Gut Toxicity During Hemopoietic Stem Cell Transplantation May Predict Acute Graft-Versus-Host Disease Severity in Patients

Johansson, Jan‐Erik; Ekman, Tor

doi:10.1007/s10620-006-9404-x

Cited by 48 publications

(48 citation statements)

References 20 publications

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“…Then, inflammatory cellderived IL-1β might cooperate with multiple innate and adaptive effector pathways (39) to propagate an inflammatory reaction. In humans, IL-1β up-regulation following DNA damage is observed in cancer patients with mucositis (28), a severe pathologic condition affecting most patients treated with standard chemotherapy or radiation therapy (28,40). Anti-IL-1β treatment may thus ameliorate mucositis as well as multiple disorders associated with barrier permeability, including burn injuries (33), head and neck trauma (41), cardiogenic shock (42), alcoholic intoxication (43), and graft-vs.-host disease (40).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, IL-1β up-regulation following DNA damage is observed in cancer patients with mucositis (28), a severe pathologic condition affecting most patients treated with standard chemotherapy or radiation therapy (28,40). Anti-IL-1β treatment may thus ameliorate mucositis as well as multiple disorders associated with barrier permeability, including burn injuries (33), head and neck trauma (41), cardiogenic shock (42), alcoholic intoxication (43), and graft-vs.-host disease (40). Furthermore, preventive anti-IL-1β treatment may obviate the common need for chemoradiation therapy suspension as a result of mucositis and improve patients' quality of life during treatment.…”

Section: Discussionmentioning

confidence: 99%

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Critical role for IL-1β in DNA damage-induced mucositis

Kanarek¹,

Grivennikov

Leshets³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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β-TrCP, the substrate recognition subunit of SCF-type ubiquitin ligases, is ubiquitously expressed from two distinct paralogs, targeting for degradation many regulatory proteins, among which is the NF-κB inhibitor IκB. To appreciate tissue-specific roles of β-TrCP, we studied the consequences of inducible ablation of three or all four alleles of the E3 in the mouse gut. The ablation resulted in mucositis, a destructive gut mucosal inflammation, which is a common complication of different cancer therapies and represents a major obstacle to successful chemoradiation therapy. We identified epithelial-derived IL-1β as the culprit of mucositis onset, inducing mucosal barrier breach. Surprisingly, epithelial IL-1β is induced by DNA damage via an NF-κB-independent mechanism. Tissue damage caused by gut barrier disruption is exacerbated in the absence of NF-κB, with failure to express the endogenous IL-1β receptor antagonist IL-1Ra upon fourallele loss. Antibody neutralization of IL-1β prevents epithelial tight junction dysfunction and alleviates mucositis in β-TrCP-deficient mice. IL-1β antagonists should thus be considered for prevention and treatment of severe morbidity associated with mucositis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Critical role for IL-1β in DNA damage-induced mucositis

Kanarek¹,

Grivennikov

Leshets³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Nonetheless, persistent microbial translocation during HIV infection owing to increased gut permeability could exercise unfavorable effects on the disease course through multiple mechanisms (12). The effects of microbial translocation on the nervous system are unappreciated to date in diseases-such as inflammatory and altered permeability bowel diseases (64), graft-versus host disease (65), and lymphangiectasia (66)-in which it is posited to be a pathogenic factor.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

Maingat

Viappiani

Zhu

et al. 2009

The Journal of Immunology

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Lentivirus infections including HIV and feline immunodeficiency virus (FIV) cause neurovirulence, which is largely mediated by innate immunity. To investigate the interactions between neurovirulence and repeated conditioning by innate immune activation, models of lentivirus infection were exposed to LPS. Gene expression in HIV-infected (HIV+) and control (HIV−) patient brains was compared by real time RT-PCR and immunocytochemistry. Supernatants from mock and HIV-infected monocyte-derived macrophages exposed to LPS were applied to human neurons. FIV-infected (FIV+) and control (FIV−) animals were exposed repeatedly to LPS postinfection together with concurrent neurobehavioral testing, viral load, and host gene analyses. Brains from HIV+ individuals exhibited induction of CD3ε, CXCL10, and granzyme A expression (p < 0.05). Supernatants from HIV+ monocyte-derived macrophages induced CXCL10 expression in neurons, which was diminished by IL-10 treatment (p < 0.05). LPS-exposed FIV+ animals demonstrated lower plasma and brain viral loads (p < 0.05). Neuronal CXCL10 expression was increased in FIV+ animals but was suppressed by LPS exposure, together with reduced brain CD3ε and granzyme A expression (p < 0.05). In conjunction with preserved NeuN-positive neuronal counts in parietal cortex (p < 0.05), FIV+ animals exposed to LPS also showed less severe neurobehavioral deficits (p < 0.05). Repeated LPS exposures suppressed CXCL10 in the brain and ensuing T cell infiltration with a concomitant reduction in neurovirulence. Thus, innate immune chronic conditioning exerted beneficial effects on neurovirulence through suppression of a specific chemotactic factor, CXCL10, mediated by IL-10, leading to reduced leukocyte infiltration and release of neurotoxic factors.

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“…6 However, the same mechanism is thought to have an important role for the significant increase in aGVHD in patients with higher degrees of gastrointestinal injury and mucosal permeability during HSCT. 7 It thus seems logical that it is the total amount of bacterial components that enters the systemic circulation that correlate with the risk of aGVHD, and that the amount needed to trigger aGVHD differs among patients, depending on whether other risk factors are present or not. If so, it may be that BSI or mucositis alone will suffice to trigger aGVHD in some patients, whereas in others the combination is required.…”

mentioning

confidence: 99%