Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization

Kuipers, Hedwich F.; Rieck, Mary; Gurevich, Irina; Nagy, Nadine; Butte, Manish J.; Negrin, Robert S.; Wight, Thomas N.; Steinman, Lawrence; Bollyky, Paul L.

doi:10.1073/pnas.1525086113

Cited by 66 publications

(77 citation statements)

References 51 publications

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“…We demonstrated recently that 4-MU treatment prevents autoimmune disease in the EAE mouse model of MS [16]. We also examined whether the route of delivery impacted the efficacy of 4-MU in this model.…”

Section: Oral But Not Ip 4-mu Prevents Autoimmunitymentioning

confidence: 99%

“…This drug has been shown to inhibit HA production in multiple cell lines and tissue types both in vitro and in vivo [17,[37][38][39][40]. We have reported that 4-MU treatment prevented or reversed autoimmune disease in mouse models of T1D and MS [13,16].…”

Section: Introductionmentioning

confidence: 95%

“…Mouse splenocytes were isolated from BALB/c mice, as described previously [16]. Briefly, spleens were homogenized through a strainer and red blood cells were lysed in the cell suspensions.…”

Section: Immune Cell Activation and Cytokine Analysismentioning

confidence: 99%

“…2d). In the DORmO model, the weight of mice fed 4-MU chow eventually overtook those of mice fed control chow, due probably to 4-MU-mediated amelioration of disease severity in these mice [13,16].…”

Section: -Mu Induces Temporary Weight Lossmentioning

confidence: 99%

“…*P < 0Á05, **P < 0Á01, ***P < 0Á001, Mann-Whitney comparing treated mice with untreated mice (n 5 5-10 animals per group). cells in mice fed 5% 4-MU chow [16]. We therefore next examined how 4-MU dosage affects the impact of 4-MU on T cell subset polarization, as assessed by cytokine production.…”

Section: -Mu Dosage Impacts T Helper (Th) Subset Polarizationmentioning

confidence: 99%

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The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice

Kuipers

Nagy

Ruppert

et al. 2016

Clinical and Experimental Immunology

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1These authors contributed equally to this study. SummaryRecently, there has been considerable interest in using 4-methylumbelliferone (4-MU) to inhibit hyaluronan (HA) synthesis in mouse models of cancer, autoimmunity and a variety of other inflammatory disorders where HA has been implicated in disease pathogenesis. In order to facilitate future studies in this area, we have examined the dosing, treatment route, treatment duration and metabolism of 4-MU in both C57BL/6 and BALB/c mice. Mice fed chow containing 5% 4-MU, a dose calculated to deliver 250 mg/mouse/day, initially lose substantial weight but typically resume normal weight gain after 1 week. It also takes up to a week to see a reduction in serum HA in these animals, indicating that at least a 1-week loading period on the drug is required for most protocols. At steady state, more than 90% of the drug is present in plasma as the glucuronidated metabolite 4-methylumbelliferyl glucuronide (4-MUG), with the sulphated metabolite, 4-methylumbelliferyl sulphate (4-MUS) comprising most of the remainder. Chow containing 5% but not 0Á65% 4-MU was effective at preventing disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, as well as in the DORmO mouse model of autoimmune diabetes. While oral 4-MU was effective at preventing EAE, daily intraperitoneal injections of 4-MU were not. Factors potentially affecting 4-MU uptake and plasma concentrations in mice include its taste, short half-life and low bioavailability. These studies provide a practical resource for implementing oral 4-MU treatment protocols in mice.

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Section: Oral But Not Ip 4-mu Prevents Autoimmunitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Immune Cell Activation and Cytokine Analysismentioning

confidence: 99%

Section: -Mu Induces Temporary Weight Lossmentioning

confidence: 99%

Section: -Mu Dosage Impacts T Helper (Th) Subset Polarizationmentioning

confidence: 99%

See 3 more Smart Citations

The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice

Kuipers

Nagy

Ruppert

et al. 2016

Clinical and Experimental Immunology

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Cytokine Secreting Microparticles Engineer the Fate and the Effector Functions of T‐Cells

et al. 2018

Self Cite

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T-cell immunotherapy is a promising approach for cancer, infection, and autoimmune diseases. However, significant challenges hamper its therapeutic potential, including insufficient activation, delivery, and clonal expansion of T-cells into the tumor environment. To facilitate T-cell activation and differentiation in vitro, core-shell microparticles are developed for sustained delivery of cytokines. These particles are enriched by heparin to enable a steady release of interleukin-2 (IL-2), the major T-cell growth factor, over 10+ d. The controlled delivery of cytokines is used to steer lineage specification of cultured T-cells. This approach enables differentiation of T-cells into central memory and effector memory subsets. It is shown that the sustained release of stromal cell-derived factor 1α could accelerate T-cell migration. It is demonstrated that CD4+ T-cells could be induced to high concentrations of regulatory T-cells through controlled release of IL-2 and transforming growth factor beta. It is found that CD8+ T-cells that received IL-2 from microparticles are more likely to gain effector functions as compared with traditional administration of IL-2. Culture of T-cells within 3D scaffolds that contain IL-2-secreting microparticles enhances proliferation as compared with traditional, 2D approaches. This yield a new method to control the fate of T-cells and ultimately to new strategies for immune therapy.

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Glycosaminoglycans’ Ability to Promote Wound Healing: From Native Living Macromolecules to Artificial Biomaterials

Yang,

Lu,

Gou

et al. 2023

Advanced Science

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Glycosaminoglycans (GAGs) are important for the occurrence of signaling molecules and maintenance of microenvironment within the extracellular matrix (ECM) in living tissues. GAGs and GAG‐based biomaterial approaches have been widely explored to promote in situ tissue regeneration and repair by regulating the wound microenvironment, accelerating re‐epithelialization, and controlling ECM remodeling. However, most approaches remain unacceptable for clinical applications. To improve insights into material design and clinical translational applications, this review highlights the innate roles and bioactive mechanisms of native GAGs during in situ wound healing and presents common GAG‐based biomaterials and the adaptability of application scenarios in facilitating wound healing. Furthermore, challenges before the widespread commercialization of GAG‐based biomaterials are shared, to ensure that future designed and constructed GAG‐based artificial biomaterials are more likely to recapitulate the unique and tissue‐specific profile of native GAG expression in human tissues. This review provides a more explicit and clear selection guide for researchers designing biomimetic materials, which will resemble or exceed their natural counterparts in certain functions, thereby suiting for specific environments or therapeutic goals.

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Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization

Cited by 66 publications

References 51 publications

The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice

The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice

Cytokine Secreting Microparticles Engineer the Fate and the Effector Functions of T‐Cells

Glycosaminoglycans’ Ability to Promote Wound Healing: From Native Living Macromolecules to Artificial Biomaterials

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