHD are desirable. In this study, the ocular phenotype was described in a murine, chemotherapy-based, minor-mismatch GVHD model mimicking early-onset chronic oGVHD, with corneal epitheliopathy, inflammation of the lacrimal glands, and blepharitis. Additionally, corneal lymphangiogenesis was observed as part of oGVHD pathogenesis for the first time, thus opening up the investigation of lymphangiogenesis as a potential therapeutic and diagnostic tool.
| S-EPMC8228997 | biostudies-literature
Project description:PURPOSE: To assess the effects of preoperative patient characteristics on clinical outcomes of corneal crosslinking (CXL) treatment in patients with progressive keratoconus. METHODS: This retrospective study comprised 96 eyes of 96 patients who had unilateral CXL treatment for progressive keratoconus. All patients underwent a complete ophthalmological examination and corneal topography at baseline and 1 year. Subgroup analyses were performed according to the age (<30 and ≥ 30 years), gender, preoperative corrected distance visual acuity (CDVA, <0.3 and ≥ 0.3 logMAR (log of the minimum angle of resolution)), preoperative maximum keratometry (K, <54 and ≥ 54 D), baseline topographic cone location (central, paracentral, and peripheral), and preoperative thinnest pachymetry (<450 and ≥ 450 μm) to determine the associations between preoperative patient characteristics and outcomes (changes in visual acuity and maximum keratometry) of CXL treatment. RESULTS: In the entire study population, mean CDVA and maximum K significantly improved after CXL treatment (P<0.001). Patients with a preoperative CDVA of 20/40 Snellen equivalent or worse (≥ 0.3 logMAR) experienced more visual improvement after CXL treatment (P<0.001). However, an age ≥ 30 years and a baseline thinnest pachymetry less than 450 μm were found significantly associated with more flattening in maximum keratometry (P=0.024, P=0.005 respectively). Gender, preoperative maximum K, and baseline topographic cone location did not show significant effect on postoperative visual acuity and maximum keratometry (P>0.05). CONCLUSIONS: In patients with progressive keratoconus, age, baseline visual acuity, and baseline thinnest pachymetry seem to affect the success of the CXL treatment.
| S-EPMC3890756 | biostudies-other