Biology Reference
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In these scenarios, the kinetics and pathology of tissue injury along with the
expression of chemokines and their specific contribution to GVHD induc-
tion may be significantly altered.
Antigenic disparity between donor and host
The extent to which inbred mice used for HCT experiments are genetically
“matched” or “mismatched” is another important variable that affects the
speed and severity of GVHD development. The degree of genetic disparity
between donor and host can range from being fully allogeneic (complete
MHC mismatch), to isolated differences at MHC class I or class II only, to
strain combinations that are MHC matched but differ at multiple minor
antigens—a scenario that perhaps most closely reflects the situation that
exists in a matched unrelated donor HCT in the clinical setting. In addition,
other models utilize a haploidentical “parent into F1” system (P → F1) that
is unidirectional with regard to T-cell recognition.
Other parameters
Other variables in GVHD models can include the amount and purity of
donor T cells administered; the presence of subclinical, unrecognized infec-
tions in the mouse colony (i.e., helicobacter, parvovirus); and the presence
of tumors when graft-versus-tumor (GVT) effects are evaluated in the con-
text of GVHD. Ultimately, all of these variables need to be considered when
attempting to reconcile the literature on chemokines and GVHD; a specific
chemokine may have one effect in a lethal TBI model of GVHD and the
opposite effect in a model using no conditioning.
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Chemokines and the development of acute GVHD
GVHD pathophysiology
The pathophysiology of GVHD is complex and involves aspects of the adap-
tive and the innate immune responses (reviewed in [1] ). GVHD can occur
in acute or chronic forms that differ in their kinetics, tissue pathology, and
underlying immune mechanisms. GVHD target organs are vulnerable to
injury from both soluble and cellular effectors. The gastrointestinal (GI) tract
is particularly critical to the propagation of early inflammatory events that
are the hallmark of acute GVHD, and it is also the target of an immunologic
feedback loop involving synergistic interactions between cells of lymphoid and
myeloid lineages [7] . Infiltrating alloreactive lymphocytes not only contribute
to mucosal damage, which facilitates the translocation of microbial produc-
tions such as lipopolysaccharide (LPS) into the systemic circulation, but also
produce IFN-γ, which greatly enhances the sensitivity of mononuclear cells
to LPS stimulation [7] . When triggered by LPS, “IFN-γ-primed” mononuclear
cells release cytopathic amounts of TNF-α and other cytokines that exacerbate
intestinal injury and mucosal permeability [8] . The resulting proinflammatory
environment directly enhances chemokine expression in target organs [9] and
contributes to the recruitment of donor-derived T cells, monocytes/macro-
phages, and neutrophils to sites of inflammation ( Figure 17.1 ).
The development of GVHD is believed to occur in discrete stages [1] . In this
context, the contribution of chemokines to the evolution of this disease can
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