The sweets standing at the borderline between allo‐ and xenotransplantation

Jang, Kyoung‐Soon; Kim, Yun‐Gon; Adhya, Mausumi; Park, Haemin; Kim, Byung‐Gee

doi:10.1111/xen.12030

Cited by 13 publications

(12 citation statements)

References 76 publications

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“…have elegantly demonstrated production of Gal‐ and Neu5Gc‐deficient double‐knockout pigs using zinc finger nucleases, which elicit a significantly decreased in vitro antibody response compared to a Gal‐KO standard . Even with this progress, it is still recognized that the porcine glycome presents opportunities to generate more immunologically analogous porcine tissues . In addition to knocking out antigenic epitopes, the expression of human proteins, such as complement or coagulation regulatory factors, may improve engraftment and survival .…”

Section: Is There An Established Donor Islet Source?mentioning

confidence: 99%

Islet cell xenotransplantation: a serious look toward the clinic

Samy

Martin

Turgeon

et al. 2014

Xenotransplantation

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Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near-physiologic function and yearlong survival in clinically relevant pig to primate model systems. These proof-of-concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this commentary, we examine recent progress in islet xenotransplantation, with a critical eye towards the gaps between the current state of the art and the state required for appropriate clinical investigation.

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Section: Is There An Established Donor Islet Source?mentioning

confidence: 99%

Islet cell xenotransplantation: a serious look toward the clinic

Samy

Martin

Turgeon

et al. 2014

Xenotransplantation

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“…Studies have shown that a-1,3-galactosyle (a-Gal) antigen in xenograft is one of the main target antigens in animal tissues and organs that cause acute rejection reaction after transplantation [8,9]. a-Gal is a kind of cell secreted glycoproteins or glycolipids that containing galactosamine core terminal residues, which exists as a cell surface molecule in most species, except humans and old world monkeys [10].…”

Section: Introductionmentioning

confidence: 99%

Xenogeneic bone matrix immune risk assessment using GGTA1 knockout mice

Shao

Ling

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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Homeotransplantation of bones for replacement therapy have been demonstrated reliably in clinical data. However, human donor bones applicable for homeotransplantation are in short supply, which facilitates the search for suitable alternatives, such as xenografts grafts. The α-Gal antigen-related immune risk of xenografts directly affects the safety and effectiveness of the biomaterials and limits their applications in the clinic. The immune risk can be prevented by depletion or breaking anti-Gal antibody prior to transplant. Therefore, how to assess the immune risk of the bone substitutes and select the reliable animal research model become extremely important. In this study, we prepared lyophilized bone substitutes (T1) and Guanghao Biotech bone substitutes (T2, animal-derived biomaterials with α-Gal antigen decreased), aimed to assess the immune risk of xenografts bone substitutes on GGTA1 knockout mice. The α-Gal antigen contents of T1 and T2 were firstly detected by ELISA method in vitro. The bone substitutes were then implanted subcutaneously into GGTA1 knockout mice for 2, 4 and 12 weeks, respectively. The total serum antibody levels, anti-α-Gal antibody levels, inflammatory cytokine and splenic lymphocyte surface molecules were detected and histology analysis of skin and thymus were performed to systematically evaluate the immune response caused by the T1 and T2 bone substitutes in mice. In vitro results showed that the amount of α-Gal epitopes in T1 bone substitutes was significantly higher than T2 bone substitutes, and the clearance rate of α-Gal antigen in T2 bone substitutes achieved about 55.6%. Results of antibody level in vivo showed that the T1 bone substitutes group possessed significantly higher total IgG, IgM, IgA and anti-α-Gal IgG levels than T2 and control group, while T2 group showed no significant changes of these indexes compared with control. In terms of inflammatory cytokines, T1 bone substitutes showed evidently higher levels of IL-4, IL-12P70 and IL-10 than T2 and control, while T2 group was comparable to control. No changes in the levels of splenic lymphocyte surface molecules were found in the three groups (T1, T2 and control group) during the experimental periods. The pathological results demonstrated that the inflammatory response in T2 group was lighter than the T1 group, which was in accordance with the inflammatory cytokines levels. The above results indicated that the process of antigen removal effectively reduced the α-Gal antigens content in T2 bone substitutes, which caused little immune response in vivo and could be used as bone healing materials. This study also demonstrated that GGTA1 knockout mice can be used as a routine tool to assess the immune risk of animal-derived biomaterials.

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“…In this study, we describe the NSG/a-Gal null mouse, which is capable of engrafting human HSCs and can be used for preclinical evaluation of viral and tumor-based a-Gal epitope vaccines. In addition, it could be used in the xenotransplantation studies, in which the binding of anti-Gal Ab to the a-Gal epitope is the main cause of tissue rejection (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

A New Humanized Mouse Model Mimics Humans in Lacking α-Gal Epitopes and Secreting Anti-Gal Antibodies

Saleh

Chandra

Lin

et al. 2020

The Journal of Immunology

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Mice have been used as accepted tools for investigating complex human diseases and new drug therapies because of their shared genetics and anatomical characteristics with humans. However, the tissues in mice are different from humans in that human cells have a natural mutation in the a1,3 galactosyltransferase (a1,3GT) gene and lack a-Gal epitopes on glycosylated proteins, whereas mice and other nonprimate mammals express this epitope. The lack of a-Gal epitopes in humans results in the loss of immune tolerance to this epitope and production of abundant natural anti-Gal Abs. These natural anti-Gal Abs can be used as an adjuvant to enhance processing of vaccine epitopes to APCs. However, wild-type mice and all existing humanized mouse models cannot be used to test the efficacy of vaccines expressing a-Gal epitopes because they express a-Gal epitopes and lack anti-Gal Abs. Therefore, in an effort to bridge the gap between the mouse models and humans, we developed a new humanized mouse model that mimics humans in that it lacks a-Gal epitopes and secretes human anti-Gal Abs. The new humanized mouse model (Hu-NSG/a-Gal null) is designed to be used for preclinical evaluations of viral and tumor vaccines based on a-Gal epitopes, human-specific immune responses, xenotransplantation studies, and in vivo biomaterials evaluation. To our knowledge, our new Hu-NSG/a-Gal null is the first available humanized mouse model with such features.

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The sweets standing at the borderline between allo‐ and xenotransplantation

Cited by 13 publications

References 76 publications

Islet cell xenotransplantation: a serious look toward the clinic

Islet cell xenotransplantation: a serious look toward the clinic

Xenogeneic bone matrix immune risk assessment using GGTA1 knockout mice

A New Humanized Mouse Model Mimics Humans in Lacking α-Gal Epitopes and Secreting Anti-Gal Antibodies

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