A Strategy for Suppressing Macrophage-mediated Rejection in Xenotransplantation

Maeda, Akira; Lo, Pei‐Chi; Sakai, Rieko; Noguchi, Yuki; Kodama, Tatsuhiko; Yoneyama, Tomohisa; Toyama, Chiyoshi; Wang, Han-Tang; Esquivel, Emilio; Jiaravuthisan, Patmika; Choi, Thuy Vy; Takakura, Chihiro; Eguchi, Hiroshi; Tazuke, Yuko; Watanabe, Masaru; Nagashima, Hiroshi; Okuyama, Hiroomi; Miyagawa, Shuji

doi:10.1097/tp.0000000000003024

Cited by 14 publications

(10 citation statements)

References 91 publications

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“…21 (v) Inhibition of macrophage activation via signal regulatory protein alpha by transgenic expression of human CD47. 22,23 (vi) Suppression of inflammation by transgenic expression of human tumor necrosis factor-alpha-induced protein 3 (alias A20) 24 or human heme oxygenase 1 (HMOX1). 25 (vii) Elimination or downregulation of porcine major histocompatibility complex (MHC) molecules, that is, swine leukocyte antigen (SLA) class I (encoded by 3 functional class Ia genes, SLA-1, -2, and -3, and 3 class Ib genes, SLA-6, -7, and -8) and class II (encoded by the α-and β-chain genes for SLA-DR, -DQ, -DM, and -DO proteins) (reviewed in Hammer et al 26 and Ladowski et al 27 ).…”

Section: Pigs As Organ Donors-physiological and Immunological Aspectsmentioning

confidence: 99%

Pathways to Clinical Cardiac Xenotransplantation

Reichart¹,

Längin

Denner

et al. 2021

Transplantation

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Heart transplantation is the only long-lasting lifesaving option for patients with terminal cardiac failure. The number of available human organs is however far below the actual need, resulting in substantial mortality of patients while waiting for a human heart. Mechanical assist devices are used to support cardiac function but are associated with a high risk of severe complications and poor quality of life for the patients. Consistent success in orthotopic transplantation of genetically modified pig hearts into baboons indicates that cardiac xenotransplantation may become a clinically applicable option for heart failure patients who cannot get a human heart transplant. In this overview, we project potential paths to clinical cardiac xenotransplantation, including the choice of genetically modified source pigs; associated requirements of microbiological, including virological, safety; optimized matching of source pig and recipient; and specific treatments of the donor heart after explantation and of the recipients. Moreover, selection of patients and the regulatory framework will be discussed.

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Section: Pigs As Organ Donors-physiological and Immunological Aspectsmentioning

confidence: 99%

Pathways to Clinical Cardiac Xenotransplantation

Reichart¹,

Längin

Denner

et al. 2021

Transplantation

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“…Activated macrophages may exert direct toxic effects on xenografts through production of proinflammatory cytokines, such as interleukins, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) ( 77 ). Macrophages mediate robust rejection of donor hematopoietic cells in a variety of xenogeneic settings, through the combined effects of CD47-signal regulatory protein α (SIRP-α) inhibitory receptor signaling, CD200-CD200R signaling, IFN-γ, and danger associated molecular pattern (DAMP)-toll-like receptor (TLR) signaling from damaged porcine cells ( 78 ).…”

Section: Macrophagesmentioning

confidence: 99%

Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: The first clinical steps

et al. 2022

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Xenotransplantation has the potential to solve the shortfall of human organ donors. Genetically modified pigs have been considered as potential animal donors for human xenotransplantation and have been widely used in preclinical research. The genetic modifications aim to prevent the major species-specific barriers, which include humoral and cellular immune responses, and physiological incompatibilities such as complement and coagulation dysfunctions. Genetically modified pigs can be created by deleting several pig genes related to the synthesis of various pig specific antigens or by inserting human complement‐ and coagulation‐regulatory transgenes. Finally, in order to reduce the risk of infection, genes related to porcine endogenous retroviruses can be knocked down. In this review, we focus on genetically modified pigs and comprehensively summarize the immunological mechanism of xenograft rejection and recent progress in preclinical and clinical studies. Overall, both genetically engineered pig-based xenografts and technological breakthroughs in the biomedical field provide a promising foundation for pig-to-human xenotransplantation in the future.

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“…Macrophages are a key effector cell of the innate immune system. In xenotransplantation, they exert phagocytic action and modulate adaptive immunity by contributing to cell recruitment and antigen presentation ( 13 , 14 ). Upon contact with xenogeneic cells, macrophages present xenoantigens to generate Th1 and Th17 cells in acquired immunity ( 14 ), and allow the recruitment of both CD4 + and CD8 + T cells into the islet xenograft ( 15 ).…”

Section: Macrophage-mediated Cellular Immunoresponse In Islet Xenotra...mentioning

confidence: 99%

“…In xenotransplantation, they exert phagocytic action and modulate adaptive immunity by contributing to cell recruitment and antigen presentation ( 13 , 14 ). Upon contact with xenogeneic cells, macrophages present xenoantigens to generate Th1 and Th17 cells in acquired immunity ( 14 ), and allow the recruitment of both CD4 + and CD8 + T cells into the islet xenograft ( 15 ). Macrophages also play important roles in pro-inflammatory and oxidative events that occur in xenotransplantation ( 16 , 17 ).…”

Section: Macrophage-mediated Cellular Immunoresponse In Islet Xenotra...mentioning

confidence: 99%

“…Once activated and attracted to the xenograft, macrophages are capable of graft destruction mediated via the secretion of various proinflammatory mediators, including TNF-α, reactive oxygen, nitrogen species and complement ( 14 , 21 ). Indeed, upregulated expression of inflammatory mediators and cytolytic molecules such as IL-12, IL-15, TNF-α, and iNOS were identified in the graft-infiltrating macrophages of rejecting porcine islet recipient NOD-SCID mice transferred with activated macrophages (without T cells) from mice with rejecting porcine islet xenografts ( 21 ).…”

Section: Macrophage-mediated Cellular Immunoresponse In Islet Xenotra...mentioning

confidence: 99%

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Cellular Immune Responses in Islet Xenograft Rejection

Hawthorne

et al. 2022

Front. Immunol.

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Porcine islets surviving the acute injury caused by humoral rejection and IBMIR will be subjected to cellular xenograft rejection, which is predominately mediated by CD4+ T cells and is characterised by significant infiltration of macrophages, B cells and T cells (CD4+ and CD8+). Overall, the response is different compared to the alloimmune response and more difficult to suppress. Activation of CD4+ T cells is both by direct and indirect antigen presentation. After activation they recruit macrophages and direct B cell responses. Although they are less important than CD4+ T cells in islet xenograft rejection, macrophages are believed to be a major effector cell in this response. Rodent studies have shown that xenoantigen-primed and CD4+ T cell-activated macrophages were capable of recognition and rejection of pancreatic islet xenografts, and they destroyed a graft via the secretion of various proinflammatory mediators, including TNF-α, reactive oxygen and nitrogen species, and complement factors. B cells are an important mediator of islet xenograft rejection via xenoantigen presentation, priming effector T cells and producing xenospecific antibodies. Depletion and/or inhibition of B cells combined with suppressing T cells has been suggested as a promising strategy for induction of xeno-donor-specific T- and B-cell tolerance in islet xenotransplantation. Thus, strategies that expand the influence of regulatory T cells and inhibit and/or reduce macrophage and B cell responses are required for use in combination with clinical applicable immunosuppressive agents to achieve effective suppression of the T cell-initiated xenograft response.

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A Strategy for Suppressing Macrophage-mediated Rejection in Xenotransplantation

Cited by 14 publications

References 91 publications

Pathways to Clinical Cardiac Xenotransplantation

Pathways to Clinical Cardiac Xenotransplantation

Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: The first clinical steps

Cellular Immune Responses in Islet Xenograft Rejection

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