Biology Reference
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stem cell pool and the transplanted donor hematopoietic stem cell (HSC)
[16,17]
. “Making space” while minimizing or sparing damage to the local
niche microenvironment and distal sites could facilitate more rapid hema-
tolymphoid reconstitution after HCT.
If antibody strategies also reduce inflammatory cytokine and chemokine
signals as compared to chemotherapy or radiotherapy, another benefit may
be to reduce the intensity of recipient immune responses against the graft.
The loss of detectable peripheral hematopoietic chimerism can occur grad-
ually over time
[18]
. Methods for assessment of residual HSC within mar-
row niches have not yet been developed, and it is not known whether the
effector mechanisms mediating rapid rejection of progenitor cell allografts
in peripheral sites are as efficient against progenitor cells within marrow
niches. A recent investigation showed that Tregs are associated with marrow
niches and that transplanted stem cells in the niches were lost after removal
of the Tregs. These results suggest that Tregs protect HSC from immune-
mediated damage, thereby making the niche an immune privileged site
[19]
.
Effector mechanisms of graft rejection
T cells and role of sensitization
85
PRECLINICAL STUDIES
Resistance to bone marrow allografts is mediated by recipient cell popu-
lations that survive and function after the conditioning regimen. Immune
resistance against engraftment has been studied in pre-clinical models, pri-
marily in rodents and dogs across MHC-mismatched and MHC-matched
allogeneic donor and recipient strain combinations in the absence of prior
sensitization against donor antigens. Results have demonstrated that resis-
tance can be mediated by various T-cell and NK-cell populations in the
recipient, depending primarily on the genetic disparity between the donor
and recipient and the pre-transplant conditioning regimen
[20-27]
. Experi-
ments with sublethal irradiation and MHC class I or II mismatched recipi-
ent strains demonstrated that in unsensitized recipients, CD8 and CD4
T cells surviving the conditioning regimen respectively mediated graft rejec-
tion across these differences. These same recipient populations rejected
grafts from MHC-matched donors with genetic disparities for minor histo-
compatibility antigens (MiHA)
[25,28]
.
Pre-clinical and clinical studies identified anti-donor-specific CTL obtained
after rejection. Cells obtained from recipients after rejection caused rejec-
tion after adoptive transfer into naïve secondary recipients
[29,30]
. Subse-
quent studies employed mutant and cytotoxic deficient knock-out strains to
assess the contribution of perforin, FasL and other lytic pathways in resis-
tance to hematopoietic engraftment
[31-38]
. Surprisingly, the absence of
perforin and FasL-Fas individually, and in some cases combined together,
did not prevent resistance by T and NK effectors after lethal total body irra-
diation (TBI) conditioning in MHC-mismatched recipients
[31,36,37]
. The
inability to identify individual cytolytic or cytokine pathways responsible
for resistance in these models suggests that many individual effector mech-
anisms can cause rejection.
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