FK506 as an adjuvant of tolerogenic DNA vaccination for the prevention of experimental autoimmune encephalomyelitis

Kang, Youmin; Zhao, Jia; Liu, Yue; Chen, Aoshuang; Zheng, Guoxing; Yu, Yang; Mi, Jianjie; Zou, Qiang; Wang, Bin

doi:10.1002/jgm.1387

Cited by 19 publications

(25 citation statements)

References 30 publications

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“…Addition of antigen specificity to such an approach may reduce undesired side effects associated with global immunosuppression that accompanies many of the current immunomodulatory therapies available (4-7). Indeed, several groups have begun investigating antigen-specific immunotherapies to treat autoimmune disorders (22)(23)(24)(25)(26)(27)(28)(32)(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

Northrup

Sestak

Sullivan

et al. 2014

AAPS J

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Abstract. Autoimmune diseases such as multiple sclerosis (MS) are characterized by the breakdown of immune tolerance to autoantigens. Targeting surface receptors on immune cells offers a unique strategy for reprogramming immune responses in autoimmune diseases. The B7 signaling pathway was targeted using adaptations of soluble antigen array (SAgA) technology achieved by covalently linking B7-binding peptides and disease causing autoantigen (proteolipid peptide (PLP)) to hyaluronic acid (HA). We hypothesized that co-delivery of a B7-binding peptide and autoantigen would suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Three independent B7-targeted SAgAs were created containing peptides to either inhibit or potentially stimulate the B7 signaling pathway. Surprisingly, all SAgAs were found to suppress EAE disease symptoms. Altered cytokine expression was observed in primary splenocytes isolated from SAgA-treated mice, indicating that SAgAs with different B7-binding peptides may suppress EAE through different immunological mechanisms. This antigenspecific immunotherapy using SAgAs can successfully suppress EAE through co-delivery of autoantigen and peptides targeting with the B7 signaling pathway.KEY WORDS: antigen-specific immunotherapy; B7/CD28:CTLA-4 co-stimulatory pathway; experimental autoimmune encephalomyelitis (EAE); proteolipid peptide; soluble antigen array.

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Section: Discussionmentioning

confidence: 99%

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

Northrup

Sestak

Sullivan

et al. 2014

AAPS J

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“…In addition, DNA vaccination may activate different effectors including cytotoxic responses and autoantibody production which can lead to different effect of DNA vaccination on EAE prevention and treatment [19]. We previously found naïve mice immunized with p2MOG35/FK506 markedly impaired the Th17/Th1 responses and increased Th2 responses for EAE prevention [4]. In present study, p2MOG35/FK506 treatment of EAE mice suppressed Th17/Th1 cells responses consistently while Th2 cells responses was not enhanced.…”

Section: Discussionmentioning

confidence: 44%

“…FK506, as immunosuppressive agent, effectively promoted immunologic tolerance [19]. We previously found that naïve mice immunized with p2MOG35/FK506 induced Treg cells and effectively prevented EAE [4]. Here, the relevance of these findings was established for EAE treatment, in which p2MOG35/FK506 also augmented the induction of Treg cells and resulted in amelioration of EAE.…”

Section: Discussionmentioning

confidence: 83%

“…EAE can be induced in rodents by immunization with myelin proteins, such as myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) or peptides [2], [3]. Much work has been focused on devising strategies to enhance therapeutic induction of Treg cells, which can be achieved by using DNA vaccine encoding autoantigens or derived peptides [4], [5], [6]. The induction of autoantigen-specific Treg cells can result in the local dampening of autoimmune processes even if the antigen specificities of the autoaggressive T cells are not known.…”

Section: Introductionmentioning

confidence: 99%

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Treg Cell Resistance to Apoptosis in DNA Vaccination for Experimental Autoimmune Encephalomyelitis Treatment

et al. 2012

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BackgroundRegulatory T (Treg) cells can be induced with DNA vaccinations and protect mice from the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Tacrolimus (FK506) has been shown to have functions on inducing immunosuppression and augmenting apoptosis of pathologic T cells in autoimmune disease. Here we examined the therapeutic effect of DNA vaccine in conjunction with FK506 on EAE.Methodology/Principal FindingsAfter EAE induction, C57BL/6 mice were treated with DNA vaccine in conjunction with FK506. Functional Treg cells were induced in treated EAE mice and suppressed Th1 and Th17 cell responses. Infiltrated CD4 T cells were reduced while Treg cells were induced in spinal cords of treated EAE mice. Remarkably, the activated CD4 T cells augmented apoptosis, but the induced Treg cells resisted apoptosis in treated EAE mice, resulting in alleviation of clinical EAE severity.Conclusions/SignificanceDNA vaccine in conjunction with FK506 treatment ameliorates EAE by enhancing apoptosis of CD4 T cells and resisting apoptosis of induced Treg cells. Our findings implicate the potential of tolerogenic DNA vaccines for treating MS.

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“…This concept and its potential application to trigger self-tolerance in autoimmune diseases were conceived by Kang et al [130]. These authors validated this hypothesis by demonstrating that FK506 (tacrolimus) associated with MOG was prophylactic in encephalomyelitis [131]. In this context, we hypothesized that active VitD could also behave as a tolerogenic adjuvant if associated with a CNS-specific antigen.…”

Section: Prophylactic Effect Of Vitd On Eaementioning

confidence: 78%

Therapeutic and Prophylactic Potential of Vitamin D for Multiple Sclerosis

Zorzella-Pezavento¹,

Ishikawa²,

Fraga-Silva³

et al. 2017

A Critical Evaluation of Vitamin D - Clinical Overview

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A plethora of investigations demonstrated that vitamin D (VitD) has a broad immunomodulatory potential. It induces tolerogenic dendritic cells in vitro leading to the development of regulatory T cells that have a key role in immunomodulation of autoimmune diseases including multiple sclerosis (MS). Studies showed that many MS patients present lower serum levels of VitD than healthy subjects. In addition, VitD supplementation has been associated with a reduced relative risk of developing MS. Considering the alterations in VitD levels in patients and also the immunomodulatory properties of VitD, it would be interesting to evaluate VitD potential as a tolerogenic adjuvant in experimental models of MS. In this context, our research team has been investigating strategies employing VitD to establish an in vivo tolerance state toward central nervous system antigens in experimental autoimmune encephalomyelitis (EAE). We observed that the association between a myelin peptide and VitD determined both therapeutic and prophylactic effects on EAE development.

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FK506 as an adjuvant of tolerogenic DNA vaccination for the prevention of experimental autoimmune encephalomyelitis

Abstract: DNA vaccination, when applied with an immunosuppressant as adjuvant, can induce antigen-specific tolerance and prevent autoimmune disease.

Cited by 19 publications

References 30 publications

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

Treg Cell Resistance to Apoptosis in DNA Vaccination for Experimental Autoimmune Encephalomyelitis Treatment

Therapeutic and Prophylactic Potential of Vitamin D for Multiple Sclerosis

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