Removal of Alpha-Gal Epitopes from Porcine Aortic Valve and Pericardium using Recombinant Human Alpha Galactosidase A

Park, Seong‐Sik; Kim, Woong-Han; Choi, Seo Young; Kim, Yong-Jin

doi:10.3346/jkms.2009.24.6.1126

Cited by 37 publications

(39 citation statements)

References 17 publications

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“…52,53 No anti-Gal binding to pig valves was observed following this enzymatic treatment, whereas untreated valves displayed extensive binding of the antibody. 51 Avoiding anti-Gal effects is also feasible by using ECM implants from GT-KO donors that lack a-gal epitopes. Disruption of the a1,3GT gene by the knockout technology has been achieved in mice 54,55 and pigs.…”

Section: Prevention Of Anti-gal Interaction With Implantsmentioning

confidence: 99%

Avoiding Detrimental Human Immune Response Against Mammalian Extracellular Matrix Implants

Galili

2015

Tissue Engineering Part B: Reviews

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This review describes the antibodies formed against mammalian extracellular matrix (ECM) implants in humans and proposes methods for avoiding the detrimental effects of these antibodies. There are two types of antibodies against ECM implants: (i) The natural anti-Gal antibody constituting ∼1% of immunoglobulins in humans. This antibody binds to a carbohydrate antigen called the α-gal epitope with the structure Galα1-3Galβ1-4GlcNAc-R. The α-gal epitope is abundant in nonprimate mammals, including on ECM proteins and proteoglycans. Moreover, anti-Gal antibody titers increase within 2-4 weeks by 10- to 100-folds in human recipients of mammalian implants or xenografts expressing α-gal epitopes. (ii) Anti-non gal antibodies formed against ECM peptide sequences differing from those in homologous proteins in humans. Most homologous proteins in mammals contain immunogenic peptides that elicit anti-non gal antibody production when introduced into humans. Formation of anti-non gal antibodies is much slower than that of elicited anti-Gal antibodies. Both anti-Gal and anti-non gal antibodies are detrimental to ECM implant regeneration in humans by binding to the ECM and directing extensive macrophage-mediated degradation of the implant. In addition, antibodies binding to ECM proteins/proteoglycans may hinder stem cells interaction with the ECM, which is required for directing stem cell differentiation. The anti-Gal immunological barrier can be avoided by using mammalian ECM implants lacking α-gal epitopes. Such implants can be engineered by enzymatic destruction of α-gal epitopes with recombinant α-galactosidase. Alternatively, implants may be obtained from α1,3galactosyltransferase knockout donor species that lack α-gal epitopes. Since postimplantation production of anti-non gal antibodies is a slow process, the detrimental effects of these antibodies may be avoided by accelerating stem cells recruitment into implants, thus accelerating the regeneration process. Acceleration of stem cell recruitment may be achieved by introducing α-gal nanoparticles into the implant. α-Gal nanoparticles present multiple α-gal epitopes, which bind anti-Gal and induce recruitment of macrophages by generating complement chemotactic factors. Fc/Fcγ receptor interaction between anti-Gal coating α-gal nanoparticles and recruited macrophages activates the macrophages to secrete "pro-healing" cytokines/growth factors that recruit stem cells. These recruited cells are instructed by the implanted ECM to regenerate the implant before anti-non gal antibodies can reach detrimental titers.

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Section: Prevention Of Anti-gal Interaction With Implantsmentioning

confidence: 99%

Avoiding Detrimental Human Immune Response Against Mammalian Extracellular Matrix Implants

Galili

2015

Tissue Engineering Part B: Reviews

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“…29,31 Unfortunately, the a1,3-galactosyltransferase knockout pig is not yet available for mass production within a clinical setting. In our previous study, 2,4,5,8 it was proved that enzymatic treatment using a-galactosidase is an effective method of removing a-Gal epitopes, which is easy to use and inexpensive. [13][14][15] Although a-Gal may reappear in the a-galactosidase treated organs after a certain time, 15 a-Gal would not reappear after enzymatic removal of a-Gal epitopes from cardiac valvular and pericardial tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Decellularization approaches proved to be effective in the prevention of calcification, presumably by suppressing residual antigenicity of bioprosthetic tissue. 11,12 Lately, our group 2,4,5,8 proved that decellularization is not enough for removal of a-Gal epitopes, and a-galactosidase can effectively remove the a-gal epitopes from xenograft heart valves and pericardium using both qualitative and quantitative analysis without affecting the mechanical properties of the tissues. Therefore, in addition to decellularization, we used enzymatic method using a-galactosidase to remove a-Gal epitopes efficiently from cardiac valvular and pericardial tissues in this study.…”

Section: Introductionmentioning

confidence: 98%

“…Therefore, in addition to decellularization, we used enzymatic method using a-galactosidase to remove a-Gal epitopes efficiently from cardiac valvular and pericardial tissues in this study. 2,4,5,8,[13][14][15] To investigate the xenoresponse in immunological environment similar to human, our group 1 have inactivated the a1,3-galactosyltransferase gene in mice by gene targeting, and have generated mice that do not synthesize the Gal epitope. [16][17][18][19] Lee et al 1 proved that bovine pericardium implanted into the a-Gal KO mice caused significant increase in anti-a-Gal antibodies, and showed some histologic evidences of chronic rejection and that a-Gal KO mouse subcutaneous implantation model might be a feasible animal model for testing efficacy of anticalcification treatments incorporating immunologic approach, such as alpha-galactosidase.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8] It is generally accepted that the degeneration of bioprostheses is multifactorial, and includes immunologic reactions, foreign body reactions, blood-surface interactions, chemical factors, infection, mechanical factors, material fatigue, and surgical factors. 9 Although the mechanism leading to premature degeneration of the implanted bioprosthesis is not yet fully understood, the immune response has been considered to play an important role as an initial trigger of the degeneration process, 10 and the xenoreactive Gala1,3-Galb1-4GlcNAc-R (a-Gal) epitope has been noted as the major antigen.…”

Section: Introductionmentioning

confidence: 99%

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In VivoEfficacy of Alpha-Galactosidase as Possible Promise for Prolonged Durability of Bioprosthetic Heart Valve Using Alpha1,3-Galactosyltransferase Knockout Mouse

Lim

Choi

Yoon

et al. 2013

Tissue Engineering Part A

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The immune response due to Galα1,3-Galβ1-4GlcNAc-R(α-Gal) epitopes is an important factor in bioprosthetic heart valve failure. The aim of this study was to evaluate the immune reaction and anticalcification effect of α-galactosidase and decellularization for glutaraldehyde (GA)/genipin fixed bovine pericardium using α1,3-galactosyltransferase knockout(α-Gal KO) mouse(C57BL/6). Bovine pericardial tissues were decellularized and treated with α-galactosidase before fixation with 0.25% GA/0.4% genipin in organic solvent (75% ethanol and 5% octanol) and treatment with glycine. The removal of α-gal epitope from the bovine pericardium was analyzed by 3,3'-Diaminobenzidine staining intensity. The bovine pericardial tissues were subcutaneously implanted into wild type mice (n=19) and α-Gal KO mice (n=66), which had been presensitized with rabbit red blood cells to maximize immunologic response or not, and anti α-Gal antibodies were measured at various time intervals. Calcium contents of the explanted tissues (n=104) were measured 3 months after implantation. The treatment of α-galactosidase effectively removed the α-gal epitopes expressed on bovine pericardial tissues. In both GA and genipin groups, titers for both anti α-Gal IgM and IgG of α-Gal KO mice increased according to the duration of implantation, and were lower in the groups with decellularization than without decellularization, and were lower in the groups with α-galactosidase+decellularization than with decellularization. The calcium contents of GA/genipin fixed tissues were lower in the groups with decellularization than without decellularization, and were lower in the groups with α-galactosidase+decellularization than with decellularization. Treatment of α-galactosidase with decellularization is useful for removal of the immunogenicity, and reduced calcification in both GA and genipin fixed bovine pericardia, supporting the hypothesis that the immune reaction may cause the calcification. Treatment of α-galactosidase has possible promise to enhance durability of bioprosthetic heart valve. To our knowledge, this is the first report that demonstrates the in vivo efficacy of α-galactosidase using presensitized α-Gal KO mouse to mimic the human immunologic environment.

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Mammalian Pericardium‐Based Bioprosthetic Materials in Xenotransplantation and Tissue Engineering

Grebenik

Gafarova

Истранов

et al. 2020

Biotechnology Journal

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Bioprosthetic materials based on mammalian pericardium tissue are the gold standard in reconstructive surgery. Their application range covers repair of rectovaginal septum defects, abdominoplastics, urethroplasty, duraplastics, maxillofacial, ophthalmic, thoracic and cardiovascular reconstruction, etc. However, a number of factors contribute to the success of their integration into the host tissue including structural organization, mechanical strength, biocompatibility, immunogenicity, surface chemistry, and biodegradability. In order to improve the material's properties, various strategies are developed, such as decellularization, crosslinking, and detoxification. In this review, the existing issues and long‐term achievements in the development of bioprosthetic materials based on the mammalian pericardium tissue, aimed at a wide‐spectrum application in reconstructive surgery are analyzed. The basic technical approaches to preparation of biocompatible forms providing continuous functioning, optimization of biomechanical and functional properties, and clinical applicability are described.

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Removal of Alpha-Gal Epitopes from Porcine Aortic Valve and Pericardium using Recombinant Human Alpha Galactosidase A

Cited by 37 publications

References 17 publications

Avoiding Detrimental Human Immune Response Against Mammalian Extracellular Matrix Implants

Avoiding Detrimental Human Immune Response Against Mammalian Extracellular Matrix Implants

In VivoEfficacy of Alpha-Galactosidase as Possible Promise for Prolonged Durability of Bioprosthetic Heart Valve Using Alpha1,3-Galactosyltransferase Knockout Mouse

Mammalian Pericardium‐Based Bioprosthetic Materials in Xenotransplantation and Tissue Engineering

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