Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy

Wang, Duncheng; Shanina, Iryna; Toyofuku, Wendy M.; Horwitz, Marc S.; Scott, Mark D.

doi:10.1371/journal.pone.0145179

Cited by 9 publications

(88 citation statements)

References 54 publications

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“…The PEGylated cells themselves, or the resultant purified Treg cells, can be adoptively transferred to induce systemic tolerance in the recipient. Importantly, our studies demonstrated that the secretome of PEGylated-MLR also exerted a tolerogenic effect in vitro and in vivo [25][26][27][29][30][31][32][33][34]. In parallel to the PEGylated cells, the control MLR ( Figure 4B) was used to generate a proinflammatory secretome, or with further purification, miRNA preparation that could induce a controlled inflammatory response in unactivated T cells [25][26][27][29][30][31][32][33][34].…”

Section: A New Approach To the Biomodulation Of The Treg:teff Ratiomentioning

confidence: 85%

“…As demonstrated in Figure 7A, the onset and incidence of diabetes was assessed and correlated with the Treg:Teff ratio of the mice [31][32][33][34][35]. As shown, 75% of the untreated NOD mice, but only 40% of the TA1 treated mice, developed T1D.…”

Section: Treatment Of Autoimmune Diseases Via Treg:teff Modulationmentioning

confidence: 94%

“…In this chapter we will discuss a novel biomodulatory approach that more effectively, and directly, target the Treg:Teff ratio by increasing or decreasing Treg cells while simultaneously, and inversely, decreasing of increasing Teff subsets (Figure 4). This approach, derived from our work on the polymer-based bioengineering of allogeneic T cells and their use directly, or via the production of acellular microRNA (miRNA), to induce a tolerogenic or proinflammatory state characterized by significant changes in the Treg:Teff ratio [23][24][25][26][27][28][29][30][31][32][33][34][35].…”

Section: A New Approach To the Biomodulation Of The Treg:teff Ratiomentioning

confidence: 99%

“…Previous work from our laboratory demonstrated that the covalent grafting (PEGylation) of methoxy(polyethylene glycol) [mPEG] to one leukocyte population resulted in abrogation of the MHC-mediated proliferation of Teff cells [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Moreover, these studies demonstrated that, consequent to impaired cell:cell communication (Figure 4C), the weak allostimulation induced a tolerogenic/anergic state both in vitro and in vivo ( Figure 4A) [29][30][31][32][33][34]41]. The PEGylated cells themselves, or the resultant purified Treg cells, can be adoptively transferred to induce systemic tolerance in the recipient.…”

Section: A New Approach To the Biomodulation Of The Treg:teff Ratiomentioning

confidence: 99%

“…Importantly, the active component of the TA1 and IA1 therapeutics are miRNAsnot cytokines or other potential immunomodulatory effectors [31,34,35]. The role of miRNA can be seen by the loss of immunomodulatory activity of TA1 and IA1 conditioned murine plasma upon treatment with RNase ( Figure 6).…”

Section: A New Approach To the Biomodulation Of The Treg:teff Ratiomentioning

confidence: 99%

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Biological Modulation of the Treg:Teff Ratio: From Immunosuppression to Immunoactivation

Yang¹,

Scott²

2020

Immunosuppression

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T cell-mediated immunomodulation can be, in simple terms, defined as altering the normal Treg:Teff ratio. Immunosuppression skews the net Treg:Teff ratio toward the 'tolerogenic' Treg component, while immunoactivation skews the response toward the 'proinflammatory' Teff component. In the treatment of autoimmune diseases, achieving an immunosuppressive state is a desirable goal in order to prevent ongoing injury by activated Teff cells. In contrast, an innate, or induced, immunosuppressive state can be deleterious and prevent pathogen-induced disease while allow for the progression of cancer. Indeed, a current goal of cancer therapy is attenuating an existing endogenous immunosuppressive state that prevents effective T cell-mediated immunorecognition of cancer cells. Thus, the biological modulation of the Treg:Teff ratio provides a unique approach for treating both autoimmune diseases and cancers. Using a biomanufacturing system, miRNAenriched immunotherapeutic has been generated that either induce (TA1) or overcome (IA1) an immunosuppressive state. As will be shown, these therapeutics show efficacy both in vitro and in vivo in the prevention of autoimmune Type 1 diabetes and in enhancing the ability of resting immune cells to recognize and inhibit cancer cell growth. The successful development of these cost-effective, and easily biomanufactured, secretome-based therapeutics may prove useful in treating both autoimmune diseases and cancer.

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Section: A New Approach To the Biomodulation Of The Treg:teff Ratiomentioning

confidence: 85%

Section: Treatment Of Autoimmune Diseases Via Treg:teff Modulationmentioning

confidence: 94%

Section: A New Approach To the Biomodulation Of The Treg:teff Ratiomentioning

confidence: 99%

Section: A New Approach To the Biomodulation Of The Treg:teff Ratiomentioning

confidence: 99%

Section: A New Approach To the Biomodulation Of The Treg:teff Ratiomentioning

confidence: 99%

See 3 more Smart Citations

Biological Modulation of the Treg:Teff Ratio: From Immunosuppression to Immunoactivation

Yang¹,

Scott²

2020

Immunosuppression

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Differential Leukocyte MicroRNA Responses Following Pan T Cell, Allorecognition and Allosecretome-Based Therapeutic Activation

Yang

Toyofuku

Scott

2021

Arch. Immunol. Ther. Exp.

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Effective immunomodulation of T-cell responses is critical in treating both autoimmune diseases and cancer. Our previous studies have demonstrated that secretomes derived from control or methoxypolyethylene glycol mixed lymphocyte alloactivation assays exerted potent immunomodulatory activity that was mediated by microRNAs (miRNA). The immunomodulatory effects of biomanufactured miRNA-based allo-secretome therapeutics (SYN, TA1, IA1 and IA2) were compared to Pan T-cell activators (PHA and anti-CD3/CD28) and lymphocyte alloactivation. The differential effects of these activation strategies on resting peripheral blood mononuclear cells (PBMC) were assessed via T-cell proliferation, subset analysis and miRNA expression profiles. Mitogen-induced PBMC proliferation (> 85%) significantly exceeded that arising from either allostimulation (~ 30%) or the pro-inflammatory IA1 secretome product (~ 12%). Consequent to stimulation, the ratio of CD4 to CD8 cells of the resting PBMC (CD4:CD8; 1.7 ± 0.1) decreased in the Pan T cell, allrecognition and IA1 activated cells (averages of 1.1 ± 0.2; 1.2 ± 0.1 and 1.0 ± 0.1). These changes arose consequent to the expansion of both CD4+CD8+ and CD4–CD8– populations as well as the shrinkage of the CD4 subset and the expansion of the CD8 T cells. Importantly, these activation strategies induced vastly different miRNA expression profiles which were associated with significant differences in cellular differentiation and biological function. These findings support the concept that the “differential patterns of miRNA expression” regulate the biologic immune response in a “lock and key” manner. The biomanufacturing of miRNA-enriched secretome biotherapeutics may be a successful therapeutic approach for the systemic treatment of autoimmune diseases (TA1) and cancer (IA1).

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Inhibition of allogeneic cytotoxic T cell (CD8+) proliferation via polymer-induced Treg (CD4+) cells

et al. 2017

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While our previous studies have demonstrated that polymer-grafting to MHC disparate leukocytes inhibits CD4 cell proliferation, the effects of PEGylation on the alloproliferation of CD8 cytotoxic T cells (CTL) was not examined. As shown here, PEGylation of allogeneic leukocytes prevents the generation of the CTL response responsible for acute rejection. The loss of CTL proliferation is consequent to the polymer-based attenuation of allorecognition and the induction of T regulatory cells (Tregs). Interestingly, the Tregs are primarily generated via the differentiation of non-proliferating naive T cells. Importantly, the Tregs are functional and effectively induce a tolerogenic environment when transferred to an alloresponsive environment. The use of polymer-modified leukocytes provides a unique approach to effectively maximize the biologic production of functional Tregs both in vitro and in vivo. By using this approach it may be possible to attenuate unwanted alloresponses (e.g., graft rejection) or to treat autoimmune diseases.

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Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy

Cited by 9 publications

References 54 publications

Biological Modulation of the Treg:Teff Ratio: From Immunosuppression to Immunoactivation

Biological Modulation of the Treg:Teff Ratio: From Immunosuppression to Immunoactivation

Differential Leukocyte MicroRNA Responses Following Pan T Cell, Allorecognition and Allosecretome-Based Therapeutic Activation

Inhibition of allogeneic cytotoxic T cell (CD8+) proliferation via polymer-induced Treg (CD4+) cells

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