Limitations of IL-2 and Rapamycin in Immunotherapy of Type 1 Diabetes

Baeyens, Audrey; Pérol, Louis; Fourcade, Gwladys; Cagnard, Nicolas; Carpentier, Wassila; Woytschak, Janine; Boyman, Onur; Hartemann, A.; Piaggio, Eliane

doi:10.2337/db13-0214

Cited by 42 publications

(46 citation statements)

References 46 publications

(69 reference statements)

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“…While low-dose rIL-2 administration selectively targets pancreatic Tregs and prevents diabetes development, treatment with high doses of rIL-2 (250,000–500,000 IU) enhances pathogenic effector responses and precipitates the onset of T1D in pre-diabetic NOD mice [35,93,99]. The opposite effects of high and low doses of IL-2 illustrate the differential effects of IL-2 dosage in regulating the Treg:Teff balance.…”

Section: Low-dose Il-2 Therapy To Treat Autoimmune Diseasementioning

confidence: 99%

“…In addition to a IL-2/IL-2R complex therapy, some groups have explored the potential benefits of combining IL-2 with rapamycin administration to more selectively target IL-2 to Tregs [35,105,107]. Rapamycin is an inhibitor of the PI3K/AKT/mTOR pathway that has the ability to prevent IL-2-dependent expansion of Teff without affecting Treg function [108].…”

Section: Low-dose Il-2 Therapy To Treat Autoimmune Diseasementioning

confidence: 99%

“…This differential effect is due to the fact that Tregs express high levels of the PTEN and, unlike effector CD4 + and CD8 + T cells, do not activate the downstream targets of the PI3K pathway in response to IL-2 [108]. Although combinational therapies have shown positive synergistic effects in some experimental models [105,107], further studies are needed to elucidate the overall clinical benefits and to explain the detrimental effects observed in other studies [35,109]. …”

Section: Low-dose Il-2 Therapy To Treat Autoimmune Diseasementioning

confidence: 99%

“…Recent studies show that low-dose IL-2 regimens can be safely administered to patients [31–34] and have potent immunosuppressive effects [31,32,35], thus evidencing the potential of low-dose IL-2-based immunotherapies to treat autoimmune disorders. Here, we review our current knowledge about low-dose IL-2-based immunotherapies, and discuss the potential mechanisms underlying the clinical benefits of these treatments, focusing on the potential role of IL-2-based immunotherapies in Treg and Tfh cells.…”

mentioning

confidence: 99%

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Beyond Regulatory T Cells: The Potential Role for IL-2 to Deplete T-Follicular Helper Cells and Treat Autoimmune Diseases

Ballesteros-Tato¹

2014

Immunotherapy

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Low-dose IL-2 administration suppresses unwanted immune responses in mice and humans, thus evidencing the potential of IL-2 to treat autoimmune disorders. Increased Tregs activity is one of the potential mechanisms by which low-dose IL-2 immunotherapy induces immunosuppression. In addition, recent data indicate that IL-2 may contribute to prevent unwanted self-reactive responses by preventing the developing of T-follicular helper cells, a CD4+ T-cell subset that expands in autoimmune disease patients and promotes long-term effector B-cell responses. Here we discuss the mechanisms underlying the clinical benefits of low-dose IL-2 administration, focusing on the role of this cytokine in promoting Treg-mediated suppression and preventing self-reactive T-follicular helper cell responses.

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Section: Low-dose Il-2 Therapy To Treat Autoimmune Diseasementioning

confidence: 99%

Section: Low-dose Il-2 Therapy To Treat Autoimmune Diseasementioning

confidence: 99%

Section: Low-dose Il-2 Therapy To Treat Autoimmune Diseasementioning

confidence: 99%

mentioning

confidence: 99%

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Beyond Regulatory T Cells: The Potential Role for IL-2 to Deplete T-Follicular Helper Cells and Treat Autoimmune Diseases

Ballesteros-Tato¹

2014

Immunotherapy

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“…In NOD mice, IL-2 in combination with rapamycin reduced β-cell division and glucose metabolism (Baeyens et al, 2013), despite previously being demonstrated to protect NOD mice from diabetes (Rabinovitch et al, 2002), and in other mouse models rapamycin reduced β-cell survival and function (Tanemura et al, 2012;Yang et al, 2012b), also providing a possible explanation for the outcome in humans. Translating therapies from mice to humans is therefore challenging, particularly with regard to IL-2 therapy in the context of T1D.…”

Section: Il-2 To Expand Tregmentioning

confidence: 97%

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

Reeves¹

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Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β cells. The current treatment for the fatal insulin-deficiency in T1D is injection of exogenous insulin. Despite the dramatic increase in survival from the use of exogenous insulin, complications develop from imperfect glycemic control and exogenous insulin does not rectify the underlying cause of disease, the diabetogenic autoimmune response. Hence, there is a need for an effective therapy that impedes the progress of the pathogenic autoimmune response. β cell-reactive CD8 + In the NOD mouse model of T1D, insulin is the primary β-cell antigen that elicits disease. As such, I have investigated T-cell tolerance to insulin in an adoptive transfer setting in which TCR transgenic (G9) CD8 + T cells specific for insulin B15-23 (InsB15-23) were transferred to transgenic mice over-expressing proinsulin in APC. Subsequently, I examined the effect of introducing transgenic proinsulin expression on diabetes development in wild type NOD mice.When transferred to mice transgenically expressing proinsulin, naïve G9 T cells proliferated extensively prior to undergoing rapid deletion. In proinsulin transgenic recipients, the remaining population of G9 T cells displayed reduced T-cell receptor (TCR) expression and bound less InsB15-23-loaded, H2-K d -tetramer compared to G9 T cells that had been transferred to non-transgenic NOD recipients. Interestingly, TCR down-regulation represented that which occurred for OVA-specific CD8 + T cells transferred to mice expressing OVA in APC in a non-autoimmune prone strain.Importantly, naïve G9 T cells did not expand or produce the important effector cytokine, interferon (IFN)-γ, in response to InsB15-23 immunisation after transfer to proinsulin transgenic mice. These data confirm naïve G9 T cells undergo rapid deletion and inactivation after transfer to mice transgenically-expressing proinsulin, despite genetic tolerance defects in NOD mice. Memory CD8 + T cells (Tmem) perpetuate β-cell autoimmunity and pose a distinct barrier to immunotherapy. It was pertinent to determine whether inactivation of insulin-specific CD8 + Tmem also occurs after transfer to mice expressing proinsulin in APC. To test inactivation of insulin-specific CD8 + Tmem, G9 Tmem were generated using an in vitro culture method. Cultured G9 Tmem were validated by assessing phenotypic markers and cytokine production. Similarly to naïve G9 T cells, G9 Tmem proliferated extensively and most G9 Tmem were rapidly deleted after transfer to mice overexpressing proinsulin in APC. The remaining, non-deleted population of G9 Tmem was infrequent ii and exhibited reduced TCR expression. Furthermore, G9 Tmem did not expand or produce IFN-γ in response to InsB15-23 immunisation, consistent with functional inactivation. These results demonstrate transgenic proinsulin expression in APC overcomes genetic defects in NOD mice to induce tolerance in insulin-specific CD8 + Tmem.From the data described above, transgenic proinsulin expression is tolerogenic for in...

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Biomaterials‐based nanoparticles conjugated to regulatory T cells provide a modular system for localized delivery of pharmacotherapeutic agents

Marshall

Cserny

Wang

et al. 2022

J Biomedical Materials Res

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Type 1 diabetes (T1D) presents with two therapeutic challenges: the need to correct underlying autoimmunity and restore β‐cell mass. We harnessed the unique capacity of regulatory T cells (Tregs) and the T cell receptor (TCR) to direct tolerance induction along with tissue‐localized delivery of therapeutic agents to restore endogenous β‐cell function. Specifically, we designed a combinatorial therapy involving biomaterials‐based poly(lactic‐co‐glycolic acid) nanoparticles co‐loaded with the Treg growth factor, IL‐2, and the β‐cell regenerative agent, harmine (a tyrosine‐regulated kinase 1A [DYRK1A] inhibitor), conjugated to the surface of Tregs. We observed continuous elution of IL‐2 and harmine from nanoparticles for at least 7 days in vitro. When conjugated to primary human Tregs, IL‐2 nanoparticles provided sufficient IL‐2 receptor signaling to support STAT5 phosphorylation for sustained phenotypic stability and viability in culture. Inclusion of poly‐L‐lysine (PLL) during nanoparticle‐cell coupling dramatically increased conjugation efficiency, providing sufficient IL‐2 to support in vitro proliferation of IL‐2‐dependent CTLL‐2 cells and primary murine Tregs. In 12‐week‐old female non‐obese diabetic mice, adoptive transfer of IL‐2/harmine nanoparticle‐conjugated NOD.BDC2.5 Tregs, which express an islet antigen‐specific TCR, significantly prevented diabetes demonstrating preserved in vivo viability. These data provide the preclinical basis to develop a biomaterials‐optimized cellular therapy to restore immune tolerance and promote β‐cell proliferation in T1D through receptor‐targeted drug delivery within pancreatic islets.

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Limitations of IL-2 and Rapamycin in Immunotherapy of Type 1 Diabetes

Cited by 42 publications

References 46 publications

Beyond Regulatory T Cells: The Potential Role for IL-2 to Deplete T-Follicular Helper Cells and Treat Autoimmune Diseases

Beyond Regulatory T Cells: The Potential Role for IL-2 to Deplete T-Follicular Helper Cells and Treat Autoimmune Diseases

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

Biomaterials‐based nanoparticles conjugated to regulatory T cells provide a modular system for localized delivery of pharmacotherapeutic agents

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