Transgenic pigs designed to express human CD59 and H‐transferase to avoid humoral xenograft rejection

Costa, Cristina; Zhao, Lisa; Burton, Willis V.; Rosas, Cristina; Bondioli, K. R.; Williams, Barry L.; Hoagland, T.A.; Dalmasso, Agustin P.; Fodor, William L.

doi:10.1034/j.1399-3089.2002.0o142.x

Cited by 56 publications

(37 citation statements)

References 56 publications

(146 reference statements)

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“…They can also promote a humoral response by stimulating resting and activated B cells (58). This approach has already been shown to address different DXR components, as HT expression reduces Ab reactivity and hCD59 inhibits complement activation (48). This effect may also contribute to protection from ADCC mediated by NK cells, monocytes/macrophages, and granulocytes, which all have receptors for both Ab and complement (59).…”

Section: Figurementioning

confidence: 99%

Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

Costa

Barber

Fodor

2002

The Journal of Immunology

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Delayed xenograft rejection is a major hurdle that needs to be addressed to prolong graft survival in pig-to-primate xenotransplantation. NK cell activation has been implicated in delayed xenograft rejection. Both Ab-dependent and independent mechanisms are responsible for the high susceptibility of porcine cells to human NK cell-mediated cytotoxicity. Previous reports demonstrated a role of Galα1,3-Gal Ag in triggering the Ab-independent responses. We hypothesize that expression of CD80 and/or CD86 on porcine cells may also play a role in NK cell activation as human NK cells express a variant of CD28. Our initial analysis showed that porcine endothelial cells and fibroblasts express CD86, but not CD80. Genetic engineering of these cells to express hCD152-hCD59, a chimeric molecule designed to block CD86 in cis, was accompanied by a reduction in susceptibility to human NK cell-mediated cytotoxicity. The use of a specific anti-porcine CD86-blocking Ab and the NK92 and YTS cell lines further confirmed the involvement of CD86 in triggering NK cell-mediated lysis of porcine cells. Maximal protection was achieved when hCD152-hCD59 was expressed in H transferase-transgenic cells, which show reduced Galα1,3-Gal expression. In this work, we describe two mechanisms of human NK cell-mediated rejection of porcine cells and demonstrate that genetically modified cells resist Ab-independent NK cell-mediated cytotoxicity.

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Section: Figurementioning

confidence: 99%

Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

Costa

Barber

Fodor

2002

The Journal of Immunology

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“…Similarly, Crry-transgenic mice were protected from CIA [126]. Complement gene therapy has also been used to control hyper-acute and acute rejection in transplanted organs [170,171]. Here, co-expression of CD55 and CD59 by genetransfection enhanced the protective effects [172].…”

Section: Acknowledgementsmentioning

confidence: 99%

A Review of Current Knowledge of the Complement System and the Therapeutic Opportunities in Inflammatory Arthritis

Mizuno

2006

CMC

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The complement activation system, a key component of the innate immune system, protects the host from microorganisms such as bacteria, and other foreign threats including abnormal cells. However, it is also double-edged in that it can have negative effects in the host; excessive complement activation damages the host and can even kill in anaphylactic shock and septic shock. Regulation of the complement system is a useful strategy to control inflammatory diseases, including inflammatory arthritis. Rheumatoid arthritis is a common inflammatory disease worldwide. Many medicines are developed to control inflammation, including recently developed biological response modifiers such as anti-TNF and IL-6 agents. Nevertheless, in some patients disease remains difficult to control because of complications, side effects and tolerance of medicines. In inflammatory arthritis, including rheumatoid arthritis, there is abundant evidence implicating complement activation in humans and animal models. Therefore, anti-complement agents might be beneficial as part of clinical treatment. However, at present, there are still no applicable agents for therapeutic regulation of excessive complement activation in chronic disease. Novel agents in development might be useful as a strategy to control complement activation. Here I describe recent knowledge of the complement system in inflammatory arthritis, the recent developments in anti-complement agents and their considerable potential for the future.

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“…However, recent advances that use pigs transgenic for human complement regulatory proteins have been able to knock out by homologous recombination the enzyme that produces the "offending" carbohydrate antigen. This strategy has been utilized with some success with human decay-accelerating factor, allowing transgenic pig organs to be transplanted into primates (34). Other efforts are underway.…”

Section: The Next 50 Years: Hope and Promisementioning

confidence: 99%

Organ Transplantation

Doyle¹,

Lechler²,

Turka³

2004

Journal of the American Society of Nephrology

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The ancient dream of successful organ transplantation was finally realized 50 yr ago, on December 23, 1954, at the Peter Bent Brigham Hospital in Boston. Over the subsequent half century, the separate disciplines of clinical transplantation and transplant immunology have made remarkable progress. The story of the convergent evolution of these two fields represents one of modern medicine's most important advances. This path of discovery has uncovered both the practical and the fantastic, and along the way, it has been marked by the awarding of more Nobel Prizes than any other field of medicine. The movement of functional organs from one individual to another and the clinical manipulation of the immune system necessary to make this movement successful have gone from being a tour de force to part of everyday clinical practice in just 50 yr. Perhaps most striking, however, is the enduring effect of these advances on the way we think and dream about medicine itself.The purpose of this review is to enable the reader to share the hope and excitement present in the disciplines of immunology and transplantation, which together stand on the brink of what we believe will be a revolutionary second half century. We will focus in equal measure on the historical context in which the first successful kidney transplant operation occurred and the current milieu of transplantation, which itself is characterized by both rapid discovery and continued controversy. Finally, predictions about both the probable and the possible landmarks for the next 50 yr of transplantation will be proposed.

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Transgenic pigs designed to express human CD59 and H‐transferase to avoid humoral xenograft rejection

Cited by 56 publications

References 56 publications

Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

A Review of Current Knowledge of the Complement System and the Therapeutic Opportunities in Inflammatory Arthritis

Organ Transplantation

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