Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 103

In a subsequent study, donor T cells were polarized by in vitro stimula-
tion in the presence of sirolimus, thereby decreasing their susceptibility
to apoptosis and improving their ability to survive after adoptive transfer
in vivo and prevent rejection in a P1 → P2 strain combination [117,118] .
Both type-2 polarized CD4 + cells and CD8 + cells suppressed type-1 polar-
ized responses by recipient cells that cause rejection [118] . Suppression of
type-1 anti-donor responses in the recipient did not require expression of
IL-4, IL-10, perforin or Fas ligand by the type-2 polarized donor cells and
was not attributable to T-regulatory function associated with Foxp3 expres-
sion. Suppression of recipient anti-donor responses was also not reversed
by exogenous administration of IL-2, IL-7 or IL-15.

Further experiments showed that type-2 donor CD4 + cells polarized in the
presence of sirolimus did not completely eliminate recipient T cells [119] .
With sufficient numbers of type-2 polarized donor CD4 cells added to the
graft, recipient T cells were polarized to type-2 cytokine production and
lost the ability to produce type-1 cytokines. Production of IL-4 by type-2
polarized donor CD4 cells and expression of STAT6 by recipient cells was
required for these effects and the consequent suppression of rejection by
recipient cells. None of the studies with polarized cells compared titrated
numbers of non-polarized cells and type-2 polarized cells in order to deter-
mine whether polarization favored the ability of donor cells to prevent
rejection as compared to their ability to cause GVHD in experiments where
donor cells could recognize recipient cells. For this reason, the benefit to be
gained by polarizing donor cells that recognize recipient alloantigens has
not yet been demonstrated.

105

One clinical trial attempted to build on the idea that beneficial donor T cells
that prevent rejection could be separated from harmful donor T cells that
cause GVHD [120] . In that study, CD4 + cells were depleted from the mar-
row, and the numbers of CD8 + cells were adjusted systematically in graded
steps for successive patients, depending on the occurrence of moderate or
severe GVHD in previously enrolled patients. In patients treated with con-
ventional regimens of high dose cyclophosphamide and TBI, removal of
CD4 + cells did not cause rejection or appreciably decrease the risk of GVHD
in patients who had a single HLA-class II or -class I mismatch. Based on the
trial design, however, it was concluded that the risk of moderate or severe
GVHD was likely to be higher than 15% at any dose of CD8 + cells associated
with less than 5% risk of graft failure. The absence of graft failure associated
with depletion of CD4 + cells supported the hypothesis that donor CD4 + cells
are not essential for preventing marrow graft rejection in humans, and the
correlation between the incidence of graft failure and the number of CD8 +
cells in the graft supported the hypothesis that donor CD8 + cells help to
prevent rejection in humans.

PASSIVE RECOGNITION (VETO CELLS)

Although cytotoxic donor CD8 + T cells can clearly prevent rejection after
recognizing alloantigens expressed by recipient effector cells, the possibil-
ity remained that other mechanisms such as veto inactivation of recipi-
ent T cells by donor T cells could also help to prevent rejection. Veto cells
represent effector cells that can be activated when recognized by other