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Functional antigen matching in corneal transplantation: matching for the HLA-A, -B and -DRB1 antigens (FANCY) - study protocol.

ABSTRACT: Penetrating keratoplasty can commonly restore vision in corneal blindness. However, immunological graft reactions may induce irreversible graft failure in a substantial percentage. Repeat keratoplasties in turn are associated with increased risk of graft failure and possibly irreversible blindness. Topical as well as systemic immunosuppressants are administered for prophylaxis. However, severe adverse effects limit long-term usage. By contrast, matching for transplantation antigens might be effective for a long time.FANCY is a prospective, controlled, randomised, double-blind, multi-centre clinical trial with two parallel arms. The primary objective is to evaluate superiority of the proposed HLA matching strategy in comparison to random graft assignment with respect to the primary endpoint 'time to first endothelial graft rejection'. Relevant inclusion criteria are age over 18 years and waiting for penetrating or endothelial lamellar keratoplasty. The most important exclusion criteria are abuse of medication and/or drugs and an anticipated waiting time for an HLA match longer than 6 months. After randomisation, patients either receive a HLA-matched graft (experimental intervention) or a random graft (control intervention). The calculated sample size is 620 patients. The trial started in 2009 with a recruitment period of 24 months. A total of 654 patients were included during this time.The primary goal of FANCY is to assess whether histocompatibility matching is feasible and effective in the broad clinical routine. However, during the course of the trial, the landscape of keratoplasty changed due to the rise of Descemet Membrane Endothelial Keratoplasty (DMEK). Nowadays, immune reactions are confined mostly to the 'high-risk' subgroups. If we would design FANCY in 2014, we would narrow down the inclusion criteria to include only the high risk patients and accept longer waiting times for a matching donor here.The unique identifying number of the FANCY trial is NCT00810472.

SUBMITTER: Bohringer D

PROVIDER: S-EPMC4292991 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Functional antigen matching in corneal transplantation: matching for the HLA-A, -B and -DRB1 antigens (FANCY) - study protocol.

Böhringer Daniel D Ihorst Gabriele G Grotejohann Birgit B Maurer Julia J Spierings Eric E Reinhard Thomas T

BMC ophthalmology 20141213

<h4>Background</h4>Penetrating keratoplasty can commonly restore vision in corneal blindness. However, immunological graft reactions may induce irreversible graft failure in a substantial percentage. Repeat keratoplasties in turn are associated with increased risk of graft failure and possibly irreversible blindness. Topical as well as systemic immunosuppressants are administered for prophylaxis. However, severe adverse effects limit long-term usage. By contrast, matching for transplantation ant ...[more]

PMID: 25496165

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Project description:BackgroundCorneal transplantation is the most frequently performed transplantation in the UK. Despite this, the therapeutic value of matching human leukocyte antigen (HLA) subtypes for transplanted corneas remains controversial. Ocular immune privilege was originally deemed to render matching unnecessary; however, more recently, matching has demonstrated improved outcomes including graft success, amongst others. This systematic review aims to evaluate the effectiveness of major and minor antigen matching on graft outcomes in corneal transplantation.MethodsStandard systematic review methodology will be used to identify, select and extract data from observational studies and clinical trials assessing the effects of HLA matching on corneal graft outcomes. Bibliographic databases (Cochrane Library, EMBASE, MEDLINE, Web of Science, Scopus), clinical trial registers, abstract and conference proceedings, in addition to dissertation, thesis and grey literature will be searched. Neither date of publication nor language will be restricted, and non-English articles will be translated where necessary. The primary outcome will be to assess corneal graft success for different degrees of HLA matching/mismatching. The precise end outcome measure varies amongst studies and includes graft rejection, immunoreaction, failure and survival. Therefore, data will be extracted across all relevant outcome parameters and grouped for subsequent statistical tests. Risk of bias assessment will be completed, appropriate to each study design. Study selection, data extraction and risk of bias assessment will be independently completed by two reviewers. Data will be tabulated, and a narrative synthesis presented. Meta-analysis will be performed where there is sufficient homogeneity between studies to warrant its effective completion. Subgroup and sensitivity analysis will be undertaken if appropriate.DiscussionMany studies have investigated the effectiveness of HLA matching for corneal transplantation. A systematic review is needed to collate and analyse this evidence. Findings of this systematic review may form the basis of evidence-based recommendations on pre-operative HLA typing and matching of corneal grafts for transplantation.Systematic review registrationPROSPERO reference CRD42020198882.

Project description:The importance of matching at the HLA C locus has not been well defined for unrelated umbilical-cord blood transplantation. The selection algorithm for umbilical-cord blood units generally considers intermediate resolution HLA typing at A and B and allele-level typing at DRB1. We aimed to establish the relative importance of additional matching at HLA C.We used Cox regression to assess retrospectively the effect of donor-recipient HLA matching on outcomes of single umbilical-cord blood transplantations for leukaemia and myelodysplastic syndrome. Our primary endpoint was transplant-related mortality. HLA typing was done with molecular techniques with a minimum of intermediate resolution for HLA A, B, and C, and at the allele-level for DRB1.The median age of our study population was 10 years (range <1-62) and 552 (69%) of 803 patients were aged 16 years or younger at transplantation. Compared with transplantations matched at HLA A, B, C, and DRB1 (n=69), transplant-related mortality risk was higher after transplantations matched at HLA A, B, and DRB1 and mismatched at HLA C (n=23; HR 3·97, 95% CI 1·27-12·40; p=0·018). Transplant-related mortality risk was also higher after transplantations with a single mismatch at HLA A, B, or DRB1 and mismatched at HLA C (n=234; 1·70, 1·06-2·74; p=0·029) compared with transplantations matched at HLA C with a single mismatch at HLA A, B, or DRB1 (n=127). Assessing the overall effect of HLA disparity on transplant-related mortality, risks were higher with units mismatched at two (n=259; 3·27, 1·42-7·54; p=0·006), three (n=253; 3·34, 1·45-7·71; p=0·005), or four (n=75; 3·51, 1·44-8·58; p=0·006) loci compared with matched units (n=69).Our data suggest that the present strategy for umbilical-cord blood unit selection should be reassessed; matching at HLA C for units that are matched at HLA A, B, or DRB1 or in the presence of a single locus mismatch at HLA A, B, or DRB1 should be included to minimise mortality risks.National Cancer Institute, National Heart Lung and Blood Institute, National Institute for Allergy and Infectious Diseases, Leukemia and Lymphoma Society, US Department of the Navy, Children's Leukemia Research Association, and INSERM.

Dataset Information

Functional antigen matching in corneal transplantation: matching for the HLA-A, -B and -DRB1 antigens (FANCY) - study protocol.

Publications

Functional antigen matching in corneal transplantation: matching for the HLA-A, -B and -DRB1 antigens (FANCY) - study protocol.

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