Chapter III. Re-establishing Tolerance

Type 1 Diabetes Therapy Beyond T Cell Targeting: Monocytes, B Cells, and Innate Lymphocytes

F. Susan Wong¹, Li Wen²

Abstract

Recent clinical trials, investigating type 1 diabetes (T1D), have focused mainly on newly diagnosed individuals who have developed diabetes. We need to continue our efforts to understand disease processes and to rationally design interventions that will be safe and specific for disease, but at the same time not induce undesirable immunosuppression. T cells are clearly involved in the pathogenesis of T1D, and have been a major focus for both antigen-specific and non-antigen-specific therapy, but thus far no single strategy has emerged as superior. As T1D is a multifactorial disease, in which multiple cell types are involved, some of these pathogenic and regulatory cell pathways may be important to consider. In this review, we examine evidence for whether monocytes, B cells, and innate lymphocytes, including natural killer cells, may be suitable targets for intervention.

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Targeted Antigen Delivery to DEC-205⁺ Dendritic Cells for Tolerogenic Vaccination

Cathleen Petzold¹, Sonja Schallenberg², Joel N.H. Stern³, Karsten Kretschmer²

Abstract

Dendritic cells (DCs) and Foxp3-expressing CD4⁺ regulatory T (Treg) cells play non-redundant roles in the maintenance of peripheral tolerance to self-antigens, thereby preventing fatal autoimmunity. A common hallmark of intra- and extra-thymic Treg cell lineage commitment is the induction of Foxp3 expression as a consequence of appropriate T cell receptor engagement with MHC class II:agonist ligand. It has now become increasingly clear that agonist ligand presentation by immature DCs in the steady state induces T cell tolerance by both recessive and dominant mechanisms, rather than promoting productive T helper cell responses. In this context, the ability of steady-state DCs to promote the extrathymic conversion of initially naïve CD4⁺Foxp3^- T cells into Foxp3⁺ Treg cells is of particular interest as it provides novel perspectives to enhance antigen-specific Treg cell function in clinical settings of unwanted immunity, such as β-cell autoimmunity.

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Tolerance Strategies Employing Antigen-Coupled Apoptotic Cells and Carboxylated PLG Nanoparticles for the Treatment of Type 1 Diabetes

Suchitra Prasad, Dan Xu, Stephen D. Miller

Abstract

The development of therapies that specifically target autoreactive immune cells for the prevention and treatment of type 1 diabetes (T1D) without inducing generalized immunosuppression that often compromises the host's ability to clear non-self antigen is highly desired. This review discusses the mechanisms and potential therapeutic applications of antigen-specific T cell tolerance techniques using syngeneic apoptotic cellular carriers and synthetic nanoparticles that are covalently cross-linked to diabetogenic peptides or proteins through ethylene carbodiimide (ECDI) to prevent and treat T1D. Experimental models have demonstrated that intravenous injection of autoantigen decorated splenocytes and biodegradable nanoparticles through ECDI fixation effectively induce and maintain antigen-specific T cell abortive activation and anergy by T cell intrinsic and extrinsic mechanisms. The putative mechanisms include, but are not limited to, the uptake and processing of antigen-coupled nanoparticles or apoptotic cellular carriers for tolerogenic presentation by host splenic antigen-presenting cells, the induction of regulatory T cells, and the secretion of immune-suppressive cytokines, such as IL-10 and TGF-β. The safety profile and efficacy of this approach in preclinical animal models of T1D, including non-obese diabetic (NOD), BDC2.5 transgenic, and humanized mice, have been extensively investigated, and will be the focus of this review. Translation of this approach to clinical trials of T1D and other T cell-mediated autoimmune diseases will also be reviewed in this chapter.

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Clinical Potential of Antigen-Specific Therapies in Type 1 Diabetes

Ken T. Coppieters¹, Birgit Sehested Hansen², Matthias G. von Herrath^1,3

Abstract

In type 1 diabetes (T1D), pancreatic beta-cells are attacked and destroyed by the immune system, which leads to a loss of endogenous insulin secretion. The desirable outcome of therapeutic intervention in autoimmune diseases is the restoration of immune tolerance to prevent organ damage. Past trials with immune suppressive drugs highlight the fact that T1D is in principle a curable condition. However, the barrier in T1D therapy in terms of drug safety is set particularly high because of the predominantly young population and the good prognosis associated with modern exogenous insulin therapy. Thus, there is a general consensus that chronic immune suppression is associated with unacceptable long-term safety risks. On the other hand, immune-modulatory biologicals have recently failed to confer significant protection in phase 3 clinical trials. However, the concept of antigen-specific tolerization may offer a unique strategy to safely induce long-term protection against T1D. In this review, we analyze the potential reasons for the failure of the different tolerization therapies, and describe how the concept of antigen-specific toleraization may overcome the obstacles associated with clinical therapy in T1D.

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Interleukin-1 Antagonists and Other Cytokine Blockade Strategies for Type 1 Diabetes

Thomas Mandrup-Poulsen

Abstract

Proinflammatory cytokines stimulate adaptive immunity and attenuate T cell regulation and tolerance induction. They also profoundly impair β-cell function, proliferation, and viability, activities of similar importance in the context of type 1 diabetes (T1D). Detailed knowledge of the molecular mechanisms of β-cell toxicity has been gathered within the last 2-3 decades. However, the efficacy of individual proinflammatory cytokine blockade in animal models of T1D has been inconsistent and generally modest, except in the context of islet transplantation. This suggests that the timing of the cytokine blockade relative to anti-β-cell immune activation is critical, and that combination therapy may be required. In randomized, placebo-controlled, clinical trials of limited power, TNF-α (but not IL-1) blockade has yielded moderate but significant improvements in glycemia, insulin requirement, and β-cell function. The safety experience with anti-cytokine biologics is still very limited in T1D. However, combinations with other biologics, at doses of adaptive and innate immune inhibitors/modulators that are suboptimal or ineffective in themselves, may generate synergies of true therapeutic benefit and safety in T1D. Critical and balanced appraisal of the preclinical and clinical evidence of efficacy and safety of anti-immune, anti-inflammatory, and anti-dysmetabolic therapeutics should thus guide future studies to move closer to novel treatments, targeting the underlying causes of β-cell failure and destruction in T1D.

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In Vivo Delivery of Nucleic Acid-Formulated Microparticles as a Potential Tolerogenic Vaccine for Type 1 Diabetes

Valentina Di Caro^1,2, Nick Giannoukakis^1,3, Massimo Trucco¹

Abstract

Originally conceived as a method to silence transcription/translation of nascent RNA, nucleic acids aimed at downregulating gene expression have been shown to act at multiple levels. Some of the intriguing features of these gene-silencing nucleic acids include activation of molecular signals in immune cells which confer tolerogenic properties. We have discovered a method to induce stable tolerogenic ability to dendritic cells ex vivo using a mixture of phosphorothioate-modified antisense DNA targeting the primary transcripts of CD40, CD80 and CD86. Autologous human dendritic cells generated in the presence of these oligonucleotides prevent and reverse type 1 diabetes (T1D) in the non-obese diabetic (NOD) strain mouse model of the human disease, and have been shown to be safe in established diabetic human patients. Even though this ex vivo approach is clinically feasible, we have gone beyond a cell therapy approach to develop a "population-targeting" microsphere formulation of the three antisense oligonucleotides. Effectively, such a product could constitute an "off-the-shelf" vaccine. In this paper, we describe the progress made in developing this approach, as well as providing some insight into potential molecular mechanisms of action.

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