Page 1870 - Hematology_ Basic Principles and Practice ( PDFDrive )

1662 Part X Transplantation

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some animal models of chronic GVHD, are also involved. Among including acute GVHD, the conditioning regimen, or age-related
the myriad clinical features of chronic GVHD, three definitive signs involution and atrophy. In chronic GVHD the ability of the thymus
appear to be risk factors for increased mortality: (1) extensive skin to delete autoreactive T cells (negative selection) and to induce toler-
GVHD involving greater than 50% of the body surface area, (2) ance is impaired. 24,351,352 Chronic GVHD could also be a product of
platelet count of less than 100,000/µL, and (3) progressive onset and T cells that have undergone relatively chronic antigen stimulation as
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acute GVHD that continues uninterrupted beyond day 100. a result of the presence of inexhaustible and ubiquitous MiHA
However, chronic GVHD remains, except in cases with obvious antigens. Allo-T cells under circumstances of chronic MiHA antigen
features, a difficult diagnosis; response to therapy is even more dif- stimulation can induce syndromes resembling those induced by the
ficult to assess. Recent criteria established by the NIH consensus chronic antigen stimulation in autoimmune diseases. This concept is
conference might prove to be beneficial in establishing uniform also consistent with the proposal of acute GVHD as a risk factor for
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guidelines for diagnosis, treatment, and response. The NIH con- chronic GVHD. The antigens targeted in chronic GVHD could be
sensus criteria are currently being evaluated. the same dominant ones targeted in acute GVHD, but the reactive
T cells could be different; for example, they may secrete TGF-β.
Recent data have shown that the balance between Treg and conven-
Differential Diagnosis tional T-cells is critical for chronic GVHD. 171
Cytokines: TGF-β has been implicated in the development of
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The distinction between chronic and acute GVHD has been tradi- fibrosis and chronic GVHD. IL-17 and subsequent T-cell differ-
tionally based on the time of onset. However, with the advent of entiation along the Th17 pathway have recently been strongly associ-
low-intensity HCT, that distinction has become less relevant. The ated with cGVHD. IL-17 was shown more recently to result in
NIH working group has, in addition to the two main categories of colony stimulating factor (CSF)1-dependent macrophage accumula-
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GVHD, added two subcategories. The broad category of acute tion in skin and lung, which drives tissue fibrosis. Systemic IL-17
GVHD includes (1) classic acute GVHD (maculopapular rash, levels increase late after clinical BMT, at a time when chronic GVHD
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nausea, vomiting, anorexia, profuse diarrhea, ileus, or cholestatic develops. Inhibition of Th17 differentiation and CSF1 appear to
hepatitis), occurring within 100 days after transplantation or donor be relevant to the development of chronic GVHD.
leukocyte infusion (DLI), (without diagnostic or distinctive signs of IL-2 is critical for Treg homeostasis. Recent data have shown that
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chronic GVHD), and (2) persistent, recurrent, or late acute GVHD: Treg: conventional T-cell balance is critical for chronic GVHD. In
features of classic acute GVHD without diagnostic or distinctive addition, inhibition of terminal cytokines involved in fibrosis, such
manifestations of chronic GVHD occurring beyond 100 days of as TGF-β and IL-13, represent additional targets; however, TGF-β
transplantation or DLI (often seen after withdrawal of immune inhibition may be problematic given its important role in Treg
suppression). The broad category of chronic GVHD includes (1) homeostasis.
classic chronic GVHD without features characteristic of acute B cells: In some patient subsets, responses to rituximab, pres-
GVHD and (2) an overlap syndrome in which features of chronic ence of MiHA-specific antibodies, and the presence of chronic
and acute GVHD appear together. In the absence of histologic or GVHD after T-cell depletion (TCD) allo-BMT would indicate that
clinical signs or symptoms of chronic GVHD, the persistence, in addition to donor T cells, donor B cells might be a direct effector
recurrence, or new onset of characteristic skin, GI tract, or liver or might have a role in priming T cells as APCs. 354,355 Murine
abnormalities should be classified as acute GVHD regardless of the models demonstrated a pathogenic role for donor B cells and allo-
time after transplantation. With appropriate stratification, patients antibody production in causing experimental chronic GVHD. It is
with persistent, recurrent, or late acute GVHD or overlap syndrome also clear that T follicular helper (T FH ) cells and IL-21 play impor-
can be included in clinical trials with patients who have chronic tant roles in the development of chronic GVHD via the stimulation
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GVHD. of germinal center B cells and alloantibody generation. Two
tyrosine kinases expressed in the hepatocellular carcinoma (TEC)
CHRONIC GRAFT-VERSUS-HOST family of kinases, IL-2–inducible kinase (ITK) and Bruton tyrosine
kinase (BTK), share close homology and play critical roles in both
DISEASE: PATHOPHYSIOLOGY T-cell and B-cell function. ITK helps to drive T-cell activation and
differentiation while BTK is essential for B-cell receptor signaling.
The pathophysiology of chronic GVHD is generally much less well In mouse studies treatment with ibrutinib, an ITK and BTK inhibi-
understood than that of acute GVHD and has undergone less inten- tor, reversed lung pathology and pulmonary dysfunction in mice
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sive experimental modeling. It is important to recognize that with established chronic GVHD in a model dependent on coopera-
chronic GVHD was originally defined as a temporal rather than a tion between T FH and germinal center B cells; additionally, ibrutinib
clinical or pathophysiologic entity. The initial clinical reports of reduced the progression of sclerodermatous chronic GVHD in
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chronic GVHD described abnormalities that occurred at least 150 mice. Targeting syk in B cells has been shown to mitigate chronic
days after stem cell infusion. 346,347 By convention, day 100 after stem GVHD in several models. Syk deletion in vivo was effective in
cell infusion is used as an arbitrary divider between acute and chronic treating established chronic GVHD, as was a small-molecule inhibi-
GVHD. But some manifestations of acute GVHD occur after day tor of Syk, fostamatinib, which normalized germinal center forma-
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100, and some manifestations of chronic GVHD may occur before tion and decreased activated CD80/86(+) dendritic cells. In
day 100. Thus it is preferable to consider the clinical symptoms and multiple distinct models of sclerodermatous chronic GVHD, clini-
signs per se rather than their timing of onset. cal and pathologic disease manifestations were not eliminated when
Relatively little is known about the pathophysiology of chronic mice were therapeutically treated with fostamatinib, though both
GVHD. This is in part because of the absence of appropriate animal clinical and immunologic effects could be observed in one of these
models that can capture the kinetics and the protean manifestation scleroderma models.
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of chronic GVHD. However, recent studies using multiple models
that collectively mimic many of the chronic GVHD manifestations
have begun to shed light on the complex biology. BIOMARKERS OF ACUTE GRAFT-VERSUS-HOST DISEASE
T cells: Based on certain clinical features chronic GVHD has been
considered to be an autoimmune disease, with some experimental Less progress has been made with biomarkers for chronic GVHD
data suggesting that chronic GVHD results from defective central than for acute GVHD; nevertheless, several are beginning to emerge.
negative selection, which leads to the generation of autoreactive CXCL9 has been identified and validated in several hundred patients
clones that escape tolerogenic mechanisms operating in the periph- from at least two HCT centers. 7,359 Other biomarkers with potential
ery. 349,350 The autoreactive cells of chronic GVHD are associated with utility include soluble B-cell activation factor (sBAFF), anti-dsDNA
a damaged thymus, which can be injured by several mechanisms, antibody, soluble IL-2 receptor alpha (sIL-2Rα), and soluble CD13