Chemokines and graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 389

to how the function of these molecules may be exploited to provide maxi-
mal therapeutic benefit after HCT. Finally, we highlight recent studies that
have explored the role of chemokines in the context of clinical GVHD.

The study of GVHD: a changing paradigm

To interrogate the role of a particular cytokine or chemokine in the develop-
ment of GVHD in the laboratory, the experimental model employed must be
biologically relevant and accurately reflect clinical disease. In recent years,
the clinical spectrum of GVHD has been modified by the use of reduced
intensity conditioning regimens and the administration of alternate stem
cell sources and donor leukocyte infusions. Furthermore, the development
of animal models that employ a variety of endpoints to study the pathogen-
esis of GVHD has made the evaluation and comparison of data from dif-
ferent laboratories challenging. Although GVHD is still initiated primarily
by the interaction between donor T cells and host APCs in each scenario,
modification of several additional parameters can significantly influence
the contribution of a particular cytokine or chemokine to the evolution of
acute and/or chronic GVHD. In this context, several key factors must be
considered when interpreting data produced from the various in vivo mod-
els used to study this process [2] .

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Conditioning intensity

The intensity of conditioning delivered prior to HCT is one of the most impor-
tant variables to consider. The majority of animal models use some degree
of total body irradiation (TBI), which serves at least two important func-
tions: TBI reduces (or ablates) host hematopoiesis and immunosuppresses
the recipient to facilitate the engraftment of donor cells. Administration
of “lethal” conditioning results in death from hematopoietic failure if the
recipient is not rescued by a donor stem cell infusion, whereas host hema-
topoiesis recovers (and may in fact be a target of the GVH response) when
“sublethal” conditioning is applied. Several studies have clarified, however,
that intense conditioning also results in the release of several inflammatory
cytokines, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ),
interleukin-1 (IL-1), and IL-6, emanating from diffuse, nonspecific dam-
age that occurs to host tissues. In fact, alteration of TBI intensity directly
correlates with the extent of intestinal injury, the degree of macrophage
priming, and the severity of systemic GVHD that occurs after allogeneic
HCT [3] . Subsequent inflammatory cytokine release and tissue destruction
result in GVHD pathology similar in kinetics and scope to that seen after
conventional conditioning delivered before clinical HCT. Cytokines such as
TNF-α directly upregulate chemokine expression [4,5] and therefore repre-
sent a link between the inflammatory signals induced by conditioning and
enhanced chemokine expression observed after allogeneic HCT. Similarly,
cytokines produced by effector cells infiltrating a specific target tissue can
regulate the local chemokine milieu [6] , further emphasizing the impor-
tance of systemic and local cytokine-chemokine cross talk in GVHD induc-
tion. By contrast, some murine GVHD models use sublethal conditioning
regimens or no conditioning whatsoever. These models tend to include the
transfer of large numbers of purified or unfractionated donor lymphocytes.