Sensing danger: toll-like receptors and outcome in allogeneic hematopoietic stem cell transplantation

Kornblit, Brian; Müller, Klaus

doi:10.1038/bmt.2016.263

Cited by 18 publications

(17 citation statements)

References 70 publications

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“…In fact, chemotherapy-induced epithelial damage activates a first inflammatory response driven by epithelial cells and tissue monocytes and macrophages. [43][44][45] Subsequently, inflammation-induced tissue damage leads to increased permeability and ulceration of the intestinal mucosa, with translocation of bacteria and pathogen-associated molecular patterns, which trigger a second systemic inflammatory response possibly resulting in fever. [43][44][45][46] To emphasize this close link between mucositis and fever, the term 'febrile mucositis' was introduced by Walter et al 45…”

Section: F I G U R Ementioning

confidence: 99%

Citrulline as a biomarker of bacteraemia during induction treatment for childhood acute lymphoblastic leukaemia

Pietri

Frandsen

Christensen

et al. 2020

Pediatric Blood & Cancer

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Background: Systemic infections are a major cause of morbidity in children with acute lymphoblastic leukaemia (ALL). However, identification of patients at increased risk is still a challenge. Knowing that both neutropaenia and gastrointestinal toxicity are risk factors for bacteraemia, we aimed at comparing absolute neutrophil counts (ANC) and plasma citrulline levels (indicating enterocyte loss) in children with ALL with and without bacteraemia during induction treatment. Procedure: We prospectively included 61 children with ALL treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol. ANC and plasma C-reactive protein (CRP) were measured on treatment days 1, 8, 15, 22 and 29. Plasma citrulline was measured on days 1, 8, 15 and 29. Bacteraemia episodes during induction treatment were recorded retrospectively. Results: Nineteen of sixty-one (31%) patients experienced bacteraemia occurring on median day 13 (range 5-20). Patients with bacteraemia during induction treatment had lower citrulline level on day 15 (P < .01) compared to patients without bacteraemia, indicating more severe enterocyte loss. Nevertheless, ANC was similar in the two patient groups on days 8 and 15. CRP was negatively correlated with same-day citrulline (P < .03 for all) and ANC (P < .04 for all). Conclusions: During chemotherapy-induced neutropaenia, plasma citrulline may help identify patients at increased risk of bacteraemia.

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Section: F I G U R Ementioning

confidence: 99%

Citrulline as a biomarker of bacteraemia during induction treatment for childhood acute lymphoblastic leukaemia

Pietri

Frandsen

Christensen

et al. 2020

Pediatric Blood & Cancer

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“…Gastrointestinal mucositis reflects release of damage-associated molecular patterns that are sensed by pattern recognition receptors such as Toll like-receptors, causing release of inflammatory cytokines propagating an inflammatory response 19– 21 . This is followed by an ulceration phase and finally resolution 19 .…”

Section: Mucositismentioning

confidence: 99%

“…This is followed by an ulceration phase and finally resolution 19 . The normal intestinal microbiome may play a protective role by stimulating endothelial cell proliferation and mucous production, and intestinal dysbiosis due to chemotherapy and antibiotics could aggravate mucositis, but this awaits clinical validation 21– 23 . Severe mucositis disrupts the intestinal immunological barrier and is a risk factor for systemic infections, although it has been most intensively studied in the hSCT setting 22, 24 .…”

Section: Mucositismentioning

confidence: 99%

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

et al. 2017

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During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.

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“…In a murine study of the MyD88, that mediates TLR signaling, recipients of MyD88 knock out grafts experienced unabated tumor growth. In contrast recipients of MyD88 wild type grafts showed evidence of GvL responses, suggesting an important role of TLRs on GvL [41,42]. Forodesine works by dual mechanism in leukemia patients.…”

Section: Clinical Evidence Of Immune Activation With Pnp Inhibitorsmentioning

confidence: 99%

Purine Nucleoside Phosphorylase Inhibitors as Novel Immuno-Oncology Agent and Vaccine Adjuvant

Bantia¹

2020

Int J Immunol Immunother

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Background: Purine Nucleoside Phosphorylase (PNP) deficiency in humans causes lymphopenia and this provided the rationale for developing PNP inhibitors as immunosuppressive agents. However, careful re-evaluation of clinical history of PNP deficient patients and clinical experience with PNP inhibitors together with new experimental data suggest inhibition of PNP may have immune activating effects through elevation of guanosine and activation of various tolllike receptors (TLRs). This paper proposes a mechanism of action for the immune activating effects of PNP inhibition. Methods: To evaluate in vitro TLR activation, by PNP inhibitor and the purine nucleosides that are elevated with PNP inhibition, HEK293 cells expressing various TLRs linked to the SEAP reporter group was used. To evaluate forodesine as vaccine adjuvant, well known mouse models of tetanus toxoid vaccine and Hepatitis B vaccine was used. To evaluate anti-tumor and anti-bacterial effects of forodesine, syngeneic B16F10 mouse melanoma model and L.monocytogenes bacterial infection mouse model were used. Results: Guanosine demonstrated significant and robust activation of TLR2 and TLR4, in HEK293 cells. Like other TLR activators, PNP inhibitor forodesine which elevates guanosine in vivo demonstrated statistically significant increases in antibody titers and, although not significant, a trend towards increase in interferon-γ (IFN-γ) levels compared to vaccine alone groups in tetanus toxoid and Hepatitis B vaccine mouse models. Similarly, forodesine treatment improved the mouse immune system as demonstrated by significant decrease in tumor growth in mouse melanoma model, inspite of lack of direct in vitro cytotoxic effects of forodesine on malignant cells. In addition, like other TLR agonists, forodesine demonstrated significant decrease in weight loss in L.monocytogenes bacterial infection model. Discussion: In PNP inhibitor clinical trials, immune activating effects have been noted which included increased response to tetanus toxoid vaccine, graft versus leukemia effects in post hematopoietic stem cell transplant relapse acute lymphoblastic leukemia patients, and in vivo effectiveness in non-leukemic cancers in spite of lack of direct in vitro cytotoxic effects on the malignant cells. Clinical findings in PNP deficient patients include autoimmune manifestations, elevation of IL-18 levels (an IFN-γ inducer), and neurological disorders which is consistent with immune activation. Lymphopenia noted in PNP deficient patients is primarily due to constitutive activation of immune system in these patients causing immune exhaustion and T-cell elimination. Genetic studies, clinical experience with PNP inhibitors together with the preclinical data presented here clearly support the role of PNP inhibitors as immune-activating agents. Contrary to prior literature, we have confirmed that PNP inhibition has immune activating effects. Conclusion: Clinical findings in PNP deficient patients along with clinical and preclinical experience with PNP inhibitor support the u...

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Sensing danger: toll-like receptors and outcome in allogeneic hematopoietic stem cell transplantation

Cited by 18 publications

References 70 publications

Citrulline as a biomarker of bacteraemia during induction treatment for childhood acute lymphoblastic leukaemia

Citrulline as a biomarker of bacteraemia during induction treatment for childhood acute lymphoblastic leukaemia

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

Purine Nucleoside Phosphorylase Inhibitors as Novel Immuno-Oncology Agent and Vaccine Adjuvant

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