Alternative Paths to Xenotransplantation

A number of new biotechnology companies are developing pigs with human genes that will partially mask the foreignness of their organs to allow them to be transplanted into humans. Others, however, are closely studying the immune-system biochemistries of pigs and humans to find more classical, drug-based approaches to effective xenotransplantation. The first aim in both cases is the same -- to defeat the devastating and nearly immediate hyperacute rejection of pig organs by the human immune system, orchestrated by antibodies and involving powerful complement proteins, that otherwise occurs. For example, T Cell Sciences Inc., a publicly traded biotech in Needham, Mass., is working on an injectable complement inhibitor, a substance the company calls sCR1, or soluble complement receptor type 1. This agent is a soluble form of the naturally occurring complement regulator CR1, which occurs on the surface of red cells. The soluble form has been liberated from the cell surface and can be administered intravenously. LOOKING TOWARD TOLERANCE: Novel drug therapies could get xenotransplant patients over the organ-rejection "hump" to immune accommodation, syas T Cell Sciences' vice president and chief scientific officer Una S. Ryan. "We're all recognizing complement as the culprit [in hyperacute rejection]," comments Una S. Ryan, vice president and chief scientific officer of T Cell Sciences."The people who are putting complement regulatory proteins into transgenic organs are imprinting that organ for its life with complement regulatory benefits against the host complement. But what we are doing is thinking of complement regulation more in the traditional therapeutic sense, where you have a drug and the physician's judgment can be used to tailor the therapy for the patient's needs. "It may well be that you do need to regulate complement for the life of the organ. But it may also well be that you don't, and that if you get patients over the hump to where you have accommodation or modulation -- people use different words -- that, in fact, you really don't need to regulate beyond that. And I think we have more control over that process." Beyond hyperacute rejection, viewed as the most critical barrier to xenotransplantation, and other antibody-based immune responses to animal organs, a number of investigators and companies are also working on tactics to counter T-cell- mediated rejection. Long-term immunosuppression of the kind currently used in allotransplantation could be used, but higher doses might be needed in xenotransplantation. Because toxicity and infectious complications are already serious problems in transplantation, however, increased immunosuppression may not be a realistic therapeutic option. The solution, some scientists maintain, is to induce tolerance -- what T Cell Sciences' Ryan refers to as accommodation or modulation -- on the part of the host for the xenograft. With even partial tolerance, they say, drug doses could be reduced. Tolerance is the approach being pursued by BioTransplant Inc., a privately held company in Charlestown, Mass., with support from Sandoz Pharma AG of Basel, Switzerland, and based on work by David H. Sachs, a professor of surgery at Harvard Medical School and director of the transplantation biology research center at Massachusetts General Hospital. Bone marrow stem cells give rise to T cells and other immune-system cells. Between humans, bone marrow grafts have been shown, under certain circumstances, to produce a condition called mixed chimerism, which can induce tolerance. Hoping to extend this concept, Sachs has engrafted pig bone marrow cells into monkeys with the same goal. At first, the cells did not proliferate, but with the addition of pig-specific growth factors, Sachs has been able to reconstitute the immune systems of the monkeys, implying that the same might be possible with humans. According to Elliot Lebowitz, BioTransplant's president and chief executive officer, the tolerance approach used by Sachs aims "not to just suppress the whole immune system with chronic immunosuppression but to reeducate it, so that it accepts specific foreign tissue as self but otherwise stays intact to protect against pathogens and other attacks on the body." Another BioTransplant tolerance strategy, Lebowitz says, is to take copies of the donor's MHC (major histocompatibility complex) genes and transduce the recipient's bone marrow cells with those genes. The result is specific tolerance of tissue from the donor, but, again, without suppression of the immune system. - F.H. (The Scientist, Vol:9, #20, pg.11 , October 16, 1995) (Copyright © The Scientist, Inc.)

Alternative Paths to Xenotransplantation

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