Some day in the increasingly foreseeable future, pig mayedge out dog as man's (and woman's) best friend.

Xenotransplantation is the name of the movement thataims to elevate swine from mere suppliers of pork to asource of replacement organs for humans with failedhearts, lungs, kidneys and the like.

Pigs, especially mini-pigs bred for convenient size, havedonor organs that would seem to suit human anatomicaland physiological specifications. But their prospectivepatient recipients have immune systems that would makeinstant mincemeat of any porcine tissue engrafted intotheir bodies.

If a surgeon attempted to transplant a pig kidney into aperson _ as some foolhardily did in the days beforeimmunology came of age _ that organ would turn blackand die within minutes, or hours at most. Its demisewould be caused by the phenomenon of hyperacuterejection which remains the bugaboo of today's moresophisticated transplanters.

The moment a recipient's immune system discerns thepresence of such an alien body part, it dispatchesantibodies to the xenobiotic organ. There, they summonup the complement cascade, a series of proteins thatgalvanize the donor blood-vessels' lining of endothelialcells. These go right on the warpath, swelling,hemorrhaging and shutting down the veins and arterieswith thromboses.

Cutting off the complement attack at that hyperacuterejection pass has been the goal of transplantimmunologists on both sides of the Atlantic. (SeeBioWorld Today, Feb. 22, 1995, p. 1.) They havesucceeded in creating transgenic pigs geneticallyequipped with human complement-inhibiting factors.These still are at the preclinical stage of development, butshow signs of working _ as far as they go.

That's as far as fighting off hyperacute rejection. Thispromises the patient, and the surgeon, a respite of severaldays or weeks until delayed rejection kicks in.

Of course, all organ transplants done today _ 18,000 ayear in the U.S. alone _ lean on lifetime immuno-suppressants to keep the body's immune defenses (reallyoffenses now) at bay. But such drugs, primarilycyclosporin A, carry their own severe side-effects,robbing the body of the means to protect againstinfection.

To Tolerate The Intolerable

Pioneer transplant surgeon, Thomas Starzl, at theUniversity of Pittsburgh, used cyclosporin A in twoattempts to implant baboon livers into end-stage patients.They survived for 25 and 75 days, respectively, despiteheroic regimens of the anti-rejection drugs.

To prevent delayed graft rejection, in person-to-persontransplants, let alone xenobiotic ones, the current goal istolerance _ the acquired incapacity of an individual torespond to a specific antigen.

In the world of animal-to-human organ-graft research, amajor player is transplantation biologist David Sachs, ofMassachusetts General Hospital in Boston. Sachs alsochairs the scientific advisory board of BioTransplant Inc.,of Charlestown, Mass. This four-year-old firm's presidentand CEO, Elliot Lebowitz, describes it as "the leadingbiotechnology company in organ transplant technology."

Sachs is one of four scientific authorities in the field whohave adjoining articles on xenotransplantation in theSeptember issue of Nature Medicine. His paper reports on"Tolerance and xenograft survival" in efforts by hishospital and BioTransplant to endow mini-pigs withtolerance to relevant components of the human immunesystem.

"Experiments being carried out at Massachusetts GeneralHospital proceed in a very orderly and creative way,"BioTransplant's Lebowitz told BioWorld Today. Studiesare first done in rodents. Then, using Sachs' inbred mini-swine, they proceed to concordant xenografts, forinstance, baboon to monkey. They then go pig to baboon,or pig to monkey, as the most relevant clinical model, butalso the most difficult technically.

"In pig to monkey," Lebowitz continued, "we typicallyget one or two weeks of survival. Obviously thatdemonstrates overcoming hyperacute rejection." Thisthey do, not by inserting genes for complement inhibitioninto their prospective porcine donors, but by circulatingrecipient blood through columns containing the epitopesto which the natural antibodies bind.

To tackle their main target, delayed rejection, Sachs andhis co-authors have devised a system for twinning the pigand human immune systems in the recipient animals'bone marrow. This chimeric approach, Sachs reported,"involves transient ablation of the recipient's immunesystem, during which time partial donor hematopoieticrepopulation is established by a bone marrow transplant.The immune system then reconstitutes in the presence ofboth elements, and becomes tolerant to both. Mostimportant," he added, "a normal immune response to allother antigens, including pathogenic organisms, isrestored."

Survival Without Long-Term Immunosuppression

Lebowitz observed that "Recently at MassachusettsGeneral Hospital, it was demonstrated for the first timethat one can achieve this bone-marrow chimerism, andlong-term survival of a kidney transplant between ababoon and a monkey without long-termimmunosuppression, and with total kidney function."

Pig-to-monkey attempts, he went on, "were unsuccessfulbecause it turned out that pig bone marrow cells do notrespond to human cytokines, so they wouldn't engraft orproliferate."

Still more recently, Lebowitz continued, "BioTransplantcreated a proprietary library of pig cytokines, and enabledlong-term survival of the pig bone marrow in themonkey."

A second approach now in the works with rodents andmini-swine, Lebowitz said, "is to use retroviraltransduction of the recipient's own bone marrow with theporcine equivalent of the major histocompatibilitycomplex in an alternative attempt to produce tolerance."

BioTransplant has a corporate partnership with SandozPharma Ltd., of Basel, Switzerland. "When we showthem proof-of-principle in the pig-to-primateexperiments," Lebowitz said, "At that point it would bereasonable to say, `Let's develop the product, go intoclinicals, and on to commercialization.' "

On a guesswork basis, he said putting porcine donororgans into humans, employing mixed bone-marrowchimerism, "will take more than months, but a fewyears." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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