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Böhringer D, Grotejohann B, Ihorst G, Reinshagen H, Spierings E, Reinhard T. Rejection Prophylaxis in Corneal Transplant. DEUTSCHES ARZTEBLATT INTERNATIONAL 2019; 115:259-265. [PMID: 29735006 DOI: 10.3238/arztebl.2018.0259] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 07/19/2017] [Accepted: 01/11/2018] [Indexed: 11/27/2022]
Abstract
BACKGROUND Graft rejection. Twenty to thirty percent of patients with corneal transplants experience at least one rejection episode in the first 5 years after transplantation. Prophylaxis through matching for human leukocyte antigens (HLA) is controversial. We herein report the results of the Functional ANtigen matChing in keratoplastY (FANCY) trial. METHODS FANCY was a randomized, double-blind, multicenter clinical trial. The primary objective was to evaluate superiority of HLA matching versus random graft assignment. The primary endpoint was rejection-free graft survival. We included both normal-risk and high-risk indications. The study is registered with ClinicalTrials. gov (NCT00810472). RESULTS 721 patients were included, 639 patients were randomized. 474 patients underwent keratoplasty within the study; 165 patients received grafts outside the trial. One patient died and one patient was lost to follow up. We observed 33 graft rejections in the HLA matching arm (n = 224). The corresponding estimated cumulative incidence rate of immune reactions after two years was 15.7%. We observed 40 rejections in the control arm (n = 249). After two years this yields an estimated cumulative incidence rate of 17%. CONCLUSION In our heterogenous study group, HLA matching did not show a significant advantage compared to random graft assignment. The rejection rate in our sample was lower than expected. Therefore no definite conclusions can be drawn as to whether HLA matching is beneficial in corneal transplantation.
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Affiliation(s)
- Daniel Böhringer
- * The members of the FANCY Study Group are listed at the end of this article; Eye Center, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; Clinical Trials Unit, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; ADMEDICO Augenzentrum Olten, Switzerland; Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands
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Abstract
This overview describes recent developments demonstrating the significance of epitopes in HLA antibody responses and matching for organ transplantation. HLA epitopes are defined by molecular modeling and amino acid comparisons between HLA alleles and the HLAMatchmaker algorithm considers eplets as essential components. Each allele represents a distinct string of eplets and matching is done by aligning donor and recipient strings. Evidence is summarized how mismatched eplet loads affect antibody responses and transplant outcomes. Epitope-based matching has been applied not only to identify acceptable mismatches for sensitized transplant candidates but also to identify more suitably mismatched donors for nonsensitized patients. Three recently proposed theories will further our understanding of the immunogenicity of individual HLA eplets.It has become apparent that epitope-based matching is superior to antigen matching; we should be ready soon to apply this principle in the clinical transplant setting very soon.
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Yu T, Rajendran V, Griffith M, Forrester JV, Kuffová L. High-risk corneal allografts: A therapeutic challenge. World J Transplant 2016; 6:10-27. [PMID: 27011902 PMCID: PMC4801785 DOI: 10.5500/wjt.v6.i1.10] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 10/03/2015] [Accepted: 12/04/2015] [Indexed: 02/05/2023] Open
Abstract
Corneal transplantation is the most common surgical procedure amongst solid organ transplants with a high survival rate of 86% at 1-year post-grafting. This high success rate has been attributed to the immune privilege of the eye. However, mechanisms originally thought to promote immune privilege, such as the lack of antigen presenting cells and vessels in the cornea, are challenged by recent studies. Nevertheless, the immunological and physiological features of the cornea promoting a relatively weak alloimmune response is likely responsible for the high survival rate in “low-risk” settings. Furthermore, although corneal graft survival in “low-risk” recipients is favourable, the prognosis in “high-risk” recipients for corneal graft is poor. In “high-risk” grafts, the process of indirect allorecognition is accelerated by the enhanced innate and adaptive immune responses due to pre-existing inflammation and neovascularization of the host bed. This leads to the irreversible rejection of the allograft and ultimately graft failure. Many therapeutic measures are being tested in pre-clinical and clinical studies to counter the immunological challenge of “high-risk” recipients. Despite the prevailing dogma, recent data suggest that tissue matching together with use of systemic immunosuppression may increase the likelihood of graft acceptance in “high-risk” recipients. However, immunosuppressive drugs are accompanied with intolerance/side effects and toxicity, and therefore, novel cell-based therapies are in development which target host immune cells and restore immune homeostasis without significant side effect of treatment. In addition, developments in regenerative medicine may be able to solve both important short comings of allotransplantation: (1) graft rejection and ultimate graft failure; and (2) the lack of suitable donor corneas. The advances in technology and research indicate that wider therapeutic choices for patients may be available to address the worldwide problem of corneal blindness in both “low-risk” and “high-risk” hosts.
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Trufanov SV, Subbot AM, Malozhen SA, Salovarova EP, Krakhmaleva DA. [Risk factors, clinical presentations, prevention, and treatment of corneal graft rejection]. Vestn Oftalmol 2016. [PMID: 28635902 DOI: 10.17116/oftalma20161326108-116] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Corneal transplantation is the most common and successful type of allotransplantation surgery. Post-transplant immune response in keratoplasty is less pronounced than that in other transplantation procedures, which is accounted for by anatomical features of the cornea and, also, its low antigenic potential and active immunosuppression. However, the immune privilege of the cornea can be violated by neovascularization, inflammation, or trauma. Patients who require keratoplasty to restore their sight and whose immune privilege is disturbed, fall into a high-risk group and are likely to demonstrate tissue incompatibility and non-transparent engraftment. Two approaches exist as to how graft rejection can be prevented. One of them involves induction of donor-specific tolerance, the other - non-specific suppression of the recipient's immune response. To avoid tissue incompatibility, measures can be taken to restore the immune privilege of the cornea as well as to induce antigen-specific tolerance, which is considered a promising, thought yet experimental, area of modern transplantology. In clinical practice, one pays most attention to improvement of non-specific immune suppression methods based on interfering in the metabolism of immunocompetent cells. Thus, timely prescriptions and proper immunosuppressive tactics with account to possible risk factors determine the outcome in high-risk patients undergoing corneal transplantation surgery.
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Affiliation(s)
- S V Trufanov
- Research Institute of Eye Diseases, 11 A, B, Rossolimo St., Moscow, Russian Federation, 119021
| | - A M Subbot
- Research Institute of Eye Diseases, 11 A, B, Rossolimo St., Moscow, Russian Federation, 119021
| | - S A Malozhen
- Research Institute of Eye Diseases, 11 A, B, Rossolimo St., Moscow, Russian Federation, 119021
| | - E P Salovarova
- Research Institute of Eye Diseases, 11 A, B, Rossolimo St., Moscow, Russian Federation, 119021
| | - D A Krakhmaleva
- Research Institute of Eye Diseases, 11 A, B, Rossolimo St., Moscow, Russian Federation, 119021
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van Essen TH, Roelen DL, Williams KA, Jager MJ. Matching for Human Leukocyte Antigens (HLA) in corneal transplantation - to do or not to do. Prog Retin Eye Res 2015; 46:84-110. [PMID: 25601193 DOI: 10.1016/j.preteyeres.2015.01.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Revised: 01/05/2015] [Accepted: 01/07/2015] [Indexed: 12/15/2022]
Abstract
As many patients with severe corneal disease are not even considered as candidates for a human graft due to their high risk of rejection, it is essential to find ways to reduce the chance of rejection. One of the options is proper matching of the cornea donor and recipient for the Human Leukocyte Antigens (HLA), a subject of much debate. Currently, patients receiving their first corneal allograft are hardly ever matched for HLA and even patients undergoing a regraft usually do not receive an HLA-matched graft. While anterior and posterior lamellar grafts are not immune to rejection, they are usually performed in low risk, non-vascularized cases. These are the cases in which the immune privilege due to the avascular status and active immune inhibition is still intact. Once broken due to infection, sensitization or trauma, rejection will occur. There is enough data to show that when proper DNA-based typing techniques are being used, even low risk perforating corneal transplantations benefit from matching for HLA Class I, and high risk cases from HLA Class I and probably Class II matching. Combining HLA class I and class II matching, or using the HLAMatchmaker could further improve the effect of HLA matching. However, new techniques could be applied to reduce the chance of rejection. Options are the local or systemic use of biologics, or gene therapy, aiming at preventing or suppressing immune responses. The goal of all these approaches should be to prevent a first rejection, as secondary grafts are usually at higher risk of complications including rejections than first grafts.
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Affiliation(s)
- T H van Essen
- Department of Ophthalmology, J3-S, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
| | - D L Roelen
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - K A Williams
- Department of Ophthalmology, Flinders University, Adelaide, Australia
| | - M J Jager
- Department of Ophthalmology, J3-S, Leiden University Medical Center (LUMC), Leiden, The Netherlands; Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, USA; Peking University Eye Center, Peking University Health Science Center, Beijing, China.
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Abstract
Various inflammatory and non-inflammatory eye diseases are associated with specific HLA isotypes. Therefore, HLA isotyping can be a useful diagnostic tool for these diseases and has already been shown to reduce the rejection rate of corneal allografts. Unfortunately, the volume of published data and the varying quality of these publications complicate obtaining good overview in this field. This review briefly summarizes the genetic structure of the HLA system and elucidates differences between HLA classes I and II in the context of antigen presentation. Possible mechanisms of HLA associations in the field of ophthalmology are discussed, and finally different tools (e.g. genome wide association studies) for assessing associations of HLA isotypes with different ocular diseases are examined.
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Abstract
Corneal transplantation is among the most successful solid organ transplants. However, despite low rejection rates of grafts in the ‘low-risk’ setting, rejection can be as high as 70% when grafted into ‘high-risk’ recipient beds. Under normal homeostatic conditions, the avascular cornea provides a unique environment that facilitates immune and angiogenic privilege. An imbalance in pro-inflammatory, angiogenic and lymphangiogenic mediators leads to a breakdown in corneal immune privilege with a consequent host response against the donor graft. Recent developments in lamellar and endothelial keratoplasties have reduced the rates of graft rejection even more, while providing improved visual outcomes. The corneal layer against which an immune response is initiated, largely determines reversibility of the acute episode. While epithelial and stromal graft rejection may be treated with topical corticosteroids with higher success, acute endothelial rejection mandates a more aggressive approach to therapy due to the lack of regenerative capacity of this layer. However, current immunosuppressive regimens come with the caveat of ocular and systemic side effects, making prolonged aggressive treatment undesirable. With the advent of biologics, efficacious therapies with a superior side effect profile are on the horizon. In our review we discuss the mediators of ocular immune privilege, the roles of cellular and molecular immune players in graft rejection, with a focus on human leukocyte antigen and antigen presenting cells. Furthermore, we discuss the clinical risk factors for graft rejection and compare rates of rejection in lamellar and endothelial keratoplasties to traditional penetrating keratoplasty. Lastly, we present the current and upcoming measures of therapeutic strategies to manage and treat graft rejection, including an overview of biologics and small molecule therapy.
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Affiliation(s)
- Yureeda Qazi
- Ocular Surface and Imaging Center & Cornea Service Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Pedram Hamrah
- Ocular Surface and Imaging Center & Cornea Service Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA ; Schepens Eye Research Institute, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
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Schmidt S, Holzer MP, Khoramnia R, Auffarth GU. [Immunological graft rejection after autologous contralateral keratoplasty]. Ophthalmologe 2012; 109:1014-6. [PMID: 22532039 DOI: 10.1007/s00347-012-2560-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Autologous keratoplasty from an amblyopic eye to the fellow oculus ultimus is a rarely used procedure. This is due to the relatively uncommon constellation of pathology. The following article reports the case of a graft rejection after autologous keratoplasty, while the homologous graft on the amblyopic fellow eye remained clear.
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Affiliation(s)
- S Schmidt
- International Vision Correction Research Centre, Universitäts-Augenklinik Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg.
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Borderie VM, Guilbert E, Touzeau O, Laroche L. Graft rejection and graft failure after anterior lamellar versus penetrating keratoplasty. Am J Ophthalmol 2011; 151:1024-1029.e1. [PMID: 21489399 DOI: 10.1016/j.ajo.2011.01.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2010] [Revised: 12/23/2010] [Accepted: 01/02/2011] [Indexed: 11/19/2022]
Abstract
PURPOSE To compare anterior lamellar keratoplasty (ALK) with the reference surgical technique (penetrating keratoplasty [PK]) for risk of rejection. DESIGN Retrospective, comparative case series. METHODS setting: Institutional. patients: One hundred forty-nine consecutive ALK procedures (ALK group) and 149 matched PK procedures (PK group) performed for optical indication in eyes with corneal diseases not involving the corneal endothelium (ie, keratoconus, scars after infectious keratitis, stromal dystrophies, and trauma). main outcome measures: Three-year graft survival and cumulative incidence of rejection episodes. RESULTS The 3-year overall graft survival was 98.3% in the ALK group and 94.3% in the PK group (P = .03). The 3-year cumulative incidence of irreversible rejection was 0.0% in the ALK group and 5.2% in the PK group (P = .02). The 3-year cumulative incidence of rejection episodes was 10.0% in the ALK group and 23.2% in the PK group (P = .01). The average graft-to-rejection episode time was 21.6 ± 22.0 months in the PK group and 19.4 ± 12.7 months in the ALK group (P = .76). CONCLUSIONS ALK techniques dramatically decrease the risk of irreversible endothelial and stromal rejection after corneal transplantation. Immune-mediated rejection episodes are observed after ALK, but its lower graft failure rate compared with PK is at least partly the result of the absence of endothelial rejection. In addition, the incidence of rejection episodes after ALK was 50% less than that observed after PK.
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Affiliation(s)
- Vincent M Borderie
- Centre Hospitalier National d'Ophtalmologie des XV-XX, Institut de la Vision, Pierre & Marie Curie University Paris 06, 28 rue de Charenton, Paris, France.
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Guilbert E, Laroche L, Borderie V. Le rejet d’allogreffe de cornée. J Fr Ophtalmol 2011; 34:331-48. [DOI: 10.1016/j.jfo.2011.02.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 02/15/2011] [Accepted: 02/16/2011] [Indexed: 01/28/2023]
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Duquesnoy RJ. Antibody-reactive epitope determination with HLAMatchmaker and its clinical applications. ACTA ACUST UNITED AC 2011; 77:525-34. [PMID: 21410655 DOI: 10.1111/j.1399-0039.2011.01646.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Antibodies against allogeneic human leukocyte antigen (HLA) molecules are important impediments to the success of different clinical procedures including transplantation and platelet transfusion. In these settings, characterization of the repertoire of immunogenic epitopes is important for permissible mismatch determination and the identification of acceptable mismatches for sensitized patients. HLAMatchmaker is a computer algorithm that considers small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes. This review critically elaborates the concepts underlying the HLAMatchmaker and describes the usefulness of HLAMatchmaker in the clinical setting. Recent developments have increased our understanding of structural basis of HLA antigenicity (i.e. reactivity with specific antibody) and immunogenicity (i.e. its ability to induce an antibody response).
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Affiliation(s)
- R J Duquesnoy
- Division of Transplantation Pathology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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13
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Affiliation(s)
- Harminder S Dua
- Division of Ophthalmology and Visual Sciences, University of Nottingham, Nottingham NG7 2UH, England, UK.
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HLAMatchmaker-based definition of structural human leukocyte antigen epitopes detected by alloantibodies. Curr Opin Organ Transplant 2009; 14:403-9. [DOI: 10.1097/mot.0b013e32832ca2b8] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Duquesnoy RJ, Marrari M. Correlations between Terasaki's HLA class I epitopes and HLAMatchmaker-defined eplets on HLA-A, -B and -C antigens. ACTA ACUST UNITED AC 2009; 74:117-33. [PMID: 19497041 DOI: 10.1111/j.1399-0039.2009.01271.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Although the determination of human leukocyte antigen (HLA) antibody specificity has traditionally been directed toward HLA antigens, there is now increasing attention to structurally defined HLA epitopes. An understanding of the HLA epitope repertoire is important to acceptable mismatching for sensitized patients and to a new epitope-based matching algorithm aimed to reduce antibody-mediated rejection. There are two strategies to determine the HLA epitope repertoire. Terasaki's group has used an empirical method to analyze the reactivity of single allele Luminex panels with mouse monoclonal antibodies (mAbs) and absorbed/eluted alloantibodies with a computer program based on shared residues in the amino acid sequences of reactive alleles. HLAMatchmaker is a theoretical algorithm that predicts HLA epitopes on the HLA molecular surface from stereochemical modeling of epitope-paratope interfaces of antigen-antibody complexes. Our epitope repertoire is based on so-called 'eplets' representing 3-A patches of at least one polymorphic residue on the molecular surface. A comparative analysis has shown that 81/103 Terasaki's HLA class I epitopes are equivalent to individual eplets (n = 50) or pairs of eplets (n = 31) separated far enough to serve as potential contact sites for two complementarity-determining regions of antibody. An additional 12 Terasaki's epitopes (TerEps) correspond to eplets with permissible residue combinations that do not seem to affect epitope specificity. We could not identify corresponding eplets for the remaining 10 TerEps, including 8 that might be considered xeno-epitopes defined by mouse mAbs. Conversely, HLAMatchmaker has 38 additional eplets in well-exposed surface positions that do not have equivalent TerEps, and for many of them, we have found specific antibodies. These findings strengthen the concept that eplets are essential basic units of HLA epitopes and that they provide a better understanding of HLA immunogenicity (i.e. ability to induce an antibody response) and antigenicity (i.e. reactivity with specific antibody).
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Affiliation(s)
- R J Duquesnoy
- Division of Transplantation Pathology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
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Duquesnoy RJ. Clinical usefulness of HLAMatchmaker in HLA epitope matching for organ transplantation. Curr Opin Immunol 2008; 20:594-601. [DOI: 10.1016/j.coi.2008.06.010] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2008] [Accepted: 06/26/2008] [Indexed: 11/26/2022]
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Duquesnoy R, Spellman S, Haagenson M, Wang T, Horowitz MM, Oudshoorn M. HLAMatchmaker-defined triplet matching is not associated with better survival rates of patients with class I HLA allele mismatched hematopoietic cell transplants from unrelated donors. Biol Blood Marrow Transplant 2008; 14:1064-1071. [PMID: 18721770 PMCID: PMC2572684 DOI: 10.1016/j.bbmt.2008.07.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2008] [Accepted: 07/02/2008] [Indexed: 11/29/2022]
Abstract
This report addresses the concept that permissible HLA mismatching, that is, mismatches that do not generate an allogeneic response, in hematopoietic stem cell transplantation (HCT) can be determined with structural similarity of polymorphic regions. We have applied the triplet version of a structural algorithm called HLAMatchmaker, which considers short sequences involving polymorphic amino acid residues on the molecular surface as key elements of immunogenic epitopes. The triplet matching effect was analyzed in a National Marrow Donor Program dataset consisting of 744 unrelated hematopoietic cell transplantation cases with 1 HLA-A, -B, or -C mismatch and 1690 fully HLA-A, -B, -C, -DR, or -DQ allele matched cases. In multivariate models adjusting for other significant clinical risk factors, the degree of triplet mismatching did not significantly correlate with patient survival, engraftment, or acute graft-versus-host disease (aGVHD). Other structurally based strategies should be pursued to identify permissible HLA mismatches in HCT.
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Affiliation(s)
- Rene Duquesnoy
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
| | | | - Michael Haagenson
- Center for International Blood & Marrow Transplant Research, Minneapolis, Minnesota
| | - Tao Wang
- Center for International Blood & Marrow Transplant Research, Milwaukee, Wisconsin
| | - Mary M Horowitz
- Center for International Blood & Marrow Transplant Research, Milwaukee, Wisconsin
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Abstract
Topical steroids are routinely used in the postoperative treatment following penetrating keratoplasty. Due to the known side effects such as steroid-response glaucoma, cataract, and surface disorders, a broader armamentarium of topical immunomodulating drugs with comparable efficacy, better tolerance and less side effects is desirable. Cyclosporine A and FK506 eye drops are a promising alternative. A new approach involves subconjunctival drug delivering implants and locally applied antiangiogenic substances, which still have to be tested in clinical studies.
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Affiliation(s)
- F Birnbaum
- Universitätsaugenklinik Freiburg, 79106, Freiburg.
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Abstract
The unpredictability of the expected time on the waiting list has been the main barrier towards broad acceptance of human leukocyte antigen (HLA) matching in clinical routine. An algorithm for predicting the expected time on the waiting list for a histocompatible graft was recently introduced. This algorithm allows for the balancing waiting time against improvement in prognosis on an individual basis. HLAMatchmaker is a new method for identifying HLA mismatches with minor immunogenicity. This method is a valuable tool for providing patients who have a rare HLA phenotype with a histocompatible graft. In summary, new methods are now available that make histocompatibility in penetrating keratoplasty possible in almost all cases.
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Affiliation(s)
- D Böhringer
- Universitätsaugenklinik Freiburg, Killianstrasse 5, 79106 Freiburg, Freiburg.
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Valentini RP, Nehlsen-Cannarella SL, Gruber SA, Mattoo TK, West MS, Lang C, Imam AA. Intravenous immunoglobulin, HLA allele typing and HLAMatchmaker facilitate successful transplantation in highly sensitized pediatric renal allograft recipients. Pediatr Transplant 2007; 11:77-81. [PMID: 17239127 DOI: 10.1111/j.1399-3046.2006.00617.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The use of intravenous immunoglobulin (IVIG) in sensitized transplant candidates has resulted in reduced HLA antibody levels and shorter transplant wait times. In addition, the HLAMatchmaker program has been used to identify acceptable mismatches to permit transplantation in highly sensitized patients. We used IVIG desensitization in conjunction with high resolution HLA allele typing and HLAMatchmaker grading of donor offers to facilitate successful transplantation in two highly sensitized children who were awaiting second renal transplants. Both patients lost their initial transplant in <10 days to accelerated acute rejection, and were on dialysis for an average of 50 months with high panel reactive antibody (PRA) levels. They were started on monthly IVIG infusions (2 g/kg/dose). Within one wk following their third and fifth IVIG doses, both patients received a crossmatch compatible, deceased donor renal transplant selected by HLAMatchmaker as a suitable donor offer. Both patients remain rejection free with excellent renal function 19 and 15 months post-transplant, respectively. In conclusion, combining IVIG therapy and donor selection by HLA humoral epitope matching permitted successful transplantation of two highly sensitized children. Further studies in larger numbers of patients with longer follow-up are needed to determine the individual role played by, and relative importance of each component of this combined strategy.
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Affiliation(s)
- Rudolph P Valentini
- Division of Nephrology, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI 48201-2196, USA.
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Duquesnoy RJ, Askar M. HLAMatchmaker: a molecularly based algorithm for histocompatibility determination. V. Eplet matching for HLA-DR, HLA-DQ, and HLA-DP. Hum Immunol 2007; 68:12-25. [PMID: 17207708 PMCID: PMC2527859 DOI: 10.1016/j.humimm.2006.10.003] [Citation(s) in RCA: 168] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2006] [Revised: 09/12/2006] [Accepted: 10/02/2006] [Indexed: 10/24/2022]
Abstract
This report describes the design of the eplet version of HLAMatchmaker to determine class II compatibility at the structural level. This matching algorithm is based on the hypothesis, developed from molecular modeling of crystallized antigen-antibody complexes, that functional epitopes are represented by patches of surface-exposed nonself-amino acid residues surrounded by residues within a 3-A radius. Patch determinations with a molecular viewer of crystalline structural models downloaded from the Entrez Molecular Modeling Database Web site led to the identification of 44 DRB, 33DQB, 29 DQA, 20 DPB, and 9 DPA unique combinations of polymorphic positions. The residue compositions of these patches were then determined from amino acid sequences. This analysis resulted in a repertoire of 146 DRB, 74 DQB, 58 DQA, 45 DPB, and 19 DPA eplets. In many eplets, the residues are in short linear sequences, but many other eplets have discontinuous sequences of residues that cluster on or near the molecular surface. This analysis has also shown that all serologically defined DR and DQ antigens detectable by monospecific antibodies have unique eplets. Other eplets are present in groups of class II antigens, many of which appear as cross-reacting. The eplet version of HLAMatchmaker should be considered as a hypothetical model for the structural assessment of donor-recipient compatibility and the determination of mismatch acceptability for sensitized patients. This computer algorithm can be downloaded from the HLA Matchmaker Webside at http://tpis.upmc.edu.
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Affiliation(s)
- Rene J Duquesnoy
- Division of Transplantation Pathology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
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Böhringer D, Spierings E, Enczmann J, Böhringer S, Sundmacher R, Goulmy E, Reinhard T. Matching of the minor histocompatibility antigen HLA-A1/H-Y may improve prognosis in corneal transplantation. Transplantation 2006; 82:1037-41. [PMID: 17060851 DOI: 10.1097/01.tp.0000235908.54766.44] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Minor histocompatibility (H) antigens are peptides of allelic intracellular proteins that play an important role in human leukocyte antigen (HLA) matched transplantations. In an animal model of keratoplasty, minor H antigens have even been reported to exceed the immunogenicity of major H antigens (MHC). This investigation is to assess any benefit of matching the broadly expressed gender (H-Y) and HA-3 antigens in HLA-A1 donor positive human keratoplasty. METHODS A total of 229 HLA-A1 donor positive keratoplasties were analyzed. A Cox proportional hazards model and Kaplan-Meier analysis were applied to estimate the effect of H-Y or HA-3 mismatches on rejection-free graft survival. RESULTS Eighty-one cases were mismatched for H-Y (male donor to female recipient). A mean follow up of two years showed graft survival as high as 88% in the H-Y compatible group compared to only 77% in the H-Y mismatched group (P = 0.02). Eight out of 62 cases were mismatched for HA-3. No statistically significant influence of HA-3 matching on rejection-free graft survival was observed (85% vs. 73%, P=0.52). CONCLUSION HLA-A1/H-Y matching and matching for other broadly expressed minor H antigens may further improve prognosis in keratoplasty.
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Affiliation(s)
- Daniel Böhringer
- Eye Hospital and LIONS Cornea Bank Regio/Baden-Württemberg, University Hospital Freiburg, Germany.
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Duquesnoy RJ. A structurally based approach to determine HLA compatibility at the humoral immune level. Hum Immunol 2006; 67:847-62. [PMID: 17145365 PMCID: PMC2169290 DOI: 10.1016/j.humimm.2006.08.001] [Citation(s) in RCA: 232] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2006] [Revised: 07/25/2006] [Accepted: 08/02/2006] [Indexed: 11/22/2022]
Abstract
HLAMatchmaker is a structurally based matching program. Each HLA antigen is viewed as a string of epitopes represented by short sequences (triplets) involving polymorphic amino acid residues in antibody-accessible positions. HLAMatchmaker determines which triplets are different between donor and recipient, and this algorithm is clinically useful in determining HLA mismatch acceptability. Triplets provide however an incomplete description of the HLA epitope repertoire and expanded criteria must be used including longer sequences and polymorphic residues in discontinuous positions. Such criteria should consider the structural basis of antibody-antigen interactions including contact areas and binding energy, the essence of antigenicity. This report describes the development of a structurally defined HLA epitope repertoire based on stereochemical modeling of crystallized complexes of antibodies and different protein antigens. This analysis considered also data in the literature about contributions of amino acid residues to antigen-antibody binding energy. The results have led to the concept that HLA antigens like other antigenic proteins have structural epitopes consisting of 15-22 residues that constitute the binding face with alloantibody. Each structural epitope has a functional epitope of about 2-5 residues that dominate the strength and specificity of binding with antibody. The remaining residues of a structural epitope provide supplementary interactions that increase the stability of the antigen-antibody complex. Each functional epitope has one or more non-self residues and the term "eplet" is used to describe polymorphic HLA residues within 3.0-3.5 A of a given sequence position on the molecular surface. Many eplets represent short linear sequences identical to those referred to as triplets but others have residues in discontinuous sequence positions that cluster together on the molecular surface. Serologically defined HLA determinants correspond well to eplets. The eplet version of HLAMatchmaker represents therefore a more complete repertoire of structurally defined HLA epitopes and provides a more detailed assessment of HLA compatibility.
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Affiliation(s)
- Rene J Duquesnoy
- Division of Transplantation Pathology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
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Haririan A, Fagoaga O, Daneshvar H, Morawski K, Sillix DH, El-Amm JM, West MS, Garnick J, Migdal SD, Gruber SA, Nehlsen-Cannarella S. Predictive value of human leucocyte antigen epitope matching using HLAMatchmaker for graft outcomes in a predominantly African-American renal transplant cohort. Clin Transplant 2006; 20:226-33. [PMID: 16640531 DOI: 10.1111/j.1399-0012.2005.00473.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The HLAMatchmaker program is based on the donor/recipient comparison of the polymorphic triplet amino-acid sequences of the antibody-accessible regions on the human leucocyte antigen (HLA) molecule. The previous reports on its predictive value for renal allograft outcomes are conflicting. We conducted a retrospective study in a predominantly African-American (AA) cohort (N = 101, 94% AA). HLA typing was performed by molecular methods and triplet matching using HLAMatchmaker. Study end points included graft survival and incidence of acute rejection. The relationship between the number of triplet mismatches (TMM) and the degree of HLA antigen MM was evaluated using Pearson's correlation coefficient. Logistic regression models were used to examine the association between triplet matching and the study end points. Kaplan-Meier and Cox proportional hazard models were used for graft survival analysis. The strongest relationship between the number of TMM and HLA antigen MM was observed for HLA-DQ (r = 0.88). The association between triplet matching at HLA-A, -B, -DR and -DRw HLA loci and the study end points was not statistically significant. However, after grouping, the unadjusted estimates of graft survival for those with more than 10 Class I TMM were significantly worse than the others (p = 0.03). Adjusting for the effect of donor source, recipient characteristics and the immunosuppressive regimen did not change this association (hazard ratio = 0.2, confidence interval = 0.04-1.1). We conclude that triplet matching using HLAMatchmaker can provide useful prognostic information in kidney transplantation and that more than 10 donor/recipient Class I HLA TMM is predictive of worse graft outcome.
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Affiliation(s)
- Abdolreza Haririan
- Division of Nephrology, Department of Medicine, Wayne State University School of Medicine, Detroit, MI, USA.
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Ardjomand N, Komericki P, Klein A, Mattes D, El-Shabrawi Y, Radner H. [ABO blood group expression in corneal allograft failures]. Ophthalmologe 2006; 102:981-6. [PMID: 15812644 DOI: 10.1007/s00347-005-1199-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND ABO blood group antigens are only expressed by the epithelial cells of normal human corneas. Since AB0 blood group antigens are also known to be expressed on stromal and endothelial cells of inflamed corneas, this study aimed to investigate the extend of ABO blood group antigen expression in corneal allograft failures. MATERIAL AND METHODS Twenty-two failed corneal allografts of 22 patients were examined. In 12 cases the patients had clinically proven corneal allograft rejection. In 10 cases there was no evident history of allograft rejection and the diagnosis graft failure due to chronic endothelial cell loss was made. Immunohistochemical staining of paraffin embedded sections was performed with monoclonal mouse antibodies to human blood group antigen A or B using the streptavidin-biotin-peroxidase complex technique. RESULTS Blood group antigens A or B were expressed by stromal keratocytes in 5 out of 12 and by endothelial cells in 7 out of 12 corneas with clinically proven immunologic graft rejection. Corneal transplants with chronic endothelial cell loss expressed blood group antigens A and/or B on the endothelial cells in three out of ten cases. CONCLUSION The results of this study show that ABO blood group antigens can be up-regulated in cases of corneal allograft failure, especially in cases of immune mediated graft rejection. This phenomenon might play a role in corneal allograft rejection.
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Affiliation(s)
- N Ardjomand
- Universitäts-Augenklinik, Medizinische Universität, Graz, Osterreich.
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Duquesnoy RJ, Mulder A, Askar M, Fernandez-Vina M, Claas FHJ. HLAMatchmaker-Based Analysis of Human Monoclonal Antibody Reactivity Demonstrates the Importance of an Additional Contact Site for Specific Recognition of Triplet-Defined Epitopes. Hum Immunol 2005; 66:749-61. [PMID: 16112022 DOI: 10.1016/j.humimm.2005.04.002] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2005] [Revised: 03/23/2005] [Accepted: 04/01/2005] [Indexed: 11/23/2022]
Abstract
Five HLA-A3 reactive human monoclonal antibodies (mAbs) originating from a parous woman were screened against HLA-typed panels by means of complement-dependent lymphocytotoxicity, high-definition ELISA, and flow cytometry with single antigen beads. Antibody reactivity profiles were compared with triplet amino acid sequence polymorphisms identified by HLAMatchmaker, and a three-dimensional structural modeling program (Cn3D of the National Center for Biotechnology Information) was used to determine the topography of epitopes recognized by each mAb. These mAbs originated from a woman who during pregnancy developed antibodies to the paternal HLA-A3 antigen of her child. Each mAb was specific for one mismatched triplet on HLA-A3, and the reactivity patterns of these IgM-type mAbs were practically the same in lymphocytotoxicity and antigen-binding assays. One mAb was specific for 163dT, a unique triplet present only on A3. The other mAbs reacted with 62Qe, 142mI, or 144tKr; these triplets are present on different groups of HLA-A alleles, some of which, however, did not react. Topographic modeling of triplet-defined epitopes identified clusters of polymorphic surface residues that were shared between reactive alleles. These clusters may serve as primary contact sites for the specificity-determining complementarity-determining region (CDR) loops of antibody. The reactivity with these mAbs required also the presence of self-sequence elsewhere on the HLA molecular surface as a critical secondary contact site for antibody, likely through another CDR loop. For instance, the reactivity of the 62Qe-specific mAb required the presence of a glycine residue in position 56 and the reactivity of the 142mI-specific mAb required the presence of the GTLRG sequence in positions 79-83. Conversely, there were many other amino acid differences between the mAb-reactive alleles and HLA-A3 that did not prevent antibody binding. For instance, the 62Qe-specific mAb-reactive alleles had 35 and the 142mI-reactive alleles had 50 of such "permissive" residue differences. An HLAMatchmaker-based analysis of the reactivity of human mAbs will increase our understanding of the structural definition of HLA epitopes and their reactivity with alloantibodies.
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Affiliation(s)
- René J Duquesnoy
- University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
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Takemoto S, Port FK, Claas FHJ, Duquesnoy RJ. HLA matching for kidney transplantation. Hum Immunol 2005; 65:1489-505. [PMID: 15603878 DOI: 10.1016/j.humimm.2004.06.008] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2004] [Accepted: 06/17/2004] [Indexed: 12/24/2022]
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