Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 84

Pre-clinical studies have examined resistance in recipients pre-sensitized
to donor alloantigens as a model reflecting sensitization caused by trans-
fusions or pregnancy in humans [39] . Resistance induced by sensitization
to donor MHC or MiHA antigens correlated with cell-mediated responses
[21,40] . Isolation of CD8 + CD4 - NK1.1 − T cells from MHC-matched MiHA-
mismatched mice primed to donor antigens mediated resistance after
adoptive transfer into lethally irradiated naïve recipients [41] . Resistance
was not diminished when sensitized CD8 T cells lacking perforin and Fas
dependent cytotoxic capacity were tested in adoptive transfer experiments
or when transfer of these CD8 T cells was combined with the use of TNFR1
deficient donor marrow and antibody against TL1a [41] . Therefore, fol-
lowing sensitization to donor antigens, responses against MiHA disparate
donor cells were mediated by effector cells lacking several major cytolytic
pathways, failing as observed in non-sensitized responses, to identify indi-
vidual effector mechanisms responsible for resistance.

Depletion of recipient CD8 T cells before HCT abolished resistance induced
by sensitization to donor MiHA [42] . The specificity of sensitization was
demonstrated in experiments with congenic strain combinations where
B6 (H2 b ) recipients were primed against MHC-matched BALB.B MiHA and
then challenged with grafts from BALB.B donors or from MHC-mismatched
BALB/c (H2 d ) donors that could not present the BALB-related MiHA in the
correct H2 b context required for recognition by presensitized recipient cells
[42] . BALB.B allografts were rejected, but BALB/c allografts were not [42] .

86

CLINICAL STUDIES

By the mid-1970s, marrow transplantation was established as the therapy of
choice for aplastic anemia in patients under the age of 40 who had an HLA-
identical donor. Before 1975, marrow graft rejection occurred in 30-60% of
patients prepared with the standard cyclophosphamide regimen. Reactivity
of recipient cells after stimulation with donor cells in mixed lymphocyte
culture (MLC) was one of the factors that strongly correlated with the risk
of graft rejection [43,44] . Low-level, but significant, MLC reactivity between
HLA-identical siblings was attributed to transfusion-induced allosensitiza-
tion against minor histocompatibility antigens.

Studies in experimental animals suggested that random blood transfusions
increased the risk of graft rejection after marrow transplantation from an
HLA-identical sibling. Subsequent clinical studies confirmed the predic-
tion that transplantation before blood transfusion would reduce the risk of
graft rejection [45,46] . In the Seattle experience, only 4 of 50 untransfused
aplastic patients rejected marrow from an HLA-identical sibling after con-
ditioning with the standard cyclophosphamide regimen [46] . These results
clearly implicate adaptive immune mechanisms as a cause of graft rejection
in patients with aplastic anemia.

Transfusion-induced sensitization has not been associated with an
increased risk of rejection after HLA-matched HCT in patients with other
diseases. Transfusion- or pregnancy-induced sensitization, however, has
been associated with an increased risk of rejection after HCT with HLA-
mismatched donors. In these cases, sensitization of the recipient against
donor HLA alloantigens has been demonstrated by showing that the serum