Effect of Transgenic Expression of Human Decay—Accelerating Factor on the Inhibition of Hyperacute Rejection of Pig Organs

Cozzi, Emanuele; Yannoutsos, Nikos; Langford, Gillian; Pino-Chavez, Gilda; Wallwork, J.; White, David J.

doi:10.1007/978-3-642-60572-7_49

Cited by 68 publications

(51 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The importance of antidonor antibodies in acute vascular rejection may explain why regimens that inhibit antibody synthesis, including administration of high doses of cyclophosphamide that are often not tolerated by the recipients, allow longterm survival of pig-to-primate xenografts (4). Even with the knowledge that antibodies are important in the development of acute vascular rejection, however, the optimal regimen for prevention and treatment has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…The earliest type of rejection seen in a pig-to-primate xenograft is hyperacute rejection, which occurs within minutes to hours of transplantation (1)(2)(3) and is initiated by xenoreactive antibodies that bind to the endothelial lining of the graft vasculature, activating the complement system (2,3). Hyperacute rejection can now be overcome by depletion of antidonor antibodies or inhibition of complement (3)(4)(5). When hyperacute rejection is averted, especially by inhibition of the recipient's complement system, the xenograft becomes subject to acute vascular rejection that destroys the graft over a period of hours to days (6,7).…”

Section: Introductionmentioning

confidence: 99%

“…Some have proposed that acute vascular rejection is caused by biological processes that would occur independently of the immune reaction of the host against the graft (8). On the other hand, we have proposed that while biological incompatibility might add to the severity, acute vascular rejection is triggered by persistent interaction of xenoreactive antibodies with the xenograft, as suggested by four lines of evidence (9): ( a ) patients exposed to porcine antigens from extracorporeal circulation through porcine livers experience an increase in the titer of xenoreactive antibodies within a few days, coinciding with the time when a xenograft is subject to acute vascular rejec-tion, and suggesting that immune stimulation has occurred (21); ( b ) primates from which xenografts are removed after rejection have a sudden increase in antidonor antibody levels (22,23), implying that the xenograft was continually exposed to xenoreactive antibodies; ( c ) acute vascular rejection of allografts and concordant xenografts is associated with the presence of antidonor antibodies in the blood, or can be induced by administration of antidonor antibodies (10,24,25); and ( d ) cytotoxic agents such as cyclophosphamide that inhibit the synthesis of antibodies appear to delay or avert acute vascular rejection (4).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Lin

Weidner²,

Byrne³

et al. 1998

J. Clin. Invest.

259

161

View full text Add to dashboard Cite

Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens. (

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Lin

Weidner²,

Byrne³

et al. 1998

J. Clin. Invest.

259

161

View full text Add to dashboard Cite

show abstract

“…Many porcine cell types and all vascularized organs transplanted into primate models are rejected by both humoral and cellular mechanisms (5,6). Major advances have been made in abrogating the humoral component that leads to hyperacute rejection, mainly through complement inhibition (7)(8)(9)(10). However, even in the presence of complement inhibitors and systemic immunosuppression, xenografts are rejected due to delayed xenograft rejection (DXR) 4 (3,6,(11)(12)(13)(14).…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…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

Effect of Transgenic Expression of Human Decay—Accelerating Factor on the Inhibition of Hyperacute Rejection of Pig Organs

Cited by 68 publications

References 41 publications

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

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

Will Xenotransplantation Ever Be Feasible?

Contact Info

Product

Resources

About