NICE, France _ If a transplant surgeon put a pig heart into one ofhis patients, it would turn black in front of his eyes, in perhaps 10 or15 minutes. Cause of that sudden death: hyperacute rejection.
British transplant immunologist David White told this `what-if' storyTuesday morning here to attendees at a session on "Transgenicanimals in medicine and agriculture."
White explained that such a porcine xenograft _ an organ fromanother species transplanted into humans _ rapidly succumbs tohyperacute rejection, because "Everybody has antibodies againstpigs. They bind to the graft, and activate the complement system."
This complex of proteases, White said, is a part of the immunesystem programmed to punch holes in cells of invading organisms,when guided to their target by antibodies.
The detonator of this smart-bomb complement fuse, C3b, hecontinued, is a specific protease, convertase. What makes that C3bbomb smart enough not to destroy its body's own tissues is a seriesof proteins called regulators of complement activation. Present onevery cell in the human body, these proteins disable the complementcascade, to block it from launching friendly fire.
White's strategy of immunizing porcine donor organs againsthyperacute rejection is to make the pigs transgenic for one such fail-safe protein called DAF _ decay-accelerating factor _ whichaccelerates decay of the tissue-lethal convertase enzyme Transfectingporcine embryonic cells by lipofaction and microinjection, andputting the DAF cDNA in backwards, he and his team injected 2,443eggs, and attained a "surprisingly high" transgenic success rate of 2percent.
At Imutran Ltd. in Cambridge, England, they now have a herd ofsome 60 transgenic porkers, which carry the human DAF gene in allof their cells.
In vitro tests show that the principle works, and preclinical "primatetrials are currently under way," White told BioWorld Today,"transplanting the organs from the pigs into cynomolgus macaquemonkeys." Preliminary results will come soon.
Meanwhile, to answer the key question: How will a DAF-transfectedpig heart function? White's group built an artificial blood circuit. Inthe middle sits a transgenic porcine heart pumping human bloodaround at 700 mm of mercury, "a respectable mimic of human bloodpressure."
Both xenobiotic organ and human blood survived a four-hour testrun, while ordinary pig hearts lasted only 30 minutes. By the sametoken, the controls generated high levels of cell-lysing C3b; thetransgenics, none.
The very idea of xenograft transplantation, White told his audiencehere, grew out of a drug he co-developed in the early 1980s atCambridge University, which made organ-grafting immunologicallypractical altogether. This is the highly efficient immunosuppressant,cyclosporin A.
Its advent, he pointed out, solved one transplant road-block butrevealed another:
"Before cyclosporin A," White observed, "transplantation wasregarded as a high-tech, high-cost, high-risk, low-success activity,undertaken by a few egocentric surgeons. After cyclosporin A,organ-grafting entered the mainstream of therapy; hearts, lungs,kidneys, pancreas, assorted bits of intestines, and any combination ofthose organs all became highly transplantable."
The new limiting factor, he continued, "was not lack of money but ofdonor organs. In 1979, there was one heart transplant center in theU.S., at Stanford University. By 1980, there were 170 hearttransplant centers in the U.S., "with a surgical capacity of treating 20to 25,000 candidate patients a year, but not nearly enough humanhearts to meet that need."
In the U.K., he added, "the waiting list for kidneys is at 5,000 andgrowing."
So White thought: "Why go through this macabre exercise of waitingfor fit, young, healthy people to die, so we can treat sick people?Why don't we simply pop down to the slaughterhouse and get bitsfrom a pig to transplant?"
He, together with a heart surgeon and a Cambridge businessman,founded Imutran, "to look at xenografting in particular, andinappropriate activation of complement in general." It's a privatecompany, he said, "with one major shareholder, Warburg-Pincus ofLondon.
"Our pig work," White added, "is licensed to Sandoz Pharma, ofBasel, Switzerland, which supports our work financially withgenerous milestone payments leading up to FDA approval."
Xenografts present _ or will present _ a peculiar regulatoryparadox, White explained, answering a question from the floor:
"Are they drugs? Hardly. I don't think they [the regulators] cansubject them to standard drug-criterion studies.
"Are they implantable devices? They can hardly do a two-yearaccelerated bench test.
"People think they are biologics, whatever that means."
White sees the solution as one of two regulatory options: "Eitherreshape the current regulations, or make new and sensible ones forquality control." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.