Expression of human decay accelerating factor or membrane cofactor protein genes on mouse cells inhibits lysis by human complement

White, David J.; Oglesby, Teresa J.; Liszewski, M. Kathryn; Tedja, I.; Hourcade, Dennis E.; Wang, M.-W.; Wright, Les; Wallwork, J.; Atkinson, John P.

doi:10.1111/tri.1992.5.s1.648

Cited by 37 publications

(25 citation statements)

References 18 publications

(12 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…18 In an effort to prevent clinical hyperacute xenograft rejection, investigators have transfected human complement regulatory proteins into pigs. [19][20][21] This results only in temporary delay of xenograft destruction. 22,23 The reason is that the other mechanisms of innate immunity (shown in Table 1) promptly cause inexorable rejection.…”

Section: The Transplant Analogymentioning

confidence: 99%

Will Xenotransplantation Ever Be Feasible?

Starzl¹

1998

Journal of the American College of Surgeons

View full text Add to dashboard Cite

In several recent conferences, the principal questions have been whether Xenotransplantation technology should be encouraged and, if so, how it should be regulated. Because the prospect of successful transplantation of animal organs into humans is still remote, the rush to achieve consensus about clinical application 1,2 would be inexplicable were it not for two ostensibly unrelated issues. The first is the small but undeniable theoretical hazard of causing new human infections with the intermingling of tissues from different species. The second, advanced by animal-rights advocates, concerns the spiritual and ethical relationship of humans to animals. CLOSELY RELATED SPECIESThe rhetoric of these discussions has been heightened by the fact that all clinical organ xenotransplantations attempted since 1963 have failed, including >25 involving subhuman primate donors (19 reported or unreported chimpanzees, 10 baboons, and 1 [or 2] Rhesus monkeys). This experience began with Reemtsma and associates, 3 who proved in 1963 that kidneys from at least two subhuman primate donor species (Rhesus and chimpanzee) would not be rejected hyperacutely by humans. In fact, one of his chimpanzee xenografts functioned for 9 months. However, Reemtsma was the first to recognize that the humanoid qualities and threatened extinction of the chimpanzee would prevent its widespread use as a donor.Later in 1963, a team at the University of Colorado/Minnesota showed that baboon kidneys also would escape hyperacute rejection. In contrast to the chimpanzee, baboons flourished, and still do, in southern and central Africa. The six baboon renal xenografts of 1963 supported dialysis-free life for 6-60 days before undergoing fierce cellular rejection. 4 In addition, all of the baboon kidneys had occlusive endotheliolitis that was severe enough to cause regional parenchymal infarcts and islands of gangrene. We concluded by early 1964 that this humoral component of xenograft rejection could not be controlled with cell-directed immune suppression (azathioprine and prednisone at the time). A moratorium was selfimposed on further attempts. This hiatus lasted for 28 years, until investigations by Murase and colleagues 5 with the hamsterto-rat model appeared to justify a further trial. In this strain combination, in which the immune barrier resembles that between the baboon and human, 6 the combination of T-cell-specific immune suppression with tacrolimus plus B-cell-directed cyclophosphamide permitted the unprecedented routine survival of heart and liver xenografts for >100 days.In June 1992 and January 1993, two baboon-to-human orthotopic liver transplantations were performed in patients with chronic end-stage organ failure caused by hepatitis B virus infection.

show abstract

Section: The Transplant Analogymentioning

confidence: 99%

Will Xenotransplantation Ever Be Feasible?

Starzl¹

1998

Journal of the American College of Surgeons

View full text Add to dashboard Cite

show abstract

“…DAF limits the generation of classic and alternative complement pathway convertases [19]. The importance of these modulators have been demonstrated by experiments that have enhanced expression of these proteins by gene transfection [20]. The activities of these complement modulators are though to be speciesspecific and help to explain the phenomenon of "homologous species restriction" [21].…”

Section: Xenograft Immunitymentioning

confidence: 99%

Clinical Trials and Projected Future of Liver Xenotransplantation

1997

View full text Add to dashboard Cite

The trial and error of the pioneering xenotransplant trials over the past three decades has defined the limitation of the species used. Success was tantalizingly close with the chimpanzee, baboon, and other primates. The use of more disparate species has been frustrated by the xenoantibody barrier. Future attempts at clinical xenotransplantation will be hampered by the consideration of the species of animals and the nature of the organs to be transplanted. On one hand, primate donors have the advantage of genetic similarity (and therefore potential compatibility) and less risk of immunologic loss. On the other hand, pig donors are more easily raised, are not sentient animals, and may be less likely to harbor transmissible disease. It is recognized that the success of xenotransplantation may very with different organs. Because it is relatively resistant to antibody-mediated rejection, the liver is the organ for which there is the greatest chance of long-term success. Consideration of using xenotransplants on a temporary basis, or as a "bridge" to permanent human transplantation, may allow clinical trials utilizing hearts or kidney xenografts. Issues on metabolic compatibility and infection risks cannot be accurately determined until routine success in clinical xenotransplantation occurs. Based on a limited experience, the conventional approaches to allotransplantation are unlikely to be successful in xenotransplantation. The avoidance of immediate xenograft destruction by hyperacute rejection, achieved using transgenic animals bearing human complement regulatory proteins or modulating the antigenic target on the donor organ, is the first step to successful xenotransplantation. The ability to achieve tolerance by establishing a state of bone marrow chimerism is the key to overcoming the long-term immunologic insults and avoiding the necessarily high doses of nonspecific immunosuppression that would otherwise be required and associated with a high risk of infectious complications. Xenotransplantation faces criticism that is strongly reminiscent of that leveled against human-to-human transplantation during the late 1960s and early 1970s. Yet with persistence, the field of human-to-human transplantation has proved highly successful. This success was the result of a stepwise increase in our understanding of the biology of rejection, improvements in drug management, and experience. It is possible that xenotransplantation may not be universally successful until further technologic advances occur; yet cautious exploration of xenotransplantation appears warranted to identify those areas that require further study.

show abstract

“…9 Due to the transduction of the RCA molecule, xenogeneic cells are resistant to human complement attack. [10][11][12] To insert the HRF20 gene, as well as other therapeutic genes into vector-producing cells, the authors established a novel complement-resistant retroviral vector, which possesses the HRF20 gene as a selection gene.Complement-resistant retroviral vector (LRHL) was constructed by replacing the neomycin resistance gene (Neo R ) of the LRNL retroviral vector with the HRF20 (Figure 1). To produce virus-producing cells, LRHL retroviral vector was transduced into ⌿2 ecotropic packaging cells, and then the supernatant was poured into PA317 amphotropic packaging cells.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Establishment of complement-resistant retroviral vector by homologous restriction factor 20 gene

et al. 1998

View full text Add to dashboard Cite

Homologous restriction factor 20 (HRF20, CD59) is one of cessfully selected by complement-dependent selection, the complement regulatory factors. In this study, the which showed significant expression of the HRF20 antigen. complement-resistant retroviral vector, which possessesIn addition, these cells, transduced with tissue plasminthe HRF20 gene as a selection gene, was constructed and ogen activator (tPA) cDNA using complement-resistant examined. The virus-producing cell, transduced with retroviral vector, expressed tPA antigen after complementcomplement-resistant retroviral vector, was established dependent selection. These findings suggest that compafter complement-dependent selection. NIH3T3 and PK15 lement-resistant retroviral vector can be used for the cells transduced with this virus-producing cell were sucdouble transduction of HRF20, as well as other genes.Keywords: complement-dependent selection; gene therapy; retroviral vectorThe technique of gene transfer has been developed over the past decade and enables gene therapy to be applied to patients suffering from inherent metabolic diseases and malignancies. 1,2 The use of retroviral vectors is the most efficient method of gene therapy and their cDNA usually consists of both a therapeutic and a selection gene such as the neomycin-resistance gene or hygromycin-resistance gene. [3][4][5] Using these selection drugs, the retroviral vector-producing cells are selected 10 to 14 days after transduction. Recent investigation has demonstrated the effect of in vivo gene transfer with retroviral vector-producing cells on the treatment of experimental and clinical brain tumors using the herpes simplex virus thymidine kinase (HSVtk) gene, the mechanism of which has been termed the bystander effect. [6][7][8] However, it is difficult to introduce retroviral vector-producing cells in vivo for human gene therapy because of the immunological reaction to vector-producing cells by human complement. It has been reported that the homologous restriction factor 20 (HRF20, CD59) gene, one of the regulators of the complement activation (RCA) molecule, can be used for rapid selection of transduced cells. 9 Due to the transduction of the RCA molecule, xenogeneic cells are resistant to human complement attack. [10][11][12] To insert the HRF20 gene, as well as other therapeutic genes into vector-producing cells, the authors established a novel complement-resistant retroviral vector, which possesses the HRF20 gene as a selection gene.Complement-resistant retroviral vector (LRHL) was constructed by replacing the neomycin resistance gene (Neo R ) of the LRNL retroviral vector with the HRF20 (Figure 1). To produce virus-producing cells, LRHL retroviral vector was transduced into ⌿2 ecotropic packaging cells, and then the supernatant was poured into PA317 amphotropic packaging cells. After these cells were selected using complement-dependent selection, six colonies were grown. The expression of the HRF20 antigen on these cells was shown to be strongly positive, the mean channel shift ...

show abstract

Expression of human decay accelerating factor or membrane cofactor protein genes on mouse cells inhibits lysis by human complement

Cited by 37 publications

References 18 publications

Will Xenotransplantation Ever Be Feasible?

Will Xenotransplantation Ever Be Feasible?

Clinical Trials and Projected Future of Liver Xenotransplantation

Establishment of complement-resistant retroviral vector by homologous restriction factor 20 gene

Contact Info

Product

Resources

About