A TLR5 Agonist Inhibits Acute Renal Ischemic Failure

Fukuzawa, Nobuyuki; Petro, Marianne; Baldwin, William M.; Gudkov, Andrei V.; Fairchild, Robert L.

doi:10.4049/jimmunol.1003238

Cited by 37 publications

(32 citation statements)

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“…Because of its lower toxicity and lower immunogenicity, CBLB502 emerges as a more attractive TLR5 agonist and is currently undergoing phase I clinical trial. Mean-while, preclinical studies with mouse models have shown that CBLB502 can inhibit acute renal ischemic failure and can protect mice from dermatitis caused by local cancer radiotherapy (30,31). These reports support a notion that CBLB502 may be an effective agent in modulating beneficial immune responses.…”

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confidence: 61%

A TLR5 Agonist Enhances CD8+ T Cell-Mediated Graft-versus-Tumor Effect without Exacerbating Graft-versus-Host Disease

Ding

Bian

Leigh

et al. 2012

The Journal of Immunology

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Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and nonhematologic malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the effectiveness of the transplantation therapy. CBLB502 is a novel agonist for TLR5 derived from Salmonella flagellin. On the basis of TLR5-mediated immunomodulatory function, we examined the effect of CBLB502 on GVT activity. Using two tumor models that do not express TLR5, and thereby do not directly respond to CBLB502, we found that CBLB502 treatment significantly enhanced allogeneic CD8+ T cell-mediated GVT activity, which was evidenced by decreased tumor burden and improved host survival. Importantly, histopathologic analyses showed that CBLB502 treatment did not exacerbate the moderate graft-versus-host disease condition caused by the allogeneic CD8+ T cells. Moreover, mechanistic analyses showed that CBLB502 stimulates CD8+ T cell proliferation and enhances their tumor killing activity mainly indirectly through a mechanism that involves the IL-12 signaling pathway and the CD11c+ and CD11b+ populations in the bone marrow cells. This study demonstrates a new beneficial effect of CBLB502, and suggests that TLR5-mediated immune modulation may be a promising approach to improve GVT immunity without exacerbating graft-versus-host disease.

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confidence: 61%

A TLR5 Agonist Enhances CD8+ T Cell-Mediated Graft-versus-Tumor Effect without Exacerbating Graft-versus-Host Disease

Ding

Bian

Leigh

et al. 2012

The Journal of Immunology

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“…Such factors may play roles in CBLB502's protection of (i) the HP and GI systems against radiation (8), (ii) the kidney against ischemia-reperfusion injury (10), and (iii) the liver against Fas-mediated apoptosis (this report). In these cases, additional "prosurvival" TLR5 agonist responses may include those controlled by the STAT3 (47,48) and AP-1 pathways (49), which were previously shown to be responsible for liver resistance to Fas-mediated apoptosis (35), as well as by the PBREM, which regulates genes involved in the detoxifying metabolic capacity of the liver (50).…”

Section: Discussionmentioning

confidence: 94%

“…Moreover, CBLB502 protected mice from dermatitis and mucositis associated with local fraction irradiation of head and neck area modeling radiation treatment of patients with head and neck cancer (9). Second, the TLR5 agonist CBLB502 was shown to be effective as a tissue protectant in mouse models of renal ischemia-reperfusion injury (10). Third, bacterial flagellin and flagellin-expressing bacteria (Salmonella) have shown antitumor effects in mouse models of colon and liver metastasis of pancreatic cancer (11,12).…”

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confidence: 99%

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Burdelya

Brackett

Kojouharov

et al. 2013

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

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Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.breast cancer | colon cancer | neutrophils | natural killer cells | Salmonella T oll-like receptors (TLRs) recognize and are activated by specific patterns in molecules that are produced by a broad range of microbial pathogens but are not present in host molecules. Activation of TLRs by these pathogen-associated molecular patterns leads to induction of infection-fighting innate immune responses (1). Various TLR agonists have been considered for multiple clinical applications, including cancer immunotherapy (2-4), and one, the TLR7 agonist imiquimod, is approved for topical treatment of basal cell carcinoma (5).Although signaling pathways induced by different TLRs all result in mobilization of an innate immune response and involve activation of nuclear factor kappa B (NF-κB), the key regulator of immunity (6, 7), TLR5 is a particularly attractive candidate for therapeutic targeting for several reasons. First, bacterial flagellin, the natural ligand of TLR5, was found to have strong radioprotective effects in rodents and nonhuman primates (8). CBLB502 is a rationally designed derivative of Salmon...

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“…CBLB502 exerts radioprotective activities and inhibits acute renal ischemic failure (8)(9)(10)12). In this study, we examined the treatment of UC using CBLB502 via the effects of CBLB502 on TLR responses and IL and NF-κB signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…CBLB502 exerts radioprotective activity and is characterized as safe and highly effective in reducing the risk of death by activating nuclear factor kappa B (NF-κB) pathway (8). CBLB502 inhibits acute renal ischemic failure and is protective when given 30 min before and after ischemic kidney reperfusion (9). CBLB502 can significantly reduce the severity of dermatitis and oral mucositis caused by local radiation, and these properties are mediated via the activation of TLR5 signaling (10).…”

Section: Introductionmentioning

confidence: 99%

CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation

Xu¹,

Dong

et al. 2016

Ann. Transl. Med.

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Background: Ulcerative colitis (UC) is a nonspecific inflammatory disease for which medications and therapeutic strategies have only been moderately successful. CBLB502, a toll-like receptor 5 (TLR5) agonist derived from Salmonella flagellin, exhibits anticancer and radioprotective activities via modulation of TLRs and the nuclear factor kappa B (NF-κB) signaling pathway and can protect against acute renal ischemic failure. In this study, we intend to examine the effects of CBLB502 on both TLR responses and the interleukin (IL) and NF-κB signaling pathways in UC treatment.Methods: The UC mouse model was prepared in BALB/c mice by administering 2,4,6-trinitrobenzene sulfonic acid (TNBS). CBLB502 was used as the therapeutic drug. After CBLB502 therapy, the IL and tumor necrosis factor-α (TNF-α) levels were measured by ELISA. Total RNA and protein of colon samples was extracted.Results: We found that CBLB502 had a distinctive therapeutic effect in the UC model. In control group animals, IL-10 expression in serum was 91.48±24.38 ng/mL; this was higher than in the model group (59.36±14.46 ng/mL, P<0.05) or the treatment group (54.29±5.83 ng/mL, P<0.05). In model group animals, the concentration of TNF-α in serum was 140.11±12.70 ng/mL, which was lower than protein levels in the control group (173.86±29.26 ng/mL, P<0.05). The mRNA levels of TLR1,2,3,4,6,7,8, and 9 in the CBLB502 treatment group were significantly lower than in the model group (P<0.05). Western blot revealed that CBLB502 also reduced NF-κB expression in the mouse colon, but that NF-κB expression was not significantly lower than the model group.Conclusions: CBLB502 can reduce mucosal damage induced by TNBS and inhibit inflammation and TLR expression. The inhibition of UC by CBLB502 is strictly TLR-IL-dependent and is dose-dependent within the efficacious dose range. Therefore, our results suggested that CBLB502 might be a candidate drug for the treatment of UC.

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A TLR5 Agonist Inhibits Acute Renal Ischemic Failure

Cited by 37 publications

References 50 publications

A TLR5 Agonist Enhances CD8+ T Cell-Mediated Graft-versus-Tumor Effect without Exacerbating Graft-versus-Host Disease

A TLR5 Agonist Enhances CD8+ T Cell-Mediated Graft-versus-Tumor Effect without Exacerbating Graft-versus-Host Disease

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation

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