Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice

Otomo, Kotaro; Koga, Tomohiro; Mizui, Masayuki; Yoshida, Norimitsu; Kriegel, Christina; Bickerton, Sean; Fahmy, Tarek M.; Tsokos, George C.

doi:10.4049/jimmunol.1501603

Cited by 60 publications

(37 citation statements)

References 16 publications

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“…PLGA NPs encapsulating tolerogenic peptides or peptides and rapamycin that targeted APCs prevented or reversed disease in animal models of autoimmune diabetes and multiple sclerosis through TGFβ‐dependent induction of Treg cells . Moreover, NP‐mediated delivery of the immunosuppressive drug Ca 2+ /calmodulin‐dependent protein kinase IV inhibitor ameliorated murine SLE .…”

Section: Discussionmentioning

confidence: 99%

Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell–Targeted Nanoparticles Loaded With Interleukin‐2 and Transforming Growth Factor β

Horwitz

Bickerton

Koss

et al. 2019

Arthritis & Rheumatology

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Objective. To develop a nanoparticle (NP) platform that can expand both CD4+ and CD8+ Treg cells in vivo for the suppression of autoimmune responses in systemic lupus erythematosus (SLE).Methods. Poly(lactic-co-glycolic acid) (PLGA) NPs encapsulating interleukin-2 (IL-2) and transforming growth factor β (TGFβ) were coated with anti-CD2/CD4 antibodies and administered to mice with lupus-like disease induced by the transfer of DBA/2 T cells into (C57BL/6 × DBA/2)F 1 (BDF1) mice. The peripheral frequency of Treg cells was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti-double-stranded DNA antibody levels by enzyme-linked immunosorbent assay. Kidney disease was defined as the presence of proteinuria or renal histopathologic features.Results. Anti-CD2/CD4 antibody-coated, but not noncoated, NPs encapsulating IL-2 and TGFβ induced CD4+ and CD8+ FoxP3+ Treg cells in vitro. The optimal dosing regimen of NPs for expansion of CD4+ and CD8+ Treg cells was determined in in vivo studies in mice without lupus and then tested in BDF1 mice with lupus. The administration of anti-CD2/CD4 antibody-coated NPs encapsulating IL-2 and TGFβ resulted in the expansion of CD4+ and CD8+ Treg cells, a marked suppression of anti-DNA antibody production, and reduced renal disease.Conclusion. This study shows for the first time that T cell-targeted PLGA NPs encapsulating IL-2 and TGFβ can expand both CD4+ and CD8+ Treg cells in vivo and suppress murine lupus. This approach, which enables the expansion of Treg cells in vivo and inhibits pathogenic immune responses in SLE, could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Treg cell function associated with IL-2 deficiency.

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Section: Discussionmentioning

confidence: 99%

Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell–Targeted Nanoparticles Loaded With Interleukin‐2 and Transforming Growth Factor β

Horwitz

Bickerton

Koss

et al. 2019

Arthritis & Rheumatology

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“…This treatment has been shown to decrease IL-17 production and reduce proteinuria in the model animals. However, it did not reduce the titers of anti-DNA antibodies assuming that the treatment modality has no effect on autoreactive B cells [37]. …”

Section: Discussionmentioning

confidence: 99%

Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype

Chimote

Hajdú

Kottyan

et al. 2016

Journal of Autoimmunity

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Ca2+ signaling controls activation and effector functions of T lymphocytes. Ca2+ levels also regulate NFAT activation and CD40 ligand (CD40L) expression in T cells. CD40L in activated memory T cells binds to its cognate receptor, CD40, on other cell types resulting in the production of antibodies and pro-inflammatory mediators. The CD40L/CD40 interaction is implicated in the pathogenesis of autoimmune disorders and CD40L is widely recognized as a therapeutic target. Ca2+ signaling in T cells is regulated by Kv1.3 channels. We have developed lipid nanoparticles that deliver Kv1.3 siRNAs (Kv1.3-NPs) selectively to CD45RO+ memory T cells and reduce the activation-induced Ca2+ influx. Herein we report that Kv1.3-NPs reduced NFAT activation and CD40L expression exclusively in CD45RO+ T cells. Furthermore, Kv1.3-NPs suppressed cytokine release and induced a phenotype switch of T cells from predominantly memory to naïve. These findings indicate that Kv1.3-NPs operate as targeted immune suppressive agents with promising therapeutic potentials.

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“…NGs containing KN93 and mycophenolic acid as therapeutic moieties are prepared by cross-linking and polymerization of the diacrylate-terminated co-block polymer of poly(lactic acid-co-ethylene glycol), CD [111]. The former specifically targeted CD4+T cells and reduced experimental autoimmune encephalomyelitis while later becoming effective for treating lupus by reducing cytokine production and enhancing immunosuppression [112,113].…”

Section: Pain Managementmentioning

confidence: 99%

Polymeric Nanogels as Versatile Nanoplatforms for Biomedical Applications

Sabir

Asad

Qindeel

et al. 2019

Journal of Nanomaterials

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Nanomaterials have found extensive biomedical applications in the past few years because of their small size, low molecular weight, larger surface area, enhanced biological, and chemical reactivity. Among these nanomaterials, nanogels (NGs) are promising drug delivery systems and are composed of cross-linked polymeric nanoparticles ranging from 100 to 200 nm. NGs represent an innovative zone of research with speedy developments taking place on a daily basis. An incredible amount of focus is placed on the fabrication of NGs with novel polymers to achieve better control over the drug release. This review article covers a number of aspects of NGs including their types, associated pros and cons, and methods of preparation along with technical and economical superiority and therapeutic efficacy over each other. The last part of review summarizes the applications of NGs in the drug delivery and treatment of various diseases including brain disease, cardiovascular diseases, oxidative stress, diabetes, cancer therapy, tissue engineering, gene therapy, inflammatory disorders, pain management, ophthalmic and autoimmune diseases, and their future challenges. NGs appear to be an outstanding nominee for drug delivery systems, and further study is required to explore their interactions at the cellular and molecular levels.

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Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice

Cited by 60 publications

References 16 publications

Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell–Targeted Nanoparticles Loaded With Interleukin‐2 and Transforming Growth Factor β

Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell–Targeted Nanoparticles Loaded With Interleukin‐2 and Transforming Growth Factor β

Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype

Polymeric Nanogels as Versatile Nanoplatforms for Biomedical Applications

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