And in the latest JCI, a nice article and commentary:
J Clin Invest, June 2000, Volume 105, Number 12, 1779-1789
Copyright ¸2000 by the American Society for Clinical Investigation
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Article
Mixed chimerism and tolerance without whole body irradiation in a large
animal model
Yasushi Fuchimoto1, Christene A. Huang1, Kazuhiko Yamada1, Akira Shimizu2,
Hiroshi Kitamura2, R.B. Colvin2, Vincent Ferrara1, Michael C. Murphy1, Megan
Sykes1, Mary White-Scharf3, David M. Neville, Jr.4 and David H. Sachs1
1 Transplantation Biology Research Center, and 2 Department of Pathology,
Massachusetts General Hospital/Harvard Medical School, Boston,
Massachusetts, USA 3 BioTransplant Inc., Boston, Massachusetts, USA 4
Laboratory of Molecular Biology, National Institute of Mental Health,
Bethesda, Maryland, USA
Address correspondence to: David H. Sachs, Transplantation Biology Research
Center, Massachusetts General Hospital, MGH-East, Building 149-9019, 13th
Street, Boston, Massachusetts 02129, USA. Phone: (617) 726-4065; Fax: (617)
726-4067; E-mail: sachs@helix.mgh.harvard.edu.
Received for publication October 18, 1999, and accepted in revised form
April 26, 2000.
Mixed hematopoietic chimerism may provide a treatment for patients with
nonmalignant hematologic diseases, and may tolerize patients to organ
allografts without requiring chronic immunosuppression. However, the
toxicity of the usual conditioning regimens has limited the clinical
applicability of this approach. These regimens generally include some level
of whole body irradiation (WBI), which is thought to facilitate engraftment
either by making room for donor hematopoietic stem cells or by providing
sufficient host immunosuppression to enable donor cells to engraft. Here, we
have established mixed chimerism across both minor and major
histocompatibility barriers in swine, by using high doses of peripheral
blood stem cells in the absence of WBI. After mixed chimerism was
established, swine leukocyte antigen?matched (SLA-matched) donor skin grafts
were tolerated and maintained for a prolonged period, whereas third-party
SLA-matched skin was rejected promptly. Donor-matched kidney allografts were
also accepted without additional immunosuppression. Because of its low
toxicity, this approach has potential for a wide range of clinical
applications. Our data may indicate that niches for engrafting stem cells
are filled by mass action and that WBI, which serves to empty some of these
niches, can be omitted if the donor inoculum is sufficiently large and if
adequate host T-cell depletion is achieved before transplant.
full text for free on web:
jci.org
Also some commentary:
The future of allogeneic hematopoietic stem cell transplantation: minimizing pain, maximizing gain
Marie-T‚rŠse Little and Rainer Storb
Here's their conclusion:
Thus, the era of "no pain, no gain" in HSCT may be coming to a close, as novel nonmyeloablative transplant strategies are being developed that offer successful engraftment with limited toxicity. The preclinical swine and canine studies have demonstrated the feasibility of relatively nontoxic approaches to HSCT, and these regimens have been translated successfully to human patients with malignant and nonmalignant diseases. Nevertheless, there is a need for more study in this area to fully understand how the immune system can be harnessed to promote graft survival, to prevent GVHD, and to maximize the graft-versus-tumor effect. The challenge in the future will be to develop clever strategies for allogeneic HSCT that obviate the need for even low-dose pregrafting irradiation.
Full commentary at:
jci.org
Peter |
