Page 1865 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 108 Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses 1657

sirolimus is being used clinically to prevent and treat GVHD. clinical data from an early phase trial suggests that this may be a viable
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Several additional signaling pathways that regulate alloreactive T-cell clinical strategy. In addition to chemokines and their receptors,
responses have recently been identified, such as Notch, protein expression of selectins and integrins and their ligands also regulate
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kinase C (PKC) θ, spleen tyrosine kinase (syk), Janus-activated the migration of inflammatory cells to target organs. For example,
kinase (JAK)2, signal transducer and activator of transcription interaction between α4β7 integrin and its ligand MadCAM-1 are
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(STAT)3 and nuclear factor kappa-B (NFκB). Emerging data are important for homing of donor T cells to Peyer patches and in the
further defining a role for regulation T-cell proliferation/apoptosis initiation of intestinal GVHD. 86,229 αLβ2/intercellular adhesion
epigenetic regulation through posttranslational modification by molecule 1(ICAM1), ICAM2, ICAM3, and α4β1/vascular cell adhe-
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ubiquitination 200,201 or acetylation, or by microRNAs (miRNAs). sion molecule (VCAM)2 interactions are important for homing to
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Specifically miRNAs such as miRNA 412 and miRNA 155 modu- the lung and liver after experimental HCT. The expression of
late alloimmunity by regulation of T-cell cycling and thus mitigate CD62L on donor Tregs is critical for their regulation of acute GVHD,
GVHD. 203,204 suggesting that their migration in secondary tissues is critical for their
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regulatory effects. The migratory requirement of donor T cells to
specific lymph nodes (e.g., Peyer patches) for the induction of GVHD
Cytokines and T-Cell Differentiation might depend on other factors such as the conditioning regimen,
inflammatory milieu, etc. 86,230 Furthermore, FTY720, a pharmaco-
Classically the Th1 cytokines (IFN-γ, IL-2), TNF-α and IL-6 have logic sphingosine-1-phosphate receptor agonist, inhibited GVHD in
been implicated in the cytokine storm that occurs early after BMT murine but not in canine models of HCT. 231,232 Thus significant
and have been shown to be critical for the pathophysiology of acute species differences may also factor in the ability of these molecules to
GVHD. 83,205–208 In addition to IL-2, several other common γ-chain regulate GVHD.
cytokines (IL-21, IL-7, and IL-15) have been shown to play critical
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and potentially nonredundant roles in GVHD pathogenesis. Type
1 or Tc1/Th1 maturation is recognized as the dominant pattern in Phase 3: Effector Phase
acute GVHD. 210,211 Increased quantities of Th1-associated cytokines,
TNF and IFN-γ, in acute GVHD are associated with earlier onset The effector phase that leads to the GVHD target organ damage is
and more severe disease in preclinical models and clinical BMT. a complex cascade of multiple cellular and inflammatory effectors
Although the dominance of Th1 subsets is well established, Th2 and that further modulate each other’s responses either simultaneously or
Th17 subsets are also involved in pathology, and the balance between successively. Effector mechanisms of acute GVHD can be grouped
subsets determines acute GVHD severity, in addition to organ speci- into cellular and inflammatory effectors. Inflammatory chemokines
ficity, and the pathogenic or protective effects of any subset cannot expressed in inflamed tissues upon stimulation by proinflammatory
be viewed in isolation. 212,213 Specifically, Th2 differentiation is often effectors, such as cytokines, are specialized for the recruitment of
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seen as opposing Th1 differentiation; however, this subset is also effector cells, such as cytotoxic T lymphocytes (CTLs). Further-
recognized as causing acute GVHD but with predominant pathology more, the spatiotemporal expression of the cytochemokine gradients
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in pulmonary, hepatic, and cutaneous tissues, in contrast to the might determine not only the severity but also the unusual cluster of
strong GI association with Th1. Cutaneous pathology also may be GVHD target organs (skin, gut, and liver). 220,234
generated by Th17 cells; although they are more commonly associ-
ated with chronic GVHD, they also have been associated with acute
pathology. 215,216 Recent data have shown that blockade of L-33 Cellular Effectors
binding with the Th2 ST2 receptor during allogeneic-hematopoietic
cell transplantation by exogenous ST2-Fc infusions had a marked CTLs are the major cellular effectors of GVHD. 235,236 The principle
reduction in GVHD lethality, indicating a role for ST2 as a decoy CTL effector pathways that have been evaluated after allogeneic
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receptor modulating GVHD. Th17 differentiation is initiated by BMT are the Fas-Fas ligand (FasL), the perforin-granzyme (or granule
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IL-6, and RORγt is the defining transcription factor, whereas exocytosis), and the TNFR-like death receptors (DR), such as TNF-
maintenance and amplification relies on IL-23 and IL-21, respec- related apoptosis-inducing ligand (TRAIL: DR4, 5 ligand) and
tively. The use of RORC-deficient donor T cells results in attenuated TNF-like weak inducers of apoptosis (TWEAK: DR3 ligand). 236–241
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acute GVHD severity and lethality. Further studies are needed to The involvement of each of these molecules in GVHD has been
better define the role of this subset in late acute GVHD versus early tested by using donor cells that are unable to mediate each pathway.
chronic GVHD, as well as the relative contribution of IL-17 from Perforin is stored in cytotoxic granules of CTLs and NK cells,
CD4 and CD8 T cells to end-organ pathology. together with granzymes and other proteins. Although the exact
mechanisms remain unclear, following the recognition of a target cell
through the TCR-MHC interaction, perforin is secreted and inserted
Leukocyte Migration into the cell-membrane, forming “perforin pores” that allow gran-
zymes to enter the target cells and induce apoptosis through various
Donor T cells migrate to lymphoid tissues, recognize alloantigens on downstream effector pathways such as caspases. 242
either host or donor APCs, and become activated. They then exit the Transplantation of perforin-deficient T cells results in a marked
lymphoid tissues and traffic to the target organs and cause tissue delay in the onset of GVHD in transplants across MiHA disparities
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damage. The molecular interactions necessary for T-cell migration only, both MHC and MiHA disparities, and across isolated MHC I
and the role of lymphoid organs during acute GVHD have recently or II disparities. 236,243–247 However, mortality and clinical and histo-
become the focus of a growing body of research. Chemokines play a logic signs of GVHD were still induced even in the absence of
critical role in the migration of immune cells to secondary lymphoid perforin-dependent killing in these studies, demonstrating that the
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organs and target tissues. T-lymphocyte production of macrophage perforin-granzyme pathway plays little role in target organ damage.
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inflammatory protein-1-alpha is critical to the recruitment of CD8 A role for the perforin-granzyme pathway for GVHD induction is
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but not CD4 T cells to the liver, lung, and spleen during acute also evident in studies using donor T-cell subsets. Perforin-deficient
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GVHD. Several chemokines such as CCL2-5, CXC-chemokine or granzyme B-deficient CD8 T cells caused less mortality than
ligand (CXCL)2, CXCL9-11, CCL17, and CCL27 are overexpressed wild-type T cells in experimental transplants across a single MHC
and might play a critical role in the migration of leukocyte subsets class I mismatch. This pathway, however, seems to be less important
to target organs liver, spleen, skin, and lungs during acute GVHD. 220,223 compared with the Fas/FasL pathway in CD4-mediated GVHD. 246–248
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CXC-chemokine receptor (CXCR)3 T and CCR5 T cells cause Thus it seems that CD4 CTLs preferentially use the Fas-FasL
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acute GVHD in the liver and intestine. 220,224–226 CCR5 expression has pathway, whereas CD8 CTLs primarily use the perforin-granzyme
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also been found to be critical for Treg migration in GVHD. Recent pathway.