Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 87

differences appear to be present as, in contrast to mice, results from many
studies examining sensitized MHC-mismatched canine recipients provide
little evidence for a major role of antibody in rejection. Some variation in
conditioning, the priming process (transfusions in dogs) and timing may
underlie the differences to date. In sensitized MHC-mismatched recipients,
humoral mechanisms appear to have a less critical role in causing rejec-
tion in canine models and in humans as compared to murine models. In
sensitized MHC-matched recipients, cellular mechanisms account for
rejection in all species. Mice previously sensitized against a single mouse
MiHA (i.e. H60) using peptide pulsed syngeneic dendritic cells is sufficient
to elicit graft rejection against donor marrow expressing the MiHA [59] . In
summary, both cellular and humoral responses can be involved in rejection
elicited by MHC mismatching following sensitization against donor anti-
gens; however only cellular responses can contribute to rejection elicited by
MiHA mismatching in the absence of a concomitant MHC disparity.

CLINICAL STUDIES

Transfusions and pregnancy can induce humoral responses in addition to
cellular adaptive immune responses against alloantigens in humans. Early
studies of HCT for treatment of aplastic anemia showed an increased risk
of rejection when recipients had antibodies against HLA-identical donor
cells [60] . Subsequent studies of HCT for treatment of malignant diseases
showed an increased risk of graft failure when recipients had antibodies
against HLA-mismatched donor cells as detected in a crossmatch test with
recipient serum and donor T or B cells. In one study, 7 of 18 patients (39%)
with a positive crossmatch had graft failure, compared to 26 of 251 patients
(10%) with a negative crossmatch [47] . The presence of antibodies against
alloantigens other than those expressed by donor cells was not associated
with an increased risk of graft failure. Graft failure was not observed in any
of 13 patients with “panel-reactive” antibodies against cells from 50% of
random persons but not the donor, whereas 6 of 8 patients with such panel-
reactive antibodies and a positive crossmatch against the donor had graft
failure.

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In testing recipients for the presence of alloantibodies, assays with live cells
from panels of random persons have been replaced by solid-state meth-
ods that can identify antibodies against specific HLA antigens. Results with
these newer methods can then be used as a “virtual crossmatch” test against
a potential donor with a known HLA-mismatch. In a case-control study, 9
of 37 patients (24%) with graft failure had an antibody against donor cells
detected by this method, compared to only 1 of 78 patients (1%) without
graft failure [61] . The newer “virtual” methods have been especially helpful
in selecting cord blood donors, where donor cells are not available for direct
crossmatch testing [62] .

The results of Taylor et al. [55] suggest that rejection manifested as late graft
failure cannot be attributed to humoral mechanisms. Whether antibodies
against donor cells actually cause early graft rejection after HCT in humans
cannot be determined with certainty, because pregnancy or transfusion-
induced adaptive humoral immune responses against donor alloantigens
are likely to be accompanied by adaptive cellular immune responses,