Biology Reference
In-Depth Information
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Cytokines in graft-versus-
host disease and graft-versus-
leukemia
Kate A Markey
Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, Queensland, Australia
Kelli P A MacDonald
Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, Queensland, Australia
Geoffrey R Hill
Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, Queensland, Australia,
Royal Brisbane and Women's Hospital, Queensland, Australia
357
Introduction
Cytokines play a key role in both the initiation of graft-versus-host disease and
the ongoing propagation of pathology. Cytokines are small proteins secreted
by cells that, by their binding to specific receptors on other cells (for paracrine
activity) or their own surface (for autocrine activity), induce changes in tran-
scription patterns, protein expression, and migratory behavior. It is concep-
tually important to note that cytokines play direct roles in inducing pathology
(e.g., tumor necrosis factor (TNF) inducing apoptosis in a cell expressing the
appropriate receptor) and indirect roles, because the cytokine milieu dictates
much regarding T-cell subset composition (e.g., Th1, Th2, Th17, regulatory T
cell (Treg)) and function. Knowledge regarding the role of cytokines in graft-
versus-host disease (GVHD) pathogenesis and the potential for utilizing this
knowledge for GVHD treatment has been gleaned at many levels:
•
preclinical models of disease, largely mouse, using donors or recipients
genetically deficient in either cytokine molecules and/or their receptors;
•
cytokine inhibition studies (often with monoclonal antibodies), per-
formed in animals;
•
cytokine and cytokine polymorphism studies (in both donor and recipi-
ent) by which gene expression has been correlated with disease outcome
in clinical cohorts;
•
small-scale cytokine/receptor blocking studies with accepted, FDA-
approved drugs (e.g., for IL-2 administration);
•
larger scale clinical trials (e.g., TNF blockade in steroid refractory GVHD).
Importantly, much of the data generated in mouse systems has been extensively
validated in the clinic: with genetic studies of cytokine and cytokine receptor
polymorphisms and their relationship with transplant outcome, measurement
of cytokine levels in patients with GVHD, and ultimately, the development of
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