Publications by authors named "Daniel F P Larkin"

35 Publications

Keratoplasty for Keratoconus in Young Patients: Demographics, Clinical Features, and Post-transplant Outcomes.

Am J Ophthalmol 2021 Feb 9;226:68-75. Epub 2021 Feb 9.

From the Cornea & External Diseases Service, Moorfields Eye Hospital, London, United Kingdom (D.W., D.F.P.L.). Electronic address:

Purpose: To examine pretransplant findings and outcomes of corneal transplants for keratoconus in children.

Design: Retrospective cohort (national registry) study.

Methods: Data on all patients aged 16 or younger (n = 170) who had a first transplant for keratoconus between 2003 and 2018 in all corneal transplant centers in the UK were compared to adult patients aged 17 and older (n = 7,191). The influence of demographic variables, pretransplant corneal findings, and transplant type on 2-year visual, rejection-free, and transplant survival outcomes was examined.

Results: Children had poorer pretransplant visual acuity and higher rates of corneal vascularization and ocular surface disease than adults. However, 2-year post-transplant corrected visual acuity reached 20/20 or better in 35% of children compared to 28% of adults (P = .1). Transplant rejection and failure rates were 11% (P = .79) and 3% (P = .31), respectively, for children, which were comparable to rates for adults. Endothelial rejection was reported following penetrating keratoplasty (PK) in 13% of children (10% in adults). Irreversible rejection was not recorded for any transplant in a child. Despite a lack of difference in transplant outcomes, there was a significant age effect in the Cox regression model for transplant rejection, such that for every 5-year increase in age there was a 6% reduction in the hazard of rejection. Transplant survival following anterior lamellar keratoplasty and PK in children was similar.

Conclusions: Young keratoconus patients have excellent transplant outcomes and visual results comparable to adults. Overall, the hazard of rejection was found to decrease with advancing age. However, in this large cohort of young patients with keratoconus and poor vision, there is no evidence of outcome advantage in delaying transplant until adult years.
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http://dx.doi.org/10.1016/j.ajo.2021.02.003DOI Listing
February 2021

Clinical and confocal imaging findings in congenital corneal anaesthesia.

Br J Ophthalmol 2020 Sep 15. Epub 2020 Sep 15.

External Diseases Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK

Background/aims: Congenital corneal anaesthesia (CCA) is an uncommon cause of corneal ulceration in young patients, with a reported poor visual prognosis. We correlated clinical findings in patients with CCA with corneal sub-basal nerve plexus (SBNP) morphology and dendritiform cell density (DCD) on confocal microscopy.

Methods: A prospective, case-control study was conducted at a referral clinic. History includied presenting features in patients with CCA, clinical course and examination findings. Differences in SBNP morphology and DCD on confocal microscopy (IVCM) were compared in cases and control subjects with healthy corneas.

Results: Eight patients with CCA were examined, of which three had a diagnosis of familial dysautonomia. Age at initial diagnosis of corneal disease ranged from infancy to 22 years, the most common presentation being corneal ulceration. All patients with CCA except one with optic neuropathy had corrected visual acuity 6/18 (logMAR 0.35) or better in at least one eye. Measured corneal sensation was minimal in all patients. Major abnormalities were found on confocal microscopy in all patients with CCA, whether or not inherited, including statistically significant reduction in SBNP nerve fibre density, fibre length and branch density. Increased DCD in superficial cornea was found in all patients with CCA.

Conclusion: Good visual acuity can be maintained in eyes with corneal anaesthesia present from birth. IVCM provides direct evidence of a morphological correlate for measured corneal anaesthesia. Increased DCD may indicate an enhanced role for innate immune cells in superficial cornea in protection of the anaesthetic ocular surface.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316672DOI Listing
September 2020

Update on Herpes simplex keratitis management.

Eye (Lond) 2020 12 25;34(12):2219-2226. Epub 2020 Aug 25.

Cornea & External Diseases Service, Moorfields Eye Hospital, 162 City Road, London, EC1V 2PD, UK.

Herpes simplex keratitis (HSK) is a common, potentially blinding condition characterised by recurrent infections of the cornea, seen by both general ophthalmologists and corneal specialists. Successful treatment of recurrences reduces disease duration, prevents progressive corneal scaring leading to vision loss and reduces risk of further recurrences. In this review we discuss the relative advantages of the diagnostic laboratory investigations including polymerase chain reaction, viral culture and fluorescence-based immunohistochemistry. We review treatment strategies in selected aspects of HSK and discuss the management options in cases not responding to treatment.
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http://dx.doi.org/10.1038/s41433-020-01153-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784930PMC
December 2020

Pulsed oral corticosteroids for the treatment of vernal and atopic keratoconjunctivitis: a management plan.

Eye (Lond) 2021 Apr 1;35(4):1277-1278. Epub 2020 Jul 1.

NIHR Moorfields Biomedical Research Centre, 162 City Road, London, EC1V 2PD, UK.

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http://dx.doi.org/10.1038/s41433-020-1062-2DOI Listing
April 2021

Corneal cross-linking versus standard care in children with keratoconus - a randomised, multicentre, observer-masked trial of efficacy and safety (KERALINK): a statistical analysis plan.

Trials 2020 Jun 12;21(1):523. Epub 2020 Jun 12.

NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital, London, UK.

Background: The KERALINK trial tests the hypothesis that corneal cross-linking (CXL) treatment reduces the progression of keratoconus in comparison to standard care in patients aged 10-16 years. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written before the end of the patient follow-up, while the outcome of the trial is still unknown.

Design And Methods: KERALINK is a randomised controlled, observer-masked, multicentre trial in progressive keratoconus comparing epithelium-off CXL with standard care, including spectacles or contact lenses as necessary for best-corrected acuity. Keratoconus is a disorder of the shape of the cornea in which the normally round dome-shaped clear front window of the eye (cornea) thins progressively leading to a cone-like bulge. This impairs the ability of the eye to focus properly, causing reduced vision which requires spectacle or contact lens wear or, in a minority of patients, eventually corneal replacement by a transplant for best vision. The primary outcome measure is the between-group difference in K at 18 months adjusted for K at baseline examination. K is the value of the steepest corneal meridian as measured on Pentacam topography. Secondary outcomes are keratoconus progression, time to keratoconus progression, visual acuity, refraction, apical corneal thickness and adverse events. Patient-reported effects will be explored by questionnaires. We describe in detail the statistical aspects of KERALINK: the outcome measures, the sample size calculation, general analysis principles, the planned descriptive statistics and statistical models, and planned subgroup and sensitivity analyses.

Discussion: The KERALINK statistical analysis will provide comprehensive and precise information on the relative effectiveness of the two treatments. The plan will be implemented in May 2020 when follow-up for the trial is completed.

Trial Registration: EudraCT, 2016-001460-11. Registered on 19 May 2016.
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http://dx.doi.org/10.1186/s13063-020-04392-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291687PMC
June 2020

A randomised, controlled, observer-masked trial of corneal cross-linking for progressive keratoconus in children: the KERALINK protocol.

BMJ Open 2019 09 12;9(9):e028761. Epub 2019 Sep 12.

NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital, London, UK

Introduction: The KERALINK trial tests the hypothesis that corneal cross-linking (CXL) treatment reduces the progression of keratoconus in comparison to standard care in patients under 17 years old. KERALINK is a randomised controlled, observer-masked, multicentre trial in progressive keratoconus comparing epithelium-off CXL with standard care, including spectacles or contact lenses as necessary for best-corrected acuity.

Methods And Analysis: A total of 30 participants will be randomised per group. Eligible participants aged 10-16 years with progressive keratoconus in one or both eyes will be recruited. Following randomisation, participants will be followed up 3-monthly for 18 months. The effect on progression will be determined by K on corneal topography. The primary outcome measure is between-group difference in K at 18 months adjusted for K at baseline examination. Secondary outcomes are the effect of CXL on (1) keratoconus progression, (2) time to keratoconus progression, (3) visual acuity, (4) refraction, (5) apical corneal thickness and (6) adverse events. Patient-reported effects will be explored by questionnaires.

Ethics And Dissemination: Research Ethics Committee Approval was obtained on 30 June 2016 (ref: 14/LO/1937). Current protocol: V.5.0 (08/11/2017). Study findings will be published in peer-reviewed journals.

Trial Registration Number: European Union clinial trials register (EudraCT) 2016-001460-11.
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http://dx.doi.org/10.1136/bmjopen-2018-028761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747657PMC
September 2019

Differential effects of primary disease and corneal vascularisation on corneal transplant rejection and survival.

Br J Ophthalmol 2020 05 28;104(5):729-734. Epub 2019 Aug 28.

Moorfields Eye Hospital NHS Foundation Trust, London, UK

Aims: To investigate the relative risk of pretransplant corneal vascularisation on rate of rejection and graft failure within 5 years of surgery when categorised by indication for transplantation.We analysed all adults recorded in the UK transplant registry who had a first cornea transplant for keratoconus (KC), pseudophakic bullous keratopathy (PBK) or previous infection (viral/bacterial/fungal/protozoan) between 1999 and 2017. We analysed the number of quadrants of the recipient cornea vascularised before transplant and type of vascularisation, the interval post-transplant to rejection, if any, and the outcome at 5 years post-transplant. Risk factors for rejection and transplant failure were modelled by multivariable risk-adjusted Cox regression.

Results: Corneal vascularisation was recorded in 10%, 25% and 67% of patients with KC, PBK and infection, respectively. Individuals with PBK had an increased hazard of transplant rejection only when there were more than two quadrants of vascularisation (HR 1.5, p=0.004) when either superficial and/or deep vascularisation was present (HR 1.3 and 1.4, respectively, p=0.004). Individuals who had a transplant for previous infection had an increased hazard of rejection with four quadrants of vascularisation (HR 1.6, p=0.003). There was no risk-adjusted increase in transplant failure associated with vascularisation in any group. There was weak evidence of reduction in risk of rejection and/or failure associated with lamellar compared with penetrating transplantation in KC and PBK in vascularised recipient corneas.

Conclusion: Vascularisation is a risk factor for corneal allograft rejection within 5 years. The indication for transplantation has a clinically significant effect on the magnitude of this risk.
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http://dx.doi.org/10.1136/bjophthalmol-2019-314200DOI Listing
May 2020

Longitudinal changes in corneal leucocyte density in vivo following transplantation.

Br J Ophthalmol 2019 08 24;103(8):1035-1041. Epub 2018 Oct 24.

NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital, London, UK

Aims: To prospectively evaluate the changes in corneal leucocyte density with in vivo confocal microscopy (IVCM) following transplantation and to determine if leucocyte density post-transplant is an indicator of graft rejection risk.

Methods: IVCM imaging of cornea pre-transplant and post-transplant at 1 week, 1, 3 and 12 months. The changes in leucocyte density associated with diagnosis, vascularisation, type of keratoplasty, topical steroid and immunosuppression treatment, allograft rejection and failure within 4 years post-transplant were analysed.

Results: Sub-basal nerve plexus total central leucocyte density (SBNP-TCLD) varied with diagnosis (p<0.001), interval post-transplant (p<0.001), degree of vascularisation (p=0.001) and rejection episodes in eyes off topical steroid (p=0.01). The highest SBNP-TCLD was found in eyes with inflammation pre-transplant. Mean 12-month SBNP-TCLD in eyes which had rejection episodes was almost double that in eyes which did not (79.0 and 39.8 cells/mm, respectively). SBNP-TCLD >63.5 cells/mm was associated with a higher risk of rejection within 1 year (p=0.04) and 4 years (p=0.007). Changes in leucocyte density on the donor endothelium significantly differed between penetrating keratoplasty and deep anterior lamellar keratoplasty grafts (p<0.01) and in those in which rejection episodes were observed (p<0.001).

Conclusions: Leucocyte density varies with corneal diagnosis, extent of vascularisation and interval post-transplant. Topical steroid treatment is associated with reduced leucocyte density and risk of graft rejection. Higher endothelium leucocyte density correlates significantly with previous or subsequent rejection episodes. Leucocyte density measurement by IVCM may be useful in identifying transplants at risk of rejection.
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http://dx.doi.org/10.1136/bjophthalmol-2018-312386DOI Listing
August 2019

Descemet Membrane Endothelial Keratoplasty (DMEK) Graft Dislocation Into the Vitreous Cavity.

Cornea 2019 Feb;38(2):173-176

Vitreo-Retinal Service, Moorfields Eye Hospital, London, United Kingdom.

Purpose: To present our experience of Descemet stripping endothelial keratoplasty (DMEK) graft luxation into the vitreous cavity in 2 cases.

Methods: DMEK was performed in 2 patients with aphakic bullous keratopathy. The indications for keratoplasty were endothelial failure caused by chronic intermediate uveitis and glaucoma in 1 case and decompensated previous penetrating keratoplasty in the other. Both cases had enlarged pupils and had previously undergone pars plana vitrectomy. In both cases, the DMEK graft dislocated into the vitreous cavity during unfolding maneuvers and could not be retrieved during the same procedure.

Results: No signs of retinal detachment were observed during follow-up (6 months and 1 year). Although visualization of the graft was not possible on examination, B-scan confirmed the presence of the lenticule lying over the retina. One case underwent repeat DMEK, and 1 case underwent repeat penetrating keratoplasty. In 1 case, the graft was retrieved after a month and sent for histopathology. In both cases, corneal transparency and corrected visual acuity improved to full potential after the final procedure. Histopathology of the retrieved graft showed only endothelial cell loss and no fibrocellular proliferation.

Conclusions: The risk of fibrous proliferation and retinal detachment after posterior dislocation of DMEK grafts may be less than in grafts including corneal stroma, but pars plana vitrectomy and retrieval of the dislocated corneal transplant are still indicated after revision corneal transplant surgery where visual symptoms or signs of fibrotic change around the dislocated graft are evident.
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http://dx.doi.org/10.1097/ICO.0000000000001788DOI Listing
February 2019

Differential Survival of Penetrating and Lamellar Transplants in Management of Failed Corneal Grafts.

JAMA Ophthalmol 2018 08;136(8):859-865

UCL Institute of Ophthalmology, University College London, London, England.

Importance: An increasing proportion of corneal transplant procedures are undertaken for replacement of a failed previous graft. The proportion of lamellar transplant procedures has significantly increased. There are limited large-scale reports on regraft procedures that may help guide surgeons and patients in their choice of surgery.

Objective: To examine the corneal transplant replacement survival rates for the 3 main indications and types of regraft surgery.

Design, Setting, And Participants: This national transplant registry study examined surgery and follow-up data on all corneal transplants performed in the United Kingdom from April 1, 1999, through March 31, 2016.

Main Outcomes And Measures: Actuarial regraft 5-year survival rates were compared for the 3 main indications and types of graft: penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty for keratoconus, PK and endothelial keratoplasty (EK) for Fuchs endothelial dystrophy (FED), and pseudophakic bullous keratopathy (PBK).

Results: A total of 9925 regrafts were analyzed during the 17-year study period. Penetrating keratoplasty represented 7261 cases (73.2%) in the cohort. Endothelial keratoplasty increased by 1361.5%, from 12 (2.6%; 95% CI, 1.3%-4.5%) of all 467 regrafts during 2005-2006 to 292 (38.0%; 95% CI, 34.6%-41.6%) of 768 during 2015-2016. The median time to first regraft for all graft types was 28 months (interquartile range, 10-64 months). When examining all graft types performed for all indications, stratification of 5-year survival was found for successive grafts, with a difference in survival of 25 270 (72.5%; 95% CI, 71.7%-73.2%) from the first graft to 4224 (53.4%; 95% CI, 51.4%-55.4%) from the second graft and 1088 (37.3%; 95% CI, 33.4%-41.3%) from the second to third graft. For first regrafts in keratoconus and PBK, survival after lamellar and PK procedures was similar. For FED, there was a higher regraft survival after PK (375 [70.8%]; 95% CI, 64.6%-76.1%) compared with EK (303 [54.7%]; 95% CI, 45.8%-62.8%) (P < .001). For FED and PBK, there was no difference in first regraft survival identified between EK followed by PK vs PK followed by PK or EK followed by EK vs PK followed by EK.

Conclusions And Relevance: In this large registry-based analysis of corneal regraft survival, regraft survival was found to vary with indication for first graft surgery and for FED with type of regraft procedure performed. For FED and PBK, the permutation of graft and subsequent first regraft procedure were not associated with any survival benefit for the first regraft. These reported outcomes may assist decision-making in management of a failed corneal transplant.
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http://dx.doi.org/10.1001/jamaophthalmol.2018.1515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142952PMC
August 2018

Letter to the Editor in Response to Kim et al, "Effect of Histocompatibility Y Antigen Matching on Graft Survival in Primary Penetrating Keratoplasty."

Cornea 2018 05;37(5):e29

Cornea and External Diseases Service, Moorfields Eye Hospital, London, United Kingdom.

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http://dx.doi.org/10.1097/ICO.0000000000001539DOI Listing
May 2018

Influence of Socioeconomic Deprivation on Visual Acuity in Patients Undergoing Corneal Transplantation.

Cornea 2018 Jan;37(1):28-32

Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom.

Purpose: To determine whether there is an association between socioeconomic status and best-corrected visual acuity (BCVA) in patients undergoing corneal transplantation in the United Kingdom.

Methods: Retrospective cohort study of 4306 patients registered on the national United Kingdom Transplant Registry and undergoing penetrating keratoplasty, anterior lamellar keratoplasty, or endothelial keratoplasty in 2002, 2008, and 2013. Socioeconomic status was determined by applying a validated deprivation index to generate a score based on 5 categories. Patients' demographic details, preoperative BCVA, copathology, surgical center volume, and socioeconomic status were analyzed for univariate effects of categorical and continuous variables. Binary logistic regression was used to determine whether preoperative BCVA was affected by socioeconomic status after adjusting for other factors.

Results: A larger percentage of the most deprived group was female in each period compared with the least deprived, but this was only significant in 2002 (48.7% vs. 40.3%; P = 0.04). There was no interaction between socioeconomic status and the preoperative BCVA in the grafted eye. However, BCVA in the fellow eye was poorer for the most economically deprived patients compared with the least deprived in 2013 (P = 0.01).

Conclusions: We found no evidence of a relationship between socioeconomic deprivation and BCVA in the transplant recipient eye. However, there was clear evidence of an association between socioeconomic deprivation and reduced acuity in fellow eyes, for which barriers to access or low patient demand may be possible contributors.
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http://dx.doi.org/10.1097/ICO.0000000000001406DOI Listing
January 2018

Identification of Therapeutic Targets of Inflammatory Monocyte Recruitment to Modulate the Allogeneic Injury to Donor Cornea.

Invest Ophthalmol Vis Sci 2015 Nov;56(12):7250-9

Division of Infection and Immunity University College London, London, United Kingdom.

Purpose: We sought to test the hypothesis that monocytes contribute to the immunopathogenesis of corneal allograft rejection and identify therapeutic targets to inhibit monocyte recruitment.

Methods: Monocytes and proinflammatory mediators within anterior chamber samples during corneal graft rejection were quantified by flow cytometry and multiplex protein assays. Lipopolysaccharide or IFN-γ stimulation of monocyte-derived macrophages (MDMs) was used to generate inflammatory conditioned media (CoM). Corneal endothelial viability was tested by nuclear counting, connexin 43, and propidium iodide staining. Chemokine and chemokine receptor expression in monocytes and MDMs was assessed in microarray transcriptomic data. The role of chemokine pathways in monocyte migration across microvascular endothelium was tested in vitro by chemokine depletion or chemokine receptor inhibitors.

Results: Inflammatory monocytes were significantly enriched in anterior chamber samples within 1 week of the onset of symptoms of corneal graft rejection. The MDM inflammatory CoM was cytopathic to transformed human corneal endothelia. This effect was also evident in endothelium of excised human cornea and increased in the presence of monocytes. Gene expression microarrays identified monocyte chemokine receptors and cognate chemokines in MDM inflammatory responses, which were also enriched in anterior chamber samples. Depletion of selected chemokines in MDM inflammatory CoM had no effect on monocyte transmigration across an endothelial blood-eye barrier, but selective chemokine receptor inhibition reduced monocyte recruitment significantly.

Conclusions: We propose a role for inflammatory monocytes in endothelial cytotoxicity in corneal graft rejection. Therefore, targeting monocyte recruitment offers a putative novel strategy to reduce donor endothelial cell injury in survival of human corneal allografts.
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http://dx.doi.org/10.1167/iovs.15-16941DOI Listing
November 2015

Reply: To PMID 25089353.

Am J Ophthalmol 2015 Aug;160(2):393-4

Liverpool, United Kingdom.

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http://dx.doi.org/10.1016/j.ajo.2015.04.035DOI Listing
August 2015

Corneal transplant surgery for keratoconus and the effect of surgeon experience on deep anterior lamellar keratoplasty outcomes.

Am J Ophthalmol 2014 Dec 28;158(6):1239-46. Epub 2014 Aug 28.

St Paul's Eye Unit, 8X Link, Royal Liverpool University Hospital, Liverpool, United Kingdom. Electronic address:

Purpose: To investigate graft survival and surgical experience on clinical outcome following deep anterior lamellar keratoplasty (DALK).

Design: Multicenter cohort study.

Methods: The United Kingdom Transplant Database was used to identify patients who had undergone a first DALK or penetrating keratoplasty (PKP) for keratoconus. Data were collected at the time of surgery and at 1, 2, and 5 years postoperatively. Graft survival, best-corrected visual acuity, and refractive error were analyzed for 3 consecutive time periods. DALK outcomes were analyzed according to surgeon experience.

Results: A total of 4521 patients were included. Graft survival was 92% (95% CI: 90-92) for PKP and 90% (95% CI: 88-92) for DALK (P = .09). For corneal transplants undertaken in the periods 1999-2002, 2002-2005, and 2005-2007, graft survival was 90%, 92%, and 88% following DALK, and 93%, 91%, and 92% following PKP, respectively. There was no evidence of a difference between surgeons in terms of case mix (P = .4) or outcome (P = .2). Surgeon experience, in terms of the number of previous DALK undertaken, had no significant effect on outcome. A donor recipient trephine size disparity of 0.5 mm was associated with an increased risk of graft failure for both DALK (P = .03) and PKP (P = .002), whereas ocular surface disease was a significant risk factor for DALK (P = .04) but not PKP.

Conclusions: There has been little change in graft survival for DALK and PKP over the past decade. Ocular surface disease is an important risk factor for graft failure following DALK. A surgical learning curve for DALK could not be demonstrated in terms of clinical outcome.
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http://dx.doi.org/10.1016/j.ajo.2014.08.029DOI Listing
December 2014

Center and surgeon effect on outcomes of endothelial keratoplasty versus penetrating keratoplasty in the United Kingdom.

Am J Ophthalmol 2014 Nov 1;158(5):957-66. Epub 2014 Aug 1.

Moorfields Eye Hospital, London, United Kingdom. Electronic address:

Purpose: To compare national outcomes of endothelial keratoplasty (EK) and penetrating keratoplasty (PK) during comparable 6-year periods.

Design: Prospective cohort study of national registry data.

Methods:

Setting: United Kingdom National Transplant Registry, 2000 through 2011, inclusive.

Patient Population: All United Kingdom patients undergoing first EK (n = 2074) for Fuchs endothelial dystrophy or pseudophakic bullous keratopathy from January 2006 through December 2011. Comparison cohort of patients undergoing first PK (n = 2622, same indications, January 2000 through December 2005).

Observation Procedure: Year of surgery, surgeon and center experience, corneal diagnosis, donor factors, patient factors, and surgical risk factors were analyzed against graft survival and visual outcomes.

Results: For both Fuchs endothelial dystrophy and pseudophakic bullous keratopathy, EK achieved better average best-corrected acuity and lower refractive error. For both groups, graft failure was significantly higher for EK than PK. EK failure in Fuchs endothelial dystrophy was associated with center experience (hazard ratio [HR], 2.3; P < .0001), donor endothelial density (HR, 1.8; P = .01), glaucoma at time of surgery (HR, 2.1; P = .003), and donor age older than 75 years (HR, 1.3; P = .05). EK failure in pseudophakic bullous keratopathy was associated with center experience of fewer than 15 cases (HR, 2.0; P < .0001) and glaucoma at time of surgery (HR, 1.7; P = .002).

Conclusions: Prospective national registry data for EK showed higher graft failure than is seen in PK or in retrospective case series of EK. Higher failure rates may be acceptable given established benefits of the procedure, including lower refractive error, structural globe integrity, and faster visual recovery. Center experience influenced EK survival more than surgeon experience, and overall surgical outcomes may be improved by standardized techniques and support within experienced units.
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http://dx.doi.org/10.1016/j.ajo.2014.07.037DOI Listing
November 2014

Dendritic cell modification as a route to inhibiting corneal graft rejection by the indirect pathway of allorecognition.

Eur J Immunol 2013 Mar 18;43(3):734-46. Epub 2013 Jan 18.

Section of Molecular Immunology, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.

Dendritic cell (DC) modification is a potential strategy to induce clinical transplantation tolerance. We compared two DC modification strategies to inhibit allogeneic T-cell proliferation. In the first strategy, murine DCs were transduced with a lentiviral vector expressing CTLA4-KDEL, a fusion protein that prevents surface CD80/86 expression by retaining the co-stimulatory molecules within the ER. In the second approach, DCs were transduced to express the tryptophan-catabolising enzyme IDO. CTLA4-KDEL-expressing DCs induced anergy in alloreactive T cells and generated both CD4(+) CD25(+) and CD4(+) CD25(-) Treg cells (with direct and indirect donor allospecificity and capacity for linked suppression) both in vitro and in vivo. In contrast, T-cell unresponsiveness induced by IDO(+) DCs lacked donor specificity. In the absence of any immunosuppressive treatment, i.v. administration of CTLA4-KDEL-expressing DCs resulted in long-term survival of corneal allografts only when the DCs were capable of indirect presentation of alloantigen. This study demonstrates the therapeutic potential of CTLA4-KDEL-expressing DCs in tolerance induction.
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http://dx.doi.org/10.1002/eji.201242914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615172PMC
March 2013

Suppression of the allogeneic response by the anti-allergy drug N-(3,4-dimethoxycinnamonyl) anthranilic acid results from T-cell cycle arrest.

Immunology 2013 Feb;138(2):157-64

Section of Immunobiology, Department of Medicine, Imperial College London, London, UK.

Previously we have shown that indoleamine 2,3-dioxygenase (IDO) and the tryptophan metabolite, 3-hydroxykynurenine (3HK) can prolong corneal allograft survival. IDO modulates the immune response by depletion of the essential amino acid tryptophan by breakdown to kynurenines, which themselves act directly on T lymphocytes. The tryptophan metabolite analogue N-(3,4-dimethoxycinnamonyl) anthranilic acid (DAA, 'Tranilast') shares the anthranilic acid core with 3HK. Systemic administration of DAA to mice receiving a fully MHC-mismatched allograft of cornea or skin resulted in significant delay in rejection (median survival of controls 12 days, 13 days for cornea and skin grafts, respectively, and of treated mice 24 days (P < 0.0001) and 17 days (P < 0.03), respectively). We provide evidence that DAA-induced suppression of the allogeneic response, in contrast to that induced by tryptophan metabolites, was a result of cell cycle arrest rather than T-cell death. Cell cycle arrest was mediated by up-regulation of the cell cycle-specific inhibitors p21 and p15, and associated with a significant reduction in interleukin-2 production, allowing us to characterize a novel mechanism for DAA-induced T-cell anergy. Currently licensed as an anti-allergy drug, the oral bioavailability and safe therapeutic profile of DAA make it a candidate for the prevention of rejection of transplanted cornea and other tissues.
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http://dx.doi.org/10.1111/imm.12026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575768PMC
February 2013

Arginine depletion as a mechanism for the immune privilege of corneal allografts.

Eur J Immunol 2011 Oct 6;41(10):2997-3005. Epub 2011 Sep 6.

Section of Immunobiology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK.

The cornea is an immune privileged tissue. Since arginase has been found to modulate T-cell function by depleting arginine, we investigated the expression of arginase in the cornea and its possible role in immune privilege using a murine transplant model. We found that both the endothelium and epithelium of murine corneas express functional arginase I, capable of down-regulating T-cell proliferation in an in vitro culture system. The administration of the specific arginase inhibitor N-hydroxy-nor-L-Arg to recipient mice resulted in an accelerated rejection of allogeneic C57BL/6 (B6) corneal grafts. In contrast, in vivo blockade of arginase activity had no effect in altering the course of rejection of primary skin grafts that express little, if any, arginase. In addition, the inhibition of arginase did not alter systemic T-cell proliferation. These data show that arginase is functional in the cornea and contributes to the immune privilege of the eye, and that modulation of arginase contributes to graft survival.
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http://dx.doi.org/10.1002/eji.201141683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378701PMC
October 2011

A randomised placebo-controlled trial of topical steroid in presumed viral conjunctivitis.

Br J Ophthalmol 2011 Sep 20;95(9):1299-303. Epub 2011 Jan 20.

Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, UK.

Aims: To assess whether topical steroids improve patient comfort compared with hypromellose in acute presumed viral conjunctivitis.

Methods: Patients presenting with acute follicular conjunctivitis, presumed viral in origin, were randomised to receive either dexamethasone 0.1% or hypromellose 0.3% drops four times daily for 1 week. At review after 5-7 days patients completed questionnaires on whether they thought the treatment had helped and on their level of discomfort. A physician assessed conjunctival hyperaemia using a grading scale.

Results: 111 patients were randomised: 56 received dexamethasone drops and 55 received hypromellose lubricant drops. Eighty-eight returned for review. Most patients (39/45 (87%)) receiving dexamethasone and most of those receiving hypromellose 30/43 (70%) felt that the treatment helped. Analysis of all responses showed a significant difference between treatments (p=0.0248, rank sum test). No significant differences between dexamethasone and hypromellose arms were found in the patients' perceived level of discomfort or the physician grading of conjunctival hyperaemia. No patient experienced a serious complication.

Conclusions: There us now evidence to support the use of a short course of topical dexamethasone for patients presenting with acute follicular conjunctivitis presumed to be viral in origin. Where topical dexamethasone is prescribed we have not found it to be harmful.

Trial Registration: http://www.controlled-trials.com/ISRCTN50728656.
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http://dx.doi.org/10.1136/bjo.2010.188623DOI Listing
September 2011

3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival.

Invest Ophthalmol Vis Sci 2011 Apr 22;52(5):2640-8. Epub 2011 Apr 22.

Department of Immunology, Division of Medicine, Imperial College London, London, United Kingdom.

Purpose: IDO (indoleamine 2,3-dioxygenase) modulates the immune response by depletion of the essential amino acid tryptophan, and IDO overexpression has been shown to prolong corneal allograft survival. This study was conducted to examine the effect of kynurenines, the products of tryptophan breakdown and known to act directly on T lymphocytes, on corneal graft survival.

Methods: The effects of kynurenines on T-cell proliferation and death, T-regulatory-cell development, and dendritic cell function, phenotype, and viability were analyzed in vitro. The effect of topical and systemic administration of 3-hydroxykynurenine (3HK) on orthotopic murine corneal allograft survival was examined.

Results: T-lymphocyte proliferation was inhibited by two of the four different kynurenines: 3HK and 3-hydroxyanthranilic acid (3HAA). This effect was accompanied by significant T-cell death. Neither 3HK nor 3HAA altered dendritic cell function, nor did they induce apoptosis or pathogenicity to corneal endothelial cells. Administration of systemic and topical 3HK to mice receiving a fully mismatched corneal graft resulted in significant prolongation of graft survival (median survival of control grafts, 12 days; of treated, 19 and 15 days, respectively; P < 0.0003). While systemic administration of 3HK was associated with a significant depletion of CD4(+) T, CD8(+) T, and B lymphocytes in peripheral blood, no depletion was found after topical administration.

Conclusions: The production of kynurenines, in particular 3HK and 3HAA, may be one mechanism (in addition to tryptophan depletion) by which IDO prolongs graft survival. These molecules have potential as specific agents for preventing allograft rejection in patients at high rejection risk.
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http://dx.doi.org/10.1167/iovs.10-5793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088555PMC
April 2011

Effect of glaucoma on corneal graft survival according to indication for penetrating keratoplasty.

Am J Ophthalmol 2011 Feb 18;151(2):257-62.e1. Epub 2010 Dec 18.

St Paul's Eye Unit, Royal Liverpool Hospital, Liverpool, United Kingdom.

Purpose: To determine whether the risk of graft failure in patients with glaucoma is dependent on the indication for penetrating keratoplasty (PK).

Design: Retrospective cohort study.

Methods: All patients on the United Kingdom Transplant Registry undergoing their first PK over a 7-year period with at least 1 year of follow-up were included. Data were collected on indication for PK, presence and management of glaucoma, graft diameter, recipient risk factors, and graft survival. Kaplan-Meier survival curves, a Cox regression model, and χ(2) and t tests were used in group comparisons.

Results: A total of 6255 transplants in eyes without glaucoma and 1994 in eyes with glaucoma were analyzed. Three-year transplant survival was 86% and 72% respectively (P < .0001), and 73% in eyes with medically managed glaucoma compared to 63% in surgically managed glaucoma (P = .07). Glaucoma patients undergoing PK for pseudophakic bullous keratopathy or Fuchs dystrophy had significantly increased relative risks of graft failure (1.5 and 1.9 with topical and 2.0 and 3.1 with oral antiglaucoma medication respectively, compared to those without glaucoma). There was no equivalent significant difference for those with keratoconus, previous noncataract ocular surgery, trauma, or noninfectious ulcerative keratitis. Endothelial decompensation accounted for a significantly greater proportion of graft failure in recipients with glaucoma (topical [9%] and oral medication [13%]) than in those without glaucoma (3%) (P < .001).

Discussion: The presence of glaucoma carries an increased risk of graft failure, in particular from endothelial decompensation. This risk is, however, also dependent on the indication for PK, with transplants undertaken for primary corneal endothelial disease carrying a higher risk.
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http://dx.doi.org/10.1016/j.ajo.2010.08.018DOI Listing
February 2011

Centre-specific variation in corneal transplant outcomes in the United Kingdom.

Transplantation 2011 Feb;91(3):354-9

Cornea & External Diseases Service, Moorfields Eye Hospital, London, United Kingdom.

Background: To examine the influence of center or surgeon transplant workload on corneal transplant outcome.

Methods: In this database study, centers were categorized as high or low volume if registering more than 50 and less than 10 corneal transplants per year, respectively; surgeons were categorized as high or low volume if registering more than 30 and less than 10 transplants per year, respectively. The participants were patients aged at least 17 years receiving a first penetrating keratoplasty for keratoconus, Fuchs' endothelial disease, or pseudophakic corneal edema in a 7-year period from 1999 in (1) high-volume (n=1724) and low-volume (n=2131) centers and (2) under care of high-volume (n=1332) and low-volume (n=1949) surgeons. Main outcome measures were (1) graft survival at 5 years and (2) 2-year posttransplant best-corrected and day-to-day visual acuity and astigmatism.

Results: No significant difference in graft survival was found according to center or surgeon workload. Statistically significantly better day-to-day visual acuity was found only in patients with Fuchs' endothelial disease managed by high-volume surgeons (20/40 or better in 50% vs. 42% for low-volume surgeons). There was statistically significantly better best-corrected visual acuity in high-volume centers for Fuchs' endothelial disease and pseudophakic corneal edema and for high-volume surgeons in all disease groups.

Conclusions: Based on this national transplant cohort, when analyzed according to center volume or surgeon transplant workload, there is no variation in graft survival and only minor variation in transplant functional outcome.
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http://dx.doi.org/10.1097/TP.0b013e318201ac62DOI Listing
February 2011

Characterisation of the phenotype and function of monocyte-derived dendritic cells in allergic conjunctiva.

Br J Ophthalmol 2010 Dec 30;94(12):1662-7. Epub 2010 Aug 30.

UCL Institute of Ophthalmology, London, UK.

Background: Dendritic cells (DCs) are the most potent antigen-presenting cells involved in initiating the immune response, presenting antigens to T cells and leading to T cell proliferation. In an immature state, DCs lack accessory signals required for T cell stimulation but are highly specialised to capture antigens. Full DC maturation changes the cell surface phenotype and facilitates stimulation of T cell proliferative responses. To examine the degree of DC maturity associated with vernal keratoconjunctivitis (VKC), the authors examined the phenotype and antigen-presentation capability of blood derived DCs from VKC patients and from normal controls.

Methods: Flow cytometry was used to identify the cell surface expression of markers of DC maturity (CD83, CD86, major histocompatibility complex class II) and mixed leucocyte reactions to assess DC induction of T cell proliferation.

Results: DCs derived from VKC patients were of a more mature phenotype than those from normal controls. However, these VKC DCs had reduced capability for induction of T cell proliferation compared with DCs from controls.

Conclusion: The increased maturity of DCs in VKC patients correlates with the heightened immune responsiveness associated with this disorder. A number of mechanisms may underlie the impaired ability of DCs in atopy to stimulate T cell proliferation. This impairment of DC induction of T cell activation is likely to be one factor which contributes to the modified inflammatory response seen in VKC patients and the recognised susceptibility of these patients to viral infection.
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http://dx.doi.org/10.1136/bjo.2009.177774DOI Listing
December 2010

Sirolimus and mycophenolate as combination prophylaxis in corneal transplant recipients at high rejection risk.

Am J Ophthalmol 2010 Aug 8;150(2):179-84. Epub 2010 Jun 8.

Cornea & External Diseases Service, Moorfields Eye Hospital, City Road, London, United Kingdom.

Purpose: To examine efficacy and safety of dual sirolimus and mycophenolate mofetil systemic immunosuppression as allograft rejection prophylaxis after penetrating keratoplasty in patients at high rejection risk.

Design: Prospective, interventional case series.

Methods: settings: Single-center subspecialty clinic. patients: Six penetrating transplant recipients at high rejection risk and with no confounding additional cause for high risk of graft failure. All transplant recipient eyes had good visual potential. intervention: Treatment with oral mycophenolate mofetil in combination with sirolimus for 1 year, and sirolimus alone for 2 further years after keratoplasty at doses used in prophylaxis after cadaveric kidney transplantation. main outcomes measures: Interval to first rejection episode, transplant survival, and significant drug adverse effects. Minimum follow-up interval was 13 months after transplantation.

Results: Rejection episodes occurred in 3 patients, one of which led to transplant failure. Of the 6 transplants, 5 remained clear at latest follow-up. Hepatotoxicity required discontinuation of mycophenolate in 1 patient, and both drugs were otherwise free of significant adverse effects.

Conclusions: Sirolimus and mycophenolate mofetil in combination are effective in extending corneal transplant survival in most but not all high rejection risk patients and generally are well tolerated. Results justify further evaluation of this regimen in a larger controlled study.
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http://dx.doi.org/10.1016/j.ajo.2010.03.010DOI Listing
August 2010

Diagnostic accuracy of microbial keratitis with in vivo scanning laser confocal microscopy.

Br J Ophthalmol 2010 Aug 10;94(8):982-7. Epub 2010 Jun 10.

NIHR Biomedical Research Centre in Ophthalmology, Moorfields Eye Hospital and Institute of Ophthalmology, London, UK.

Aims: To determine the accuracy of diagnosing microbial keratitis by masked medical and non-medical observers using the Heidelberg Retina Tomograph II/Rostock Cornea Module in vivo confocal microscope.

Methods: Confocal images were selected for 62 eyes with culture- or biopsy-proven infections. The cases comprised 26 Acanthamoeba, 12 fungus, three Microsporidia, two Nocardia and 19 bacterial infections (controls). The reference standard for comparison was a positive tissue diagnosis. These images were assessed on two separate occasions by four observers who were masked to the tissue diagnosis. Diagnostic accuracy indices, kappa statistic and percentage agreement values were calculated. The Spearman correlation coefficient (r(s)) was calculated for the number of correct diagnoses versus duration of disease.

Results: The highest sensitivity and specificity values were 55.8% and 84.2%, respectively, and the lowest sensitivity and specificity values were 27.9% and 42.1%, respectively. The highest positive and lowest negative likelihood ratios were 2.94 and 0.59, respectively. Agreement values were: fair to moderate (kappa 0.22-0.44) for reference standard versus observer diagnosis, moderate to good in intraobserver variability (repeatability, kappa 0.56-0.88) and poor to moderate in interobserver variability (reproducibility, kappa 0.15-0.47). The correct diagnosis was associated with duration of disease for Acanthamoeba keratitis (r(s)=0.60, p=0.001).

Conclusions: The diagnostic accuracy of microbial keratitis by confocal microscopy is dependent on observer experience. Intraobserver repeatability was better than interobserver reproducibility. Difficulty in distinguishing host cells from pathogenic organisms limits the value of confocal microscopy as a stand-alone tool in diagnosing microbial keratitis.
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http://dx.doi.org/10.1136/bjo.2009.175083DOI Listing
August 2010

Immune modulation in corneal transplantation.

Transplant Rev (Orlando) 2008 Apr;22(2):105-15

Department of Immunology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.

Allograft rejection is the most common reason for corneal transplant failure, despite the immunologic privilege of both the graft and the anterior chamber. To prevent corneal allograft rejection, various immunomodulatory strategies have been used in experimental corneal transplantation. These include (1) anti-T-cell receptor and T-cell depletion therapy; (2) manipulation of costimulatory molecule function, including both down-regulation of positive stimulatory molecules and/or up-regulation of inhibitory molecules and overproduction of tumor necrosis factor-related, apoptosis-induced ligand; (3) modulation of cytokine production by reducing proinflammatory cytokines (tumor necrosis factor alpha, interleukin [IL]-12, and IL-1) and/or increasing immunoregulatory cytokines (IL-10 and IL-4); (4) macrophage depletion; and (5) overexpression of the immunomodulatory molecule indoleamine 2,3-dioxygenase. Although these approaches appear promising in animal corneal transplantation models, there has been very little translation of these immunomodulatory approaches in human corneal transplantation.
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http://dx.doi.org/10.1016/j.trre.2007.12.005DOI Listing
April 2008

Quality of vision and graft thickness in deep anterior lamellar and penetrating corneal allografts.

Am J Ophthalmol 2007 Feb 30;143(2):228-235. Epub 2006 Nov 30.

Cornea and External Diseases Service, Moorfields Eye Hospital, London, United Kingdom.

Purpose: To compare visual function after deep anterior lamellar keratoplasty (DALK) with visual function after penetrating keratoplasty (PK) for keratoconus and correlate this with corneal thickness.

Design: Retrospective case series.

Methods: Twenty-three patients (32 eyes) with unilateral or bilateral DALK or PK for keratoconus were analyzed for visual quality after suture removal. Evaluation included measurement of visual acuity, contrast sensitivity, and higher order aberrations (HOAs) (WaveScan; Visx, Santa Clara, California, USA). Readings were performed with both spectacle and rigid contact lens correction of refractive error. Total and residual stromal thickness after DALK was measured using optical coherence tomography (OCT) and correlated to visual quality.

Results: Eyes after PK had better visual acuity than eyes after DALK (P = .018). Subgroup analysis of DALK eyes revealed that the level of visual acuity was related to the thickness of residual recipient corneal stroma. Eyes with a recipient corneal bed thickness of <20 microm had visual acuities similar to eyes with a PK, whereas those with a recipient thickness of >80 microm had a significantly reduced visual acuity (P = .0009). Contrast sensitivity was similar in DALK and PK eyes. There was no significant difference in HOAs between eyes with DALK or PK.

Conclusions: These data suggest that the main parameter for good visual function after DALK for keratoconus is the thickness of residual recipient stromal bed. An eye with a DALK with a residual bed of <20 microm can achieve a similar visual result as a PK.
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http://dx.doi.org/10.1016/j.ajo.2006.10.043DOI Listing
February 2007

Differential effects of costimulatory pathway modulation on corneal allograft survival.

Invest Ophthalmol Vis Sci 2006 Aug;47(8):3417-22

Department of Immunology, Hammersmith Hospital, Imperial College London, UK.

Purpose: T lymphocytes have a central role in allograft rejection. On engagement of the T cell receptor by antigenic peptide-major histocompatibility complex (MHC) complex, a second "costimulatory" signal is critical to full T-cell activation or downregulation. In this study, the effect on corneal allograft survival of modulation of the costimulatory molecules programmed death-1 (PD-1) and inducible costimulatory (ICOS) molecule was examined. These molecules are known to modulate, respectively, negative or positive T-cell activation signals.

Methods: A dimeric PD-L1 immunoglobulin (Ig) fusion protein was generated to stimulate the inhibitory receptor PD-1, and a monoclonal antibody was used to block ICOS. The effect of PD-1 engagement and ICOS blockade on lymphocyte activation by in vitro T-cell proliferation and the effect on orthotopic corneal allograft survival in BALB/c mice were determined.

Results: Both reagents demonstrated T-cell inhibition in vitro. PD-L1.Ig treatment of BALB/c mice prolonged fully MHC-mismatched C3H donor corneal allograft survival, with a median survival time (MST) of 21 days. This was significantly prolonged compared to isotype control protein-treated recipients (MST 13 days, P < 0.003). Allograft survival in BALB/c recipients treated with anti-ICOS antibody showed no prolongation of survival compared with the isotype control antibody (MST, 12 days in both groups).

Conclusions: Augmented ligation of the PD-1 negative costimulatory molecule significantly prolongs corneal allograft survival. However, in contrast to findings in other allograft models, signaling through the positive costimulatory molecule ICOS appears to be less important in allogeneic rejection of cornea.
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http://dx.doi.org/10.1167/iovs.05-1597DOI Listing
August 2006