A Treg-Selective IL-2 Mutein Prevents the Formation of Factor VIII Inhibitors in Hemophilia Mice Treated With Factor VIII Gene Therapy

Chen, Alex C.; Cai, Xinghan; Li, Chong; Khoryati, Liliane; Gavin, Marc A.; Miao, Carol H.

doi:10.3389/fimmu.2020.00638

Cited by 12 publications

(8 citation statements)

References 68 publications

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“…In parallel, mouse IL-2 muteins with enhanced Treg selectivity and in vivo half-life, expanded highly suppressive Tregs in tissues ( 298 ) and controlled autoimmunity in the mouse NOD T1D model ( 299 ). Moreover, the IL-2 mutein prevented antibody response to FVIII in a mouse model of hemophilia A ( 300 ), further supporting that Tregs responding to an attenuated IL-2 mutein exert immune suppressive effects. Another class of IL-2 muteins with enhanced affinity to CD25 has also been described, although the activity and selectivity profile of such muteins need to be further evaluated ( 294 ).…”

Section: Il2-mediated Therapymentioning

confidence: 86%

Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, T cell Therapy, and IL-2 Therapy

2021

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Autoimmune diseases affect roughly 5-10% of the total population, with women affected more than men. The standard treatment for autoimmune or autoinflammatory diseases had long been immunosuppressive agents until the advent of immunomodulatory biologic drugs, which aimed at blocking inflammatory mediators, including proinflammatory cytokines. At the frontier of these biologic drugs are TNF-α blockers. These therapies inhibit the proinflammatory action of TNF-α in common autoimmune diseases such as rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn’s disease. TNF-α blockade quickly became the “standard of care” for these autoimmune diseases due to their effectiveness in controlling disease and decreasing patient’s adverse risk profiles compared to broad-spectrum immunosuppressive agents. However, anti-TNF-α therapies have limitations, including known adverse safety risk, loss of therapeutic efficacy due to drug resistance, and lack of efficacy in numerous autoimmune diseases, including multiple sclerosis. The next wave of truly transformative therapeutics should aspire to provide a cure by selectively suppressing pathogenic autoantigen-specific immune responses while leaving the rest of the immune system intact to control infectious diseases and malignancies. In this review, we will focus on three main areas of active research in immune tolerance. First, tolerogenic vaccines aiming at robust, lasting autoantigen-specific immune tolerance. Second, T cell therapies using Tregs (either polyclonal, antigen-specific, or genetically engineered to express chimeric antigen receptors) to establish active dominant immune tolerance or T cells (engineered to express chimeric antigen receptors) to delete pathogenic immune cells. Third, IL-2 therapies aiming at expanding immunosuppressive regulatory T cells in vivo.

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Section: Il2-mediated Therapymentioning

confidence: 86%

Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, T cell Therapy, and IL-2 Therapy

2021

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“…We and others have hypothesized that blocking CD25 would favor the accumulation of bioactive IL-2 and a subsequent increase in Treg cells that, in turn, would downregulate the inflammatory reaction ( Nihei et al., 2014 ; Huss et al., 2015 ). So, the game played by IL-2 and Tregs would be very sensitive to possible therapeutic manipulations by increasing or decreasing the availability of IL-2 in many different ways ( Boyman et al., 2006 ; Arenas-Ramirez et al., 2015 ; Chen et al., 2020 ; Khoryati et al., 2020 ; Solomon et al., 2020 ). Therefore, we hypothesized that blocking IL-2 during the initial phases of T. cruzi infection would also cause modifications in the inflammatory reaction.…”

Section: Discussionmentioning

confidence: 99%

The Blockade of Interleukin-2 During the Acute Phase of Trypanosoma cruzi Infection Reveals Its Dominant Regulatory Role

Nihei

Cardillo

Mengel

2021

Front. Cell. Infect. Microbiol.

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Trypanosoma cruzi infection causes Chagas’ disease in humans. The infection activates the innate and adaptative immunity in an orchestrated immune response to control parasite growth, guaranteeing host survival. Despite an effective immune response to the parasite in the acute phase, the infection progresses to a chronic stage. The parasite infects different tissues such as peripheral neurons, the brain, skeletal muscle, and heart muscle, among many others. It is evident now that tissue-specific immune responses may develop along with anti-parasite immunity. Therefore, mechanisms to regulate immunity and to ensure tissue-specific tolerance are operating during the infection. Studying those immunoregulatory mechanisms is fundamental to improve host protection or control inflammatory reactions that may lead to pathology. The role of IL-2 during T. cruzi infection is not established. IL-2 production by T cells is strongly down-modulated early in the disease by unknown mechanisms and remains low during the chronic phase of the disease. IL-2 activates NK cells, CD4, and CD8 T cells and may be necessary to immunity development. Also, the expansion and maintenance of regulatory T cells require IL-2. Thus, IL-2 may be a key cytokine involved in promoting or down-regulating immune responses, probably in a dose-dependent manner. This study blocked IL-2 during the acute T. cruzi infection by using a neutralizing monoclonal antibody. The results show that parasitemia and mortality rate was lower in animals treated with anti-IL-2. The percentages and total numbers of CD4+CD25+Foxp3+ T cells diminished within three weeks of infection. The numbers of splenic activated/memory CD4 and CD8 splenic T cells increased during the acute infection. T cells producing IFN-γ, TNF-α and IL-10 also augmented in anti-IL-2-treated infected mice. The IL-2 blockade also increased the numbers of inflammatory cells in the heart and skeletal muscles and the amount of IL-17 produced by heart T cells. These results suggest that IL-2 might be involved in the immune regulatory response during the acute T. cruzi infection, dampening T cell activation through the expansion/maintenance of regulatory T cells and regulating IL-17 production. Therefore, the IL-2 pathway is an attractive target for therapeutic purposes in acute and chronic phases of Chagas’ disease.

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“…These studies also demonstrated that Treg enrichment before FVIII challenge was more effective than concomitant treatment (24). Leveraging the same system, we recently reported that combining a Treg-selective Fc-fused IL-2 mutein with FVIII gene therapy also established durable suppression of FVIII Ab formation (25,26).…”

Section: Introductionmentioning

confidence: 86%

In Vivo Expansion of Antigen-Specific Regulatory T Cells through Staggered Fc.IL-2 Mutein Dosing and Antigen-Specific Immunotherapy

et al. 2021

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In mice, Ag administration in the absence of adjuvant typically elicits tolerogenic immune responses through the deletion or inactivation of conventional CD4 T cells and the formation or expansion of regulatory CD4 T cells (Treg). Although these Ag-specific immunotherapy (ASI) approaches are currently under clinical development to treat autoinflammatory conditions, efficacy and safety may be variable and unpredictable because of the diverse activation states of immune cells in subjects with autoimmune and allergic diseases. To reliably induce Ag-specific tolerance in patients, novel methods to control T cell responses during ASI are needed, and strategies that permanently increase Treg frequencies among Ag-specific CD4 T cells may provide long-lasting immunosuppression between treatments. In this study, we present an approach to durably increase the frequency of Ag-specific Treg in mice by administering ASI when Treg numbers are transiently increased with individual doses of a half-life-extended Treg-selective IL-2 mutein. Repeated weekly cycles of IL-2 mutein doses (day 0) followed by ASI (day 3) resulted in a 3-to 5-fold enrichment in Treg among Ag-responsive CD4 T cells. Expanded Ag-specific Treg persisted for more than 3 wk following treatment cessation, as well as through an inflammatory T cell response to an Ag-expressing virus. Combining Treg enrichment with ASI has the potential to durably treat autoimmune disease or allergy by increasing the Treg/conventional CD4 T cell ratio among autoantigen-or allergen-specific T cells. ImmunoHorizons, 2021, 5: 782-791.

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A Treg-Selective IL-2 Mutein Prevents the Formation of Factor VIII Inhibitors in Hemophilia Mice Treated With Factor VIII Gene Therapy

Cited by 12 publications

References 68 publications

Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, T cell Therapy, and IL-2 Therapy

Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, T cell Therapy, and IL-2 Therapy

The Blockade of Interleukin-2 During the Acute Phase of Trypanosoma cruzi Infection Reveals Its Dominant Regulatory Role

In Vivo Expansion of Antigen-Specific Regulatory T Cells through Staggered Fc.IL-2 Mutein Dosing and Antigen-Specific Immunotherapy

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