Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 95

who received HLA-incompatible marrow after conditioning with cyclophos-
phamide and TBI [91] . Five of 105 patients receiving marrow from a donor
other than an HLA-identical sibling had frank graft rejection, whereas only
1 of 728 leukemic patients receiving marrow from an HLA-identical sibling
had graft rejection documented by return of host cells.

The risk of rejection increases proportionately with the degree of HLA
incompatibility. In a study where serological methods were used to assess
HLA-A and B antigens and cellular proliferation assays were used to assess
HLA-D mismatching, graft failure occurred in 3 of 43 patients (7%) with
HLA-haploidentical donors who had no HLA-A, B or D-mismatched anti-
gens [47] . Graft failure occurred in 11 of 121 cases (9%) with donors who had
a single HLA mismatch, in 18 of 86 cases (21%) with donors who had 2 HLA
mismatches, and in 1 of 19 cases (5%) with donors who had 3 mismatches.

Further insight came from subsequent studies that used molecular meth-
ods to identify distinct alleles within each antigen defined by serological
methods [69] . Only 2 of 280 patients (0.7%) with chronic myeloid leuke-
mia had graft failure after HCT with HLA-A, B and C allele-matched unre-
lated donors. Graft failure was observed in only 1 of 49 patients (2%)
who had donors with a single HLA-A, B or C allele mismatch and in 11 of
56 patients (20%) of those who had donors with a single HLA-A, B or C anti-
gen mismatch.

97

Further analysis examined results with HLA-mismatched donors accord-
ing to whether the recipients were HLA-heterozygous or homozygous at
the mismatched locus [69] . Heterozygous recipients have bidirectional
mismatching that allows an HLA-specific response of the donor against
the recipient as well as an HLA-specific response of the recipient against
the donor, whereas homozygous recipients have unidirectional mismatch-
ing that allows an HLA-specific response of the recipient against the donor
without a counterbalancing HLA-specific response of the donor against the
recipient. Among cases with a single mismatched HLA-A, B or C antigen,
graft failure was observed in 7 of 51 heterozygous recipients (14%) and in 4
of 5 homozygous recipients (80%). As in the earlier study, the risk of rejec-
tion was increased when the donor had multiple HLA mismatches. Graft
failure occurred in 2 of 9 HLA-heterozygous recipients (22%) with donors
who had more than one HLA-A, B or C allele mismatch and in 11 of 67 (16%)
of those with donors who had more than one allele and antigen mismatch.

Although the use of HLA-mismatched donors is associated with an increased
risk of graft rejection, crossmatch testing and combinations of intensive
pre-transplant conditioning regimens (discussed above), high donor cell
doses (discussed below) and intensive post-transplant immunosuppressive
regimens (discussed below) can prevent rejection in most recipients.

Impact of donor cells on risk of rejection - from mice
to humans

The cellular composition of the graft profoundly affects the risk of rejection.
In addition to the hematopoietic stem cells that are necessary for restor-
ing hematopoietic function, the cell populations used for transplantation