Page 1863 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 108 Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses 1655

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(mLNs). Critically, alloantigen presentation in the mLNs imprints Phase 2: Donor T-Cell Activation, Differentiation,
gut-homing integrin signatures on donor T cells, leading to their and Migration
emigration into the GI tract where they mediate fulminant disease.
Thus anatomically distinct, donor DC subsets amplify GVHD. The infused donor T cells interact with the primed APCs leading to
GVHD once initiated by host hematopoietic and/ or nonhematopoi- the initiation of the second phase of acute GVHD. This phase
etic recipient APCs, generates a profound, localized, and lethal includes antigen presentation by primed APCs and the subsequent
feed-forward cascade of donor DC-mediated indirect alloantigen activation, proliferation, differentiation, and migration of alloreactive
presentation and cytokine secretion within the GI tract and aggravates donor T cells. After allogeneic hematopoietic stem cell transplants,
its severity. both host and donor-derived APCs are present in secondary lymphoid
Other professional APCs such as monocytes/macrophages or organs. 124,125 The T-cell receptor (TCR) of the donor T cells can
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semiprofessional APCs might also play a role in this phase. For recognize alloantigens either on host APCs (direct presentation) or
example, recent data suggest that host-type B cells might play a regu- donor APCs (indirect presentation). 126,127 In direct presentation,
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latory role under certain contexts, whereas in other contexts, they donor T cells recognize either the peptide bound to allogeneic MHC
were dispensable for GVHD induction. Similarly, host basophils have molecules or allogeneic MHC molecules without peptide. 127,128
been shown not to affect the induction or severity of acute During indirect presentation, T cells respond to the peptide generated
GVHD. 112,113 A small subset of radioresistant host-derived neutro- by degradation of the allogeneic MHC molecules presented on self-
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phils infiltrate intestines after allo-HCT and the infiltration levels are MHC. Experimental studies demonstrated that APCs derived from
dependent on the local microbial flora while such infiltration is not the host, rather than from the donor, are critical in inducing GVHD
seen in germ-free conditions. Depletion of these neutrophils has been across MiHA mismatch. 7,126 Recent data suggest that presentation of
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shown to reduce GVHD mortality. Data suggest that radiosensitive distinct target antigens by the host-type and donor-type APCs might
hematopoietic-derived APCs may not be obligatory for induction of play a differential role in mediating target organ damage. 7,129,130 In
APCs. Also, host or donor-type nonhematopoietic stem cells (such humans, most cases of acute GVHD developed when both host DCs
as endothelial cells, epithelial cells, or stromal cells) can function as and donor DCs were present in peripheral blood after BMT. 93
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APCs in the context of inflammation. The role of these cells in the
presence and absence of professional hematopoietic-derived APCs
remains to be elucidated. Costimulation
Alloantigen presentation by the host APCs has been shown to be
modulated by the local microflora and by the release of PAMPs and The interaction of donor lymphocyte TCR with the host allopeptide
also by the release of damage associated molecular patterns (DAMP) presented on the MHC of APCs alone is insufficient to induce T-cell
molecules from condition-mediated damage. Classically, tissue activation. 7,131 Both TCR ligation and costimulation via a “second”
damage releases exogenous and endogenous damage/pathogen-asso- signal through interaction between the T-cell costimulatory molecules
ciated molecules termed DAMPs/PAMPs that are detected by pattern and their ligands on APCs are required to achieve T-cell proliferation,
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recognition receptors. Examples of pattern recognition receptors differentiation, and survival. The danger signals generated in phase
include Toll-like receptors (TLR) and NOD-like receptors that result 1 augment these interactions and significant progress has been made
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in the activation of APCs. The purine nucleoside adenosine tri- on the nature and impact of these second signals. 133,134 Costimulatory
phosphate (ATP) is one DAMP whose release has been implicated as pathways are now known to deliver both positive and negative signals
an early danger signal following tissue damage after allogeneic HCT. and molecules from two major families: the B7 family and the TNF
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Elevated levels of ATP are found in peritoneal fluids of humans and receptor (TNFR) family play pivotal roles in GVHD. Interruption
mice following GVHD or irradiation. ATP interaction with the of the second signal by the blockade of various positive costimulatory
purinergic receptor P2X 7 on host APCs resulted in increased expres- molecules (CD28, ICOS, CD40, CD30, 4-1BB, and OX40) reduces
sion of costimulatory molecules CD80/CD86 and production of acute GVHD in several murine models, whereas antagonism of the
inflammatory cytokines. Interrupting this interaction reduced inhibitory signals (programmed death (PD)-1 and cytotoxic T lym-
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GVHD in experimental models. More recently, a multiprotein phocyte antigen (CTLA)-4) exacerbates the severity of acute
complex termed the Nlrp3 inflammasome was shown to respond to GVHD. 136–142 The role of adhesion molecule DNAX accessory
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DAMPs/PAMPs such as uric acid. Mice deficient in critical com- molecule-1 (DNAM-1) was recently explored in GVHD. 143,144
ponents of Nlrp3 or adaptor protein for caspase-1 cleavage demon- Splenocytes deficient in DNAM-1 and prophylactic treatment with
strated less severe GVHD. Emerging data have demonstrated a role anti–DNAM-1 antibody prevented and treated GVHD. The various
for negative regulators of DAMP responses in controlling the severity T-cell and APC costimulatory molecules and the impact on acute
of GVHD. Siglecs are a family of sialic acid binding Ig-like lectins, GVHD are summarized in Table 108.3. The specific context and the
which function as counter regulators to immune activation and hierarchy in which each of these signals plays a dominant role in the
−/−
Siglec-G animals have increased GVHD, an effect confined to modulation of GVHD remain to be determined.
radiosensitive host APCs. In contrast, the enhanced Siglec-G signal-
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ing with CD24 in wild-type animals was protective. Likewise
inhibition of endogenous DAMPs such as heparan sulfate by endog- T-Cell Subsets
enous protease inhibitors such as alpha-1 antitrypsin also mitigated
GVHD in mice. 119,120 These and other data suggest that DAMPs such T cells consist of several subsets whose responses differ based on
as ATP, heparin sulfate, and uric acid may have nonredundant roles antigenic stimuli, activation thresholds, and effector functions. The
in the aggravation of GVHD. alloantigen composition of the host determines which donor T-cell
In addition to the role of LPS, recent observations have brought subsets proliferate and differentiate.
back renewed interest in the role of the quantitative and qualitative
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contributions of microbiota-driven inflammatory signals on GVHD. CD4 , CD8 Cells and Naive/Memory T-Cell Subsets
These signals are influenced by the variety and pathogenicity of CD4 and CD8 proteins are coreceptors for constant portions of
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organisms present, and have been demonstrated to affect the severity MHC class II and class I molecules, respectively. Therefore MHC
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of GVHD. 121–123 It is apparent that GVHD mediates a loss of Paneth class I (HLA-A, HLA-B, HLA-C) differences stimulate CD8 T cells
cell-derived antimicrobial peptides that play an important role in and MHC class II (HLA-DR HLA-DP, HLA-DQ) differences stimu-
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shaping the diversity of microbiota, in addition to the use of pharma- late CD4 T cells. 145–148 In the majority of HLA-identical BMT, acute
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ceutic antimicrobials, nonetheless our mechanistic understanding of GVHD can be induced by either or both CD4 and CD8 subsets
the changes in microflora is currently limited. Understanding these in response to MiHAs. 149
mechanisms may offer manipulable targets to alter this primary, Several independent groups have found that although the naive
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inflammation-mediated, initiation phase of GVHD. (CD62L ) T cells were alloreactive and caused acute GVHD, this was