Page 1866 - Hematology_ Basic Principles and Practice ( PDFDrive )

1658 Part X Transplantation

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Fas, a TNF-receptor family member, is expressed by many tissues, skin, two major GVHD target organs. A similar increase in mono-
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including GVHD target organs. Its expression can be upregulated nuclear cell IL-1 mRNA has been shown during clinical acute
by inflammatory cytokines such as IFN-γ and TNF-α during GVHD, GVHD. Mice receiving IL-1 displayed a wasting syndrome and
and the expression of FasL is also increased on donor T cells, indicat- increased mortality that appeared to be an accelerated form of disease.
ing that FasL-mediated cytotoxicity may be a particularly important By contrast, intraperitoneal administration of IL-1 receptor antago-
effector pathway in GVHD. 236,250 FasL-defective T cells cause less nist (IL-1RA) was able to reverse the development of GVHD in the
GVHD in the liver, skin, and lymphoid organs. 245,248,250 The Fas-FasL majority of animals, providing a significant survival advantage to
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pathway is particularly important in hepatic GVHD, consistent with treated animals. However, the attempt to use IL-1RA to prevent
the keen sensitivity of hepatocytes to Fas-mediated cytotoxicity in acute GVHD in a randomized trial was not successful. 271
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experimental models of murine hepatitis. Fas-deficient recipients As a result of activation during GVHD, macrophages also produce
are protected from hepatic GVHD, but not from other organ GVHD, nitric oxide (NO), which contributes to the deleterious effects on
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and administration of anti-FasL (but not anti-TNF) monoclonal GVHD target tissues, particularly immunosuppression. NO also
antibodies (MAbs) significantly blocked hepatic GVHD damage inhibits the repair mechanisms of target tissue destruction by inhibit-
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occurring in murine models. 236,251,252 Although the use of FasL- ing proliferation of epithelial stem cells in the gut and skin. In
deficient donor T cells or the administration of neutralizing FasL humans and rats, the development of GVHD is preceded by an
MAbs had no effect on the development of intestinal GVHD in increase in serum levels of NO oxidation products. 274–276
several studies, the Fas-FasL pathway may play a role in this target IL-6 has also been identified as a critical cytokine that promotes
organ, because intestinal epithelial lymphocytes exhibit increased a proinflammatory response during GVHD. Recent data suggest that
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FasL-mediated killing potential. Elevated serum levels of soluble IL-6 might in fact be the most critical cytokine that increases GVHD
FasL and Fas have also been observed in at least some patients with severity. It has direct cytopathic effects on the GI tract following
acute GVHD. 254,255 allogeneic BMT and likely inhibits the reconstitution of Tregs. 208,277
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The use of a perforin-granzyme and FasL cytotoxic double- It plays a dominant role in mitigating lung injury after allo-BMT.
deficient (cdd) T cells, showed that they were unable to induce lethal Recent clinical trial demonstrated that targeting IL-6 early after
GVHD across MHC class I and class II disparities after sublethal transplant, particularly following high-intensity conditioning could
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irradiation. However, when recipients were conditioned with a mitigate GVHD.
+
lethal dose of irradiation, cdd CD4 T cells produced similar mortal-
+
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ity to wild-type CD4 T cells. These results were confirmed by a
recent study demonstrating that GVHD target damage can occur in BIOMARKERS OF ACUTE GRAFT-VERSUS-HOST DISEASE
mice that lack alloantigen expression on the epithelium, preventing
direct interaction between CTLs and target cells. 241 Emerging data from large datasets have identified and validated
Recently, several additional TNF family apoptosis-inducing plasma biomarkers with important prognostic value at the onset of
receptors/ligands have been identified, including TWEAK, TRAIL, symptoms of acute GVHD. Markers of systemic GVHD include
and LTβ/LIGHT, all of which have been proposed to play a role in IL-2Rα, TNFR1, IL-8, and hepatocyte growth factor. 1,279 Elafin has
GVHD and GVL responses. 136,256–262 However, whether these distinct been identified as a biomarker specific for skin GVHD, and regen-
pathways play a more specific role for GVHD mediated by distinct erating islet-derived 3-alpha (REG3α) as a biomarker of gastro-
T-cell subsets in certain situations remains unknown. Taken together, intestinal GVHD, and ST2 or the soluble IL-33 receptor as a maker
experimental data suggest some distinction between the use of differ- of resistance to therapy. 2–4,280–282
ent lytic pathways for the specific GVHD target organs and GVL, Recently, the concentrations of three of these plasma biomarkers
but the clinical applicability of these observations is as yet largely (TNFR1, ST2, and Reg3α) were used in the creation of an algorithm
unknown. that computed the probability of nonrelapse mortality (NRM) for
individual patients. 5,283 The algorithm was developed in a multicenter
training set of 328 patients, and two separate multicenter validation
Inflammatory Effectors sets of 164 and 300 patients, respectively. The investigators identified
thresholds that created three distinct Ann Arbor GVHD scores. In
Inflammatory cytokines synergize with CTLs resulting in the ampli- all three datasets (training, test, and validation), the cumulative
fication of local tissue injury and further promotion of an inflamma- incidence of 6-month NRM significantly increased as the Ann Arbor
tion, which ultimately leads to the observed target tissue destruction GVHD score increased: 8% for score 1, 27% for score 2, and 46%
in the transplant recipient. 263 for score 3 (P <.0001). Conversely, the response to primary GVHD
The cytokines TNF-α, IL-6, and IL-1 are produced by an abun- treatment decreased as the GVHD score increased: 86% for score 1,
dance of cell types during processes of both innate and adaptive 67% for score 2, and 46% for score 3, P <.0001). These findings
immunity; they often have synergistic, pleiotropic, and redundant suggest that biomarker-based scores can be used to guide risk-adapted
effects on both activation and effector phases of GVHD. 207,219 A therapy at the onset of acute GVHD. High-risk patients with a score
critical role for TNF-α in the pathophysiology of acute GVHD was of 3 are candidates for intensive primary therapy, while low-risk
first suggested over 20 years ago because mice transplanted with patients with a score of 1 are candidates for rapid tapers of systemic
mixtures of allogeneic BM and T cells developed severe skin, gut, and steroid therapy.
lung lesions that were associated with high levels of TNF-α messenger Recently the number of Paneth cells in duodenal biopsies for
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RNA (mRNA) in these tissues. Target organ damage could be GVHD has been shown to correlate with response to treatment and
inhibited by infusion of anti–TNF-α MAbs, and mortality could be with long-term survival. 6,31 The plasma concentration of REG3α, the
reduced from 100% to 50% by the administration of the soluble clinical severity of GVHD, and the histologic severity at GVHD
form of the TNF-α receptor (sTNFR), an antagonist of TNF-α. 79,82,265 diagnosis independently predicted lack of response to GVHD therapy
TNF-TNF1 interactions on donor T cells promote alloreactive T-cell 4 weeks following treatment and TRM. Patients who had all three
responses and TNF-TNFR2 interactions are critical for intestinal risk factors experienced significantly greater NRM than those with
GVHD. 211,259,266 TNF-α also seems to be an important effector any two of the risk factors (86% versus 66%, P <.001). The integra-
molecule in GVHD in skin and lymphoid tissue. 264,267 In addition, tion of clinical stage, histologic grade, and biomarkers into a single
TNF-α might also be involved in hepatic GVHD, probably by grading system may permit better risk stratification and rapid iden-
enhancing effector cell migration to the liver via the induction of tification of patients for whom standard treatment is likely to be
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inflammatory chemokines. The second major proinflammatory insufficient. 3,281
cytokine that appears to play an important role in the effector phase These biomarkers may also provide new insights into the biology
of acute GVHD is IL-1. 42,263 Secretion of IL-1 appears to occur of GVHD. For example, the IL-22-Reg3 axis protects the epithelial
predominantly during the effector phase of GVHD of the spleen and barrier function of the intestinal mucosa. Intestinal stem cells (ISCs)