A Short Pulse of IL-4 Delivered by DCs Electroporated With Modified mRNA Can Both Prevent and Treat Autoimmune Diabetes in NOD Mice

Creusot, Rémi J.; Chang, Pearl; Healey, Dan; Tcherepanova, Irina Y.; Nicolette, Charles A.; Fathman, C. Garrison

doi:10.1038/mt.2010.146

Cited by 48 publications

(56 citation statements)

References 29 publications

(46 reference statements)

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“…Thus, the use of receptor-selective superkines in mouse models will help to both better delineate the mode of action of therapies involving IL-4 and improve their efficacy 29,30 .…”

Section: Discussionmentioning

confidence: 99%

Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines

Junttila¹,

Creusot²,

Moraga³

et al. 2012

Nat Chem Biol

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Cytokines dimerize their receptors, with binding of the “second chain” triggering signaling. In the interleukin (IL)-4/13 system, different cell types express varying levels of alternative second receptor chains (γc or IL-13Rα1), forming functionally distinct Type-I or Type-II complexes. We manipulated the affinity and specificity of second chain recruitment by human IL-4. A Type-I receptor-selective IL-4 ‘superkine’ with 3700-fold higher affinity for γc was 3-10 fold more potent than wild-type IL-4. Conversely, a variant with high affinity for IL-13Rα1 more potently activated cells expressing the Type-II receptor, and induced differentiation of dendritic cells from monocytes, implicating the Type-II receptor in this process. Superkines exhibited signaling advantages on cells with lower second chain levels. Comparative transcriptional analysis reveals that the superkines induce largely redundant gene expression profiles. Variable second chain levels can be exploited to redirect cytokines towards distinct cell subsets and elicit novel actions, potentially improving the selectivity of cytokine therapy.

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“…Thus, the use of receptor-selective superkines in mouse models will help to both better delineate the mode of action of therapies involving IL-4 and improve their efficacy 29,30 .…”

Section: Discussionmentioning

confidence: 99%

Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines

Junttila¹,

Creusot²,

Moraga³

et al. 2012

Nat Chem Biol

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“…These cells are H2-K d+ and I-A g7− fibroblastic reticular cells. DCs were generated in vitro from the bone marrow of NOD mice depleted of T cells, B cells, and granulocytes after 6–7 days of culture in the presence of GM-CSF and IL-4 (Peprotech, 10 ng/mL) 52 . DAPg7 and PCRC-5 cells were transduced with the different LV particles, sorted based on similar GFP levels between transduced lines.…”

Section: Methodsmentioning

confidence: 99%

Efficient Presentation of Multiple Endogenous Epitopes to Both CD4 + and CD8 + Diabetogenic T Cells for Tolerance

Dastagir

Postigo-Fernandez

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Antigen-specific immunotherapy of type 1 diabetes, typically via delivery of a single native β cell antigen, has had little clinical benefit to date. With increasing evidence that diabetogenic T cells react against multiple β cell antigens, including previously unappreciated neo-antigens that can be emulated by mimotopes, a shift from protein- to epitope-based therapy is warranted. To this end, we aimed to achieve efficient co-presentation of multiple major epitopes targeting both CD4+ and CD8+ diabetogenic T cells. We have compared native epitopes versus mimotopes as well as various targeting signals in an effort to optimize recognition by both types of T cells in vitro. Optimal engagement of all T cells was achieved with segregation of CD8 and CD4 epitopes, the latter containing mimotopes and driven by endosome-targeting signals, after delivery into either dendritic or stromal cells. The CD4+ T cell responses elicited by the endogenously delivered epitopes were comparable with high concentrations of soluble peptide and included functional regulatory T cells. This work has important implications for the improvement of antigen-specific therapies using an epitope-based approach to restore tolerance in type 1 diabetes and in a variety of other diseases requiring concomitant targeting of CD4+ and CD8+ T cells.

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“…In contrast, other studies have shown that disease remission can be established when administering unloaded tolDCs . This may suggest that tolDCs are able to take up the relevant antigen in vivo .…”

Section: The Problem Of Targeting Autoantigen(s) – Which Ones?mentioning

confidence: 80%

“…27,42,43 More recent research shows that this is also applicable in other autoimmune diseases. 44 Furthermore, when comparing the therapeutic action of unloaded tolDCs and tolDCs loaded with a disease relevant peptide (MOG [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] in the experimental autoimmune encephalomyelitis model, Mansilla et al 45 showed that although the unloaded tolDCs inhibited disease symptoms, the MOG 40-55 -loaded tolDCs diminished disease even more.…”

Section: Tolerogenic Dendritic Cells As a Therapeutic Toolmentioning

confidence: 99%

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Targeting of tolerogenic dendritic cells towards heat‐shock proteins: a novel therapeutic strategy for autoimmune diseases?

et al. 2017

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SummaryTolerogenic dendritic cells (tolDCs) are a promising therapeutic tool to restore immune tolerance in autoimmune diseases. The rationale of using tolDCs is that they can specifically target the pathogenic T-cell response while leaving other, protective, T-cell responses intact. Several ways of generating therapeutic tolDCs have been described, but whether these tolDCs should be loaded with autoantigen(s), and if so, with which autoantigen(s), remains unclear. Autoimmune diseases, such as rheumatoid arthritis, are not commonly defined by a single, universal, autoantigen. A possible solution is to use surrogate autoantigens for loading of tolDCs. We propose that heat-shock proteins may be a relevant surrogate antigen, as they are evolutionarily conserved between species, ubiquitously expressed in inflamed tissues and have been shown to induce regulatory T cells, ameliorating disease in various arthritis mouse models. In this review, we provide an overview on how immune tolerance may be restored by tolDCs, the problem of selecting relevant autoantigens for loading of tolDCs, and why heat-shock proteins could be used as surrogate autoantigens.

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A Short Pulse of IL-4 Delivered by DCs Electroporated With Modified mRNA Can Both Prevent and Treat Autoimmune Diabetes in NOD Mice

Cited by 48 publications

References 29 publications

Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines

Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines

Efficient Presentation of Multiple Endogenous Epitopes to Both CD4 + and CD8 + Diabetogenic T Cells for Tolerance

Targeting of tolerogenic dendritic cells towards heat‐shock proteins: a novel therapeutic strategy for autoimmune diseases?

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