Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 85

of the recipient contains antibodies that bind to donor leukocytes either by
flow cytometry assays or by microcytotoxicity assays with rabbit comple-
ment [47] . The presence of such antibodies is associated with an increased
risk of rejection but does not necessarily indicate that the antibodies cause
rejection, since transfusion or pregnancy-induced sensitization generates
both humoral and cellular adaptive immune responses.

Support for the role of cellular immune responses in causing rejection in
humans has come from observations that recipient-derived lymphocytes
isolated from the blood after rejection of T-cell-depleted HLA-mismatched
grafts had cytotoxic activity against donor cells [48] . Similar direct anti-
donor cytotoxic activity has generally not been detected in lymphocytes
from patients after rejection of T-cell-depleted grafts from HLA-identical
donors. In some cases, it was possible to show that recipient-derived CD8
cells had cytotoxic specificity for mismatched donor HLA-class I antigens,
and in other cases, it was possible to show that recipient-derived CD4 cells
had cytotoxic specificity for mismatched donor HLA-class II antigens, indi-
cating that the effectors were T cells. These results support the hypothesis
that cellular adaptive immune responses can cause rejection after HCT in
humans ( Figure 5.1 ).

87

B cells and role of sensitization

PRECLINICAL STUDIES

The potential of resistance to marrow cells by humoral responses has been
considered for more than 50 years [49,50] . B cells and antibody production
are not known to cause resistance to marrow allografts in unsensitized recip-
ients. In canine models where recipients were sensitized by transfusions,

FIGURE 5.1
Components of recipient immunity that contribute to resistance against hematopoietic stem cell allografts. In unsensitized recipients without prior exposure to
donor alloantigens, naïve T cells inhibit engraftment in MHC-matched recipients, whereas both naïve T cells and NK cells can inhibit engraftment in MHC-mismatched
recipients. In recipients sensitized by prior donor antigens, memory T cells inhibit engraftment in MHC-matched recipients. The role of antibody is uncertain and could
vary among different species. In sensitized MHC-mismatched recipients, memory T cells, NK cells and antibody can all contribute to resistance.