Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 104

T cells. Following specific recognition of target antigen on the veto cell, the
attacking cell is itself suppressed or eliminated [121,122] . The passively rec-
ognized veto cells need not have receptors specific for antigens expressed
by the cells they suppress. Veto cells of donor origin might help to sustain
engraftment by “vetoing” the activity of host cells capable of causing graft
rejection. Such a mechanism would be highly attractive for clinical devel-
opment, because donor T cells that do not recognize recipient alloantigens
could not cause GVHD.

Experiments with F1 donors and parental recipients were used as one
approach to test whether donor T cells could prevent rejection through veto
activity without recognizing recipient alloantigens [123] . A veto mechanism
would be expected to prevent rejection of MHC-class I- mismatched grafts
when parental recipient effectors recognize MHC-class I antigens expressed
by F1 donor T cells that do not recognize recipient alloantigens, since the
donor MHC-class I antigens that can cause rejection are also expressed by the
donor T cells. In a series of experiments [124] , rejection was observed in 2 of
15 recipients with grafts containing 5 × 10 6 donor T cells and in 9 of 15 recipi-
ents with grafts that did not contain T cells ( p = 0.029). A veto mechanism
would not be expected to prevent rejection of MHC-class II-mismatched
grafts, since the donor MHC-class II antigens that can cause rejection are
not expressed by the donor T cells. In keeping with this prediction, it was not
possible to identify conditions where 5.0 × 10 6 donor T cells had any repro-
ducible effect in preventing rejection of MHC-class II-mismatched marrow
in parental recipients, despite careful titration of the TBI exposure.

106

In experiments with MHC-class I-mismatched grafts, as many as 5 × 10 6
donor F1 T cells were not sufficient to prevent rejection in all parental recip-
ients under conditions where engraftment was observed in some recipients
even without F1 T cells added to the graft [124] . These results clearly dif-
fer from those in experiments with bidirectional MHC-class I mismatching,
where as few as 2.5 × 10 5 donor T cells were able to prevent rejection in all
recipients under conditions where rejection was uniformly observed in all
recipients without T cells added to the marrow graft [112] .These results and
those of other investigators indicate that mechanisms involving recogni-
tion of recipient alloantigens are at least 10-fold more potent for prevent-
ing rejection, compared to mechanisms not involving such recognition.
Mechanisms involving recognition of recipient alloantigens typically result
in full donor chimerism, since the donor T cells help to eliminate recipient
cells that survive the conditioning, whereas mechanisms not involving such
recognition result in mixed chimerism, because these donor T cells cannot
eliminate recipient cells that survive the conditioning regimen.

The respective ability of CD8 + and CD4 + T cells to mediate veto activity
has been explored in different studies. The veto phenomenon was origi-
nally described as a property of CD8 + T cells, but veto activity has also been
described as a property of CD4 + T cells and results in one study suggested
that donor CD8 + T cells and CD4 + T cells had equivalent ability to prevent
marrow graft rejection through veto activity [124] .

Type-2 polarized F1 CD8 T cells were more effective than type-1 polar-
ized CD8 T cells for preventing rejection of F1 marrow in sublethally irra-
diated parental recipients or in lethally irradiated recipients that were