Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 93

DLA-non-identical unrelated donors when mycophenolate mofetil and
cyclosporin were used for post-transplant immunosuppression [87] . In the
initial clinical experience with this approach, 9 of 45 patients (20%) had graft
rejection after HCT with growth factor-mobilized blood cells from an HLA-
identical related donor. The risk of rejection was lower in patients who had
previously received myelosuppressive treatment. Addition of fludarabine at
a dose of 30 mg/m 2 /day for 3 days before the TBI exposure decreased the
risk of rejection to 3%.

Initial studies with HLA A, B serologically matched, DRB1-allele matched
unrelated donors confirmed that the risk of rejection was lower in patients
who had previously received myelosuppressive treatment and showed a
lower risk of rejection in patients who received growth factor-mobilized
blood cells instead of marrow cells [88] . In addition, a trend suggested that
donor mismatching for an HLA-class I allele in the absence of a serological
mismatch was associated with an increased risk of rejection.

It is now recognized that the agents used in the pretransplant conditioning
regimen vary in their immunosuppressive effects on recipient T cells and
myelosuppressive effects on recipient hematopoietic stem cells and pro-
genitors [88] . At the extremes, busulfan has potent myelosuppressive activ-
ity but far less immunosuppressive activity, whereas rabbit anti-thymocyte
globulin, alemtuzumab and fludarabine have potent immunosuppressive
activity and little or no myelosuppressive activity. Cyclophosphamide has
potent immunosuppressive activity and myelosuppressive effects on prolif-
erating progenitors but not on quiescent hematopoietic stem cells. TBI has
both immunosuppressive and myelosuppressive effects. In humans, the
ability of the conditioning regimen to prevent rejection is related primarily
to its efficacy in ablating recipient T cells that recognize donor alloantigens.

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Many of the myeloablative pre-transplant conditioning regimens used in
humans incorporate high-dose cyclophosphamide, an agent that over-
comes NK-mediated rejection after HCT in mice. As discussed below, the
use of HLA-heterozygous donors for patients who are HLA-homozygous at
the mismatched locus is associated with an increased risk of rejection, sug-
gesting the involvement of recipient T cells. An increased risk of graft failure
would be expected with the use of HLA-homozygous donors for patients
who are HLA-heterozygous at the mismatched HLA-class I locus if recipi-
ent NK cells cause rejection in humans. Rejection was not observed in any
of nine such patients who received high-dose cyclophosphamide as part of
the conditioning regimen [69] . Regimens of fludarabine and busulfan, and
regimens that employ low TBI exposures, however, would not be expected
to have major effects of NK cells in the recipient. As discussed above, the
possibility remains that recipient NK cells could account for rejection of
HLA-mismatched grafts in some cases [68] .

After demonstrating that fractionated TLI and antithymocyte serum could
be used to establish engraftment in mice [81] , the Stanford group showed
that a similar regimen could be used to establish engraftment after HLA-
matched related or unrelated HCT in humans [89] . All patients in this study
had initial engraftment with donor cells, but 6 of the 37 patients subse-
quently had late graft failure accompanied by autologous hematopoietic
reconstitution.