Biology Reference
In-Depth Information
hemorrhage or erythrophagocytosis. Occasionally, silent graft rejection
occurs and is detected only by examining genetic markers of donor or recip-
ient origin. Disappearance of donor cells accompanied by persistence of
recipient T cells is usually taken as the hallmark of immune-mediated graft
rejection.
This chapter will summarize the effector mechanisms of graft rejection,
which include adaptive immune responses mediated by T cells and B cells,
as well as innate immune responses mediated by natural killer (NK) cells.
Further sections will address the effects of the pretransplant condition-
ing regimen on effector mechanisms that mediate rejection, the impact of
MHC-mismatching, the role of various donor cell populations in the graft,
and the effects of post-transplant immunosuppression.
Hematopoietic space and microenvironment
Although stem cell transplants from related and non-related donors can elicit
immune-based resistance, the success of engraftment requires that donor
stem cells reach and gain entrance to microenvironmental sites that enable
signaling to drive differentiation and development. Access to “niche space”
and traction within is currently thought to be controlled by interactions that
involve cell-cell, cell-extracellular matrix as well as receptor-ligand engage-
ments
[1-4]
. Pre-clinical studies have demonstrated that although it is pos-
sible to engraft syngeneic cells using “mega-dose” infusions, overall levels
of chimerism are modest in recipients that have not been treated to reduce
the number of endogenous hematopoietic stem cells
[5-9]
. These results
parallel clinical observations from severe combined immunodeficiency
(SCID) patients, where poor engraftment is observed despite weak resis-
tance without conditioning
[10]
. In the absence of pretransplant condition-
ing, hematopoietic niches are occupied by endogenous stem cells. In this
situation, donor engraftment is prevented, since grafted cells cannot gain
access to occupied niches. Estimates from BrdU labeling studies show that
approximately 1-5% of stem and progenitor cells circulate under homeo-
static conditions, as initially suggested in the 1960s and 1970s
[11-13]
. In
unconditioned recipients, multiple infusions of highly purified hematopoi-
etic stem cells yielded higher levels of engraftment than a single infusion
totaling the same number of cells, an observation best explained by low lev-
els of niche space replacement under homeostatic conditions. These obser-
vations are consistent with results showing limited engraftment following
single megadoses of marrow cells in unconditioned recipients
[13,14]
.
84
In theory, pretransplant chemotherapy regimens can not only decrease
the number of endogenous hematopoietic stem cells but can also damage
hematopoietic niches within the marrow microenvironment (discussed
in Chapter 8). As an alternative, several pre-clinical studies have reported
some success in “antibody-mediated” conditioning, a concept considered
some years ago after it was shown that infusion of anti-MHC anti-serum
diminished the number of endogenous progenitor levels before transplant
[15]
. Studies employing antibody directed to growth factor receptors such
as mpl and c-kit provide a less globally damaging strategy compared to che-
motherapy or radiotherapy to reduce competition between the endogenous
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