AIDS Treatment News #164, December 4, 1992
John S. James

Since 1988, the U. S. government, over the objections of leading experts, has banned Federal funding of research involving transplantation to humans of tissue from aborted fetuses. Such transplants may be important for treating persons with Parkinson's disease, AIDS, or other conditions. Scientists had agreed on standards to prevent medical use of fetal tissue from causing any pressure on women to have an abortion; for example, by forbidding any payment for the tissue, and forbidding directed donation to a particular patient (who might be a friend of the donor, or have arranged for surreptitious payment). But antiabortionists argued that the fact that a stranger might benefit could possibly influence a woman's decision to have an abortion. As a result, the Bush administration overruled the expert panel set up to examine this issue, as well as an advisory committee to the director of the NIH. Congress attempted to overturn the ban through a provision in the recent NIH Reauthorization Act, but President Bush vetoed that bill.

This funding ban is likely to be removed by the Clinton administration. Meanwhile the November 26, 1992 New England Journal of Medicine reported important progress in using fetal tissue in treatment of Parkinson's disease, in a series of three articles and accompanying editorials.

Technically, the fetal-tissue ban only prevents Federal funding of research on transplanting fetal tissue into humans -- not other work with the tissue, such as laboratory studies. But the real impact has been greater than the wording of the policy would suggest, because the ban cast a stigma of Federal disfavor over the whole area of fetal- tissue research, causing scientists to avoid promising studies they would otherwise have conducted. (The ban is still in place, and AIDS TREATMENT NEWS found a reluctance among researchers interested in doing fetal- tissue studies to discuss the issue, apparently because they did not want to become involved in the politics surrounding it. Science is highly politicized because it is heavily dependent on Federal funding, permissions, and other decisions.)

The Federal funding ban has not forbidden privately-funded research. But the National Institutes of Health would normally take the lead in areas such as tissue transplantation, which are difficult, expensive, and unlikely to interest a pharmaceutical- company sponsor. It is hard to fund transplantation research otherwise, except by charging patients to volunteer for an experimental procedure -- which has been done, although it raises ethical concerns.

Tissue Transplantation in AIDS Treatment

The AIDS interest in human fetal transplantation stems largely from a paper on thymic transplantation published in 1987 by researchers at the Yale University School of Medicine. Unfortunately this promising early lead was not been followed up. Revision of the Federal policy on fetal transplantation may facilitate new studies in this area.

This paper(1) did not report on fetal tissue transplantation; instead, the tissue used came from young children who had to have part of their thymus removed during a heart operation. It was transplanted into 15 volunteers with advanced AIDS; the transplanted tissue survived, for several months at least, in eight of them. Remarkable clinical improvements occurred in some cases, although as expected the benefit appeared to be temporary. Neither antivirals nor pneumocystis prophylaxis was in use at that time (the paper was accepted for publication in July, 1986, so the work had to have been completed before then).

Nine patients showed clinical improvement two months after the operation (including one in whom live transplanted cells were not found). The most dramatic case was one patient in which CMV retinitis appeared to resolve spontaneously with no other treatment: "A severe bilateral retinitis thought to be due to cytomegalovirus (three exudates with hemorrhage in each retina and a rise in cytomegalovirus titers in both blood and cerebrospinal fluid) cleared spontaneously, a development unique in our experience with patients with AIDS. "Tuberculosis control improved in two cases, "but the clearance of resistant Pneumocystis carinii pneumonia in case 12 and a cessation of the previously intractable diarrhea in case 13 may be more significant."

T8 cells (a kind of T-cell, different from T-helper cells, which also may be important in controlling the AIDS virus) showed substantial increases in all eight of the patients in whom the transplant was successful, more than doubling in every case, and often increasing several fold. T-helper increases, however, were minor. All but one patient was anergic before the transplantation, and only two became able to produce a delayed- type hypersensitivity (DTH) response after the transplant. These results suggest that the AIDS virus (which was not being treated with AZT or any other antiviral) may have prevented improvement in the T-helper count and consequently in the DTH response, while having little effect on T8 improvement, since T8 cells are not infected by HIV.

Thymic Transplantation: Comment

Clearly these early results suggest that thymus tissue transplantation should be explored further. Several reasons may explain why it was not followed up years ago.

While the operation itself is relatively minor (the tissue is implanted in an incision in the arm), thymic tissue must be carefully prepared so that foreign T-cells, which would attack the host, are removed. A much earlier paper(2) noted that, "Fetal thymus is not innocuous. After 14 weeks in utero, sufficient mature T cells have formed in the thymus tissue to cause fatal graft vs. host disease." The Yale team cultured and grew the tissue for 14 to 16 days before transplantation (partly to test each potential transplant for viability) under conditions in which the T-cells would leave. The potential implants were tested in other ways also. Clearly good laboratory skills are required, and infection control is critical.

Also, the paper by Dwyer and others in some respects understates the results shown in the tables (a common problem which often is caused by conservative reviewers or editors, who cannot change the data but can change the interpretation). For example, we noticed that the T8 counts more than doubled in all eight cases of successful transplants; the text did not point this out. Readers who did not analyze the tables would not have found one of the most important results reported.

Another potential reason for lack of follow-up is that in this early research, the improvements were temporary. Only three of the 15 patients were alive 18 months after the transplantation (perhaps better than expected with very advanced AIDS in 1986). Of these three, the average total T- cell count, which increased 2.6 times after the transplant (mostly due to the T8 cell increase), then lost 30 percent of its after-transplant value over the next year (our calculation from the published data).

And the Federal policy on fetal tissue transplantation research also hurt. Fetal thymic tissue would be expected to work at least as well if not better than the tissue from children which was used. Even more important, as a result of the Federal policy the entire field has been largely neglected, as researchers sought less controversial areas to avoid the danger of their projects being blocked. Meanwhile, the procedure was too difficult for most physicians' offices or community clinics, and pharmaceutical companies were unlikely to be interested because the treatment was an operation transplanting human cells, not a conventional pharmaceutical product. And since there was no one in charge of the Federal effort against AIDS, no one had the mandate to recognize that an important opportunity was being lost, or the authority to get the problem addressed.

Now with a new Federal administration, the AIDS community should make sure that thymic transplantation receives attention again. It should work even better now than six years ago, since antivirals are available, and immunological knowledge has greatly improved.

Testing Drugs and Vaccines Faster: The SCID-hu Mouse

Ending the Federal bias against fetal-tissue research could also encourage faster testing of AIDS drugs and vaccines through wider use of mice with a transplanted immune system. These mice are born with severe combined immune deficiency (SCID); then they are given a human immune system by transplantation of human fetal thymus and liver tissue. Scientists eager to pursue SCID-hu studies are looking forward to an end to the Federal discouragement of fetal tissue research. Originally it had been hoped that the SCID-hu mouse would permit large-scale screening of potential AIDS drugs, by allowing testing against HIV in animals, instead of cells in a laboratory dish. For reasons which are unclear, little such screening has been done.

For those interested in technical background on the SCID-hu mouse, a review was published last year(3).

References

1. Dwyer JM, Wood CC, McNamara J, and Kinder B. Transplantation of thymic tissue into patients with AIDS: An attempt to reconstitute the immune system. Archives of Internal Medicine, March 1987; volume 147, pages 513-517.

2. R. Hong. Present and future status of thymus transplantation. Annals of Clinical Research, 1981; volume 13, pages 350-357.

3. McCune J, Kaneshima H, Krowka J. and others. The SCID-hu mouse: A small animal model for HIV infection and pathogenesis. Annual Review of Immunology, 1991; volume 9, pages 399-429.

Note: Nancy Solomon at AIDS TREATMENT NEWS contributed to the research for this article.

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