Address for correspondence: Yair Reisner, Weizmann Institute of Science, Department of Immunology, Rehovot, Israel. Voice: +972-8-9344023; fax: +972-8-9344145.
yair.reisner{at}weizmann.ac.il
Ann. N.Y. Acad. Sci. 996: 72-79 (2003).
Studies in mice and humans demonstrate that transplantation
of hematopoietic progenitors in numbers larger than commonly
used ("megadose" transplants) overcomes major genetic barriers.
In vitro studies suggest that veto cells, within the population
of hematopoietic progenitors, facilitate this favorable outcome.
Thus, when purified CD34
+ cells were added to bulk mixed-lymphocyte
reactions (MLRs) they suppressed CTLs against the donor's stimulators,
but not against stimulators from a third party. This tolerizing
activity depends on cell contact and can be blocked by the caspase
inhibitor BD-FMK, suggesting that the effector host T cells
are deleted by apoptosis upon interaction with the CD34
+ cells.
Early myeloid CD33
+ cells generated by short-term
ex vivo expansion
of CD34
+ cells also exhibit veto activity, and these cells can
be grown in large numbers. Tolerance induction can be further
enhanced by other veto cells. Perhaps the most potent veto cell
is the CD8+ CTL. However, this cell is also associated with
marked GVHD (graft-versus-host disease. GVHD can be separated
from the veto activity by generating anti-third party CTLs under
IL2 deprivation. Under such selective pressure only the stimulated
clones which make IL2 can survive, while anti-host clones die.
In vivo studies show that such anti-third party veto CTLs can
be used safely for tolerance induction without GVHD.
