Biology Reference
In-Depth Information
Impact of MHC-matching on risk of rejection - from
mice to humans
Donor MHC incompatibility has a profound effect on the risk of graft rejec-
tion. The interpretation of results in murine models, however, is compli-
cated by the phenomenon of “hybrid resistance” mediated by recipient NK
cells as discussed above. For example, an early study evaluated engraftment
of C57BL/6 marrow in three different recipient strains. T-cell-depleted
grafts containing 1.6 × 10
5
marrow cells were successfully established in
most MHC-matched, minor antigen-mismatched A.BY recipients prepared
with 1100 cGy TBI
[89]
. This marrow cell dose was not sufficient to establish
engraftment in MHC-mismatched F1 recipients, even though the parental
donor marrow expressed no MHC antigens that could be recognized by T
cells in the recipient. Engraftment of parental marrow was established in
approximately 50% of the F1 recipients prepared with 1100 cGy TBI when the
marrow cell dose was increased four-fold to 6.3 × 10
6
cells, and engraftment
was observed in all recipients when the marrow cell dose was increased to
1.0 × 10
7
cells. In these recipients, rejection was mediated by recipient NK
cells. In MHC-mismatched A/J recipients prepared with 1100 cGy TBI, how-
ever, most recipients died with graft failure, even when the graft contained
1.0 × 10
7
marrow cells. In these recipients, rejection was mediated both by
recipient NK cells and by recipient T cells that recognized MHC alloantigens
of the donor.
96
These observations, together with results of other studies, highlight key dif-
ferences between rejection mediated respectively by NK cells and T cells
in mice. NK-mediated rejection can be overcome easily by increasing the
number of cells in the graft but not by increasing the TBI exposure, whereas
T cell-mediated rejection can be overcome easily by increasing the TBI
exposure but not by increasing the marrow cell dose.
The importance of donor MHC compatibility was also demonstrated in
canine models of HCT
[90]
. A TBI exposure of 9.0 Gy is sufficient to establish
engraftment of marrow from DLA-identical littermates but not from DLA-
non-identical littermates. TBI exposures exceeding 15.0 Gy were needed to
prevent rejection of marrow from DLA-non-identical donors. The recipient
cells responsible for resistance to engraftment of DLA-non-identical mar-
row were not sensitive to anti-thymocyte serum or cyclosporin. Resistance
to engraftment of DLA-non-identical marrow could be overcome, however,
by adding donor buffy coat cells or thymocytes to the graft.
HLA incompatibility has been a major factor associated with primary or
secondary graft failure in patients with aplastic anemia. In an early study,
6 of 11 aplastic patients prepared with various non-radiation immunosup-
pressive regimens did not engraft after transplantation of marrow from a
haploidentical family member mismatched for one or two HLA antigens.
Two other patients had initial engraftment with subsequent rejection. Five
of the six patients with failure of engraftment and one of the patients with
graft rejection had not been transfused before transplantation.
A significant, though less striking, increase in the risk of primary and sec-
ondary graft failure was observed in an early study of patients with leukemia
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