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anti-donor cytotoxic antibodies were detected in 34 of 38 animals, but
only 17 rejected the marrow grafts from a DLA-mismatched donor, and 21
engrafted
[50]
. Additional studies using randomly bred DLA-mismatched
donors and recipients showed that despite the presence of anti-donor
antibodies, treatment with T-cell-depleting agents facilitated engraftment,
and the presence of lymphocytotoxic antibodies did not necessarily pre-
dict rejection
[40,51]
. These results suggested that humoral immunity does
not play a major role in resistance to either DLA-mismatched or -matched
grafts
[52,53]
.
On the other hand, several recent reports have shown that preformed anti-
body was responsible for rejection in mice after intentional sensitization to
donor antigens before lethal TBI and marrow transplantation. Priming of
MHC-mismatched recipients with donor spleen cells or skin grafts resulted
in production of anti-donor antibody that mediated rapid rejection within 3
hours after transplantation with even large numbers of MHC-mismatched
marrow cells
[54,55]
. T cells were shown to mediate rejection in B-cell-defi-
cient recipients sensitized to donor antigen, but resistance could be detected
only against much lower marrow cell doses versus the numbers which
could be rejected by preformed antibody
[54,55]
. The kinetic differences
between the antibody (within hours) and cell-mediated (~1 week) rejection
responses supports the notion that when sensitization has occurred in both
compartments, the T-cell contribution is of lesser importance.
88
A role for recipient B cells without involving antibody production was
recently proposed in the resistance against second bone marrow MHC-
mismatched allografts
[56]
. Recipients of these second grafts had been
previously exposed to donor antigens after donor marrow transplantation
with the use of costimulatory molecule blockade to induce long-term chi-
merism. Despite low levels of alloantibody after secondary transplants, T
memory cells were found to be responsible for rejection of these second
donor marrow transplants. Although the investigators could not identify
anti-donor antibody as the mediator of rejection, studies in animals lacking
B cells found significant reduction in the effector T memory population and
the strength of resistance in these recipients
[56]
.
Can preformed antibody against MiHA donor antigens contribute to mar-
row allograft rejection? A recent study proposed a correlation between the
presence of antibody generated between one MHC-matched (H2
k
) strain
combination (AKR anti-C3H) after priming and marrow graft rejection fol-
lowing lethal conditioning
[57]
. Antibody generated across MHC + non-
MHC disparity but not generated across MHC disparity alone was found
to induce rejection of third party marrow grafts following pre-incubation of
the donor cells with these sera. In contrast, in the absence of a simultane-
ous MHC disparity, depletion of CD8 T cells abolished resistance in an H2
b
-
matched MiHA disparate recipient sensitized with donor spleen cells
[42]
.
Other reports found rejection of BALB.B but not BALB/c grafts following
sensitization of MHC-matched MiHA-mismatched B6 recipients against
BALB.B donor cells, which can only be explained by T-cell recognition of
MiHA presented by H2
b
, but not by H2
d
cells in the marrow allografts
[58]
.
The findings to date with respect to resistance against MHC-mismatched
versus MHC-matched marrow allografts are therefore intriguing. Species
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