A Metalloproteinase Inhibitor Prevents Lethal Acute Graft-Versus-Host Disease in Mice

Hattori, Koichi; Hirano, Toshio; Ushiyama, Chifuyu; Miyajima, Hiroaki; Yamakawa, Norifumi; Ebata, Tomohiko; Wada, Yoshinori; Ikeda, Shoji; Yoshino, Kohichiro; Tateno, Masatoshi; Oshimi, Kazuo; Kayagaki, Nobuhiko; Yagita, Hideo; Okumura, Ko

doi:10.1182/blood.v90.2.542.542_542_548

Cited by 28 publications

(33 citation statements)

References 26 publications

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“…0.5% CMC vehicle was used as the control. Mice were injected subcutaneously with 2 mg per 0.2 ml of KB-R7785 or with 0.2 ml of 0.5% CMC [11].…”

Section: Mmp Inhibitormentioning

confidence: 99%

“…The previous study demonstrated that KB-R7785 blocks the release of TNF-K from the cell surfaces [11]. To con-¢rm that KB-R7785 would reduce the production of soluble TNF-K induced by L. monocytogenes, spleen cells obtained from naive mice were stimulated with heat-killed L. monocytogenes cells in the presence of various concentrations of KB-R7785 dissolved in 10 mM dimethylsulfoxide.…”

Section: Kb-r7785 Inhibits the Release Of Soluble Tnf-kmentioning

confidence: 99%

“…KB-R7785 reportedly inhibits MMP-mediated release of TNF-K and CD95L [11,15,16]. To investigate TNF-K dependence and implication of CD95L in KB-R7785 action, mice were injected with anti-TNF-K mAb 2 h before infection, and they were administered KB-R7785 or 0.5% CMC vehicle 24 h and 1 h before infection with 500 cfu of L. monocytogenes.…”

Section: Tnf-k Dependence Of Kb-r7785 Actionmentioning

confidence: 99%

“…Some hydroxamic acid-based MMP inhibitors have been shown to inhibit tumor in¢ltration and growth in experimental animal models or phase I/II clinical trials in pancreatic, prostatic, and ovarian cancer patients [4^7]. Moreover, these MMPs are involved in the shedding of multiple cell surface molecules such as tumor necrosis factor-K (TNF-K) [8^10] and CD95 ligand (CD95L ; FasL) [11]. These drugs are reportedly able to prevent lethality in mice caused by endotoxin shock or concanavalin A-induced hepatitis through inhibiting the processing of TNF-K [8^10, 12].…”

Section: Introductionmentioning

confidence: 99%

“…KB-R7785, a hydroxamic acid-based MMP inhibitor, inhibits MMP1, MMP3, and MMP9 [13,14]. Hattori et al [11,15,16] reported that KB-R7785 prevents acute graft-versus-host disease in mice. They demonstrated that the inhibition of the release of TNF-K and CD95L from the cell surface is involved in prevention by KB-R7785 of acute graft-versus-host disease.…”

Section: Introductionmentioning

confidence: 99%

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Effect of a matrix metalloproteinase inhibitor on host resistance against Listeria monocytogenes infection

Yamada

2000

FEMS Immunology and Medical Microbiology

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Hydroxy acid-based matrix metalloproteinase (MMP) inhibitors have been shown to inhibit tumor infiltration and growth, endotoxin shock, and acute graft-versus-host disease. Blockade of the release of soluble tumor necrosis factor-alpha (TNF-alpha) and CD95 ligand (CD95L; FasL) from cell-associated forms is reportedly involved in the mechanism of the drug effect. We investigated the effect of a MMP inhibitor, KB-R7785, on host resistance against Listeria monocytogenes infection, in which TNF-alpha is essentially required for the defense, in mice. The administration of KB-R7785 exacerbated listeriosis, while the drug prevented lethal shock induced by lipopolysaccharide and D-galactosamine. KB-R7785 inhibited soluble TNF-alpha production in spleen cell cultures stimulated by heat-killed L. monocytogenes and the drug treatment reduced serum TNF-alpha levels in infected mice, whereas the compound was ineffective on the modulation of interferon-gamma and interleukin-10 production. The effect of KB-R7785 was considered to be dependent on TNF-alpha because the drug failed to affect L. monocytogenes infection in anti-TNF-alpha monoclonal antibody-treated mice and TNF-alpha knockout mice. Anti-CD95L monoclonal antibody was also ineffective on the infection. These results suggest that induction of infectious diseases, to which TNF-alpha is critical in host resistance, should be considered in MMP inhibitor-treated hosts.

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“…0.5% CMC vehicle was used as the control. Mice were injected subcutaneously with 2 mg per 0.2 ml of KB-R7785 or with 0.2 ml of 0.5% CMC [11].…”

Section: Mmp Inhibitormentioning

confidence: 99%

Section: Kb-r7785 Inhibits the Release Of Soluble Tnf-kmentioning

confidence: 99%

Section: Tnf-k Dependence Of Kb-r7785 Actionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Effect of a matrix metalloproteinase inhibitor on host resistance against Listeria monocytogenes infection

Yamada

2000

FEMS Immunology and Medical Microbiology

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Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Mittal

Patel

Debs

et al. 2016

Journal Cellular Physiology

143

115

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Matrix metalloproteinases (MMPs) are a diverse group of proteolytic enzymes and play an important role in the degradation and remodeling of the extracellular matrix (ECM). In normal physiological conditions, MMPs are usually minimally expressed. Despite their low expression, MMPs have been implicated in many cellular processes ranging from embryological development to apoptosis. The activity of MMPs is controlled at three different stages: (1) transcription; (2) zymogen activation; and (3) inhibition of active forms by tissue inhibitor metalloproteinases (TIMPs). They can collectively degrade any component of ECM and basement membrane, and their excessive activity has been linked to numerous pathologies mainly including, but not limited to, tumor invasion and metastasis. The lack of information about several MMPs and the steady stream of new discoveries suggest that there is much more to be studied in this field. In particular, there is a need for controlling their expression in disease states. Various studies over the past 30 years have found that each MMP has a specific mode of activation, action, and inhibition. Drugs specifically targeting individual MMPs could revolutionize the treatment of a great number of health conditions and tremendously reduce their burden. In this review article, we have summarized the recent advances in understanding the role of MMPs in physiological and pathological conditions. J. Cell. Physiol. 231: 2599-2621, 2016. © 2016 Wiley Periodicals, Inc.

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siRNA against CD40 delivered via a fungal recognition receptor ameliorates murine acute graft‐versus‐host disease

Heissig

Salama

Tateno

et al. 2022

eJHaem

Self Cite

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Acute graft-versus-host disease (aGvHD) remains a major threat to a successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Although antibody-based targeting of the CD40/CD40 ligand costimulatory pathway can prevent aGvHD, side effects hampered their clinical application, prompting a need for other ways to interfere with this important dendritic T-cell costimulatory pathway.Here, we used small interfering RNA (siRNA) complexed with β-glucan allowing the binding and uptake of the siRNA/β-glucan complex (siCD40/schizophyllan [SPG]; chemical modifications called NJA-312, NJA-302, and NJA-515) into Dectin1+ cells, which recognize this pathogen-associated molecular pattern receptor. aGvHD was induced by the transplantation of splenocytes and bone marrow cells from C57BL/6J into CBF1 mice. Splenic dendritic cells retained Dectin1 expression after HSCT but showed lower expression after irradiation. The administration of siCD40/SPG, NJA-312, and NJA-302 ameliorated aGvHD-mediated lethality and tissue damage of spleen and liver, but not skin. Multiple NJA-312high injections prevented aGvHD but resulted in early weight loss in allogeneic HSCT mice. In addition, NJA-312 treatment caused delayed initial donor T and B-cell recovery but resulted in stable chimerism in surviving mice. Mechanistically, NJA-312 reduced organ damage by suppressing CCR2+, F4/80+, and IL17A-expressing cell accumulation in spleen, liver, and thymus but not the skin of mice with aGvHD. Our work demonstrates that siRNA targeting of CD40 delivered via the PAMP-recognizing lectin Dectin1 changes the immunological niche, suppresses organ-specific murine aGvHD, and induces immune tolerance after organ transplantation. Our work charts future directions for therapeutic interventions to modulate tissue-specific immune reactions using Pathogen-associated molecular pattern (PAMP) molecules like 1,3-β-glucan for cell delivery of siRNA.

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A Metalloproteinase Inhibitor Prevents Lethal Acute Graft-Versus-Host Disease in Mice

Cited by 28 publications

References 26 publications

Effect of a matrix metalloproteinase inhibitor on host resistance against Listeria monocytogenes infection

Effect of a matrix metalloproteinase inhibitor on host resistance against Listeria monocytogenes infection

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

siRNA against CD40 delivered via a fungal recognition receptor ameliorates murine acute graft‐versus‐host disease

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