Future directions

Despite the importance of allogeneic bone marrow transplantation in humans, its use presently remains restricted to the treatment of fatal disorders such as cancer, SCID and aplastic anemia. A wider use of this curative approach is limited by the occurrence of GVHD if T cell purging is not used, and by the graft rejection associated with T cell depletion.

However, two major approaches to overcome these barriers, namely the use of B7-CD28 blockade or the use of megadose T cell-depleted transplants, which have been proven successful in sublethally irradiated mice, lend the hope that the use of allogeneic hematopoietic stem cells will become safer in the near future, thereby expanding its use to the treatment of genetic disorders other than SCID, which are less acute but which can, nevertheless, be lethal over the course of years.

In addition, it is hoped that by the same approach, using nonlethal preparative regimens, induction of specific immunological tolerance towards donor-type antigens, as a prelude for transplantation of solid organs from the same donor, will also become possible.

Meanwhile, an alternative approach has captured the interest and imagination of both scientists and the public at large. Experiments in mice have shown that it is possible to insert a particular gene into the hematopoietic stem cell pool by means of retroviral vectors. It is hypothesized that a diseased bone marrow could be corrected in vitro by such 'gene therapy', and then reinfused successfully into the patient. By employing such an approach, the problems of GVHD or graft rejection could be entirely avoided. However, due to the low frequency of pluripotent stem cells in the marrow preparations, and the difficulty in stimulating self renewal of such cells in vitro, this new approach is still in the embryonic stages of development. If successful, we may have to define a new chimerism status in which transplanted cells differ from the host cells by a verv minute piece of DNA.

An alternative approach to achieving hematologic chimerism involves replacing the bone marrow or peripheral blood stem cells with cord blood hematopoietic stem cells. In 1990, Gluckman and colleagues demonstrated for the first time that cord blood can correct Fanconi anemia in a matched sibling. Both the HLA and the disease-free status of the embryo were established by prenatal testing, and transplantation could be planned for before birth. Thus, the potential number of matched sibling donors in the family could be increased. Moreover, if large numbers of cord blood preparations could be collected and cryopreserved, it could potentially increase the availability of matched unrelated donors. While this possibility is gaining increasing enthusiasm worldwide, it is still hampered by a marked incidence of engraftment failure, associated with the limited number of hematopoietic stem cells which can be collected in cord blood. Clearly, the potential of this approach could be greatly enhanced if it were possible to expand the pluripotential stem cells ex vivo. Results in animal models regarding the self renewal capacity of expanded stem cell populations are encouraging but still controversial.

Finally, studies in animals have clearly demonstrated that hematopoietic chimerism can be achieved before birth by in utero transplantation of allogeneic stem cells. The success of this approach is based on the relative ease by which tolerance can be induced in the embryonic state, compared with in adults. In the future, it is hoped genetic diseases may be corrected in utero, thus eliminating the need for intensive conditioning protocols required for transplantation in adult recipients.

See also: Alloantigens; Bone marrow and hematopo-iesis; Hematopoietic stem cell transplantation; Cell separation techniques; Graft-versus-host reaction; Immunodeficiency, primary; Radiation, effects on immune system; Tissue typing; Transplantation.

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