Translational Immunology

Mechanisms and Pharmacologic Approaches

Seng-Lai Tan

• Publisher: Academic Press
• Year: 2015
• Print ISBN: 9780128015773
• eBook ISBN: 9780128017579
• Topic: Medicine
• Subtopic: Immunology

Translational Immunology: Mechanisms and Pharmacologic Approaches highlights and summarizes the most important advances in human immunology, clinical translations, new tools to analyze therapeutic targets, and new pharmacological approaches for autoimmunity, inflammatory disorders, and cancer. The book is an essential resource for those seeking to understand the potential translational applications of burgeoning studies in human immunology, helping readers make sense of the existing and emerging scientific advances. The book grounds fundamental science in the translational realm, providing insights from world renowned researchers at the top of their game in their respective fields, in both industry and academic settings. Readers will gain an understanding of the rationale and mechanisms underlying current and emerging pharmacologic approaches for interventional immunology, the gaps therein, and new ideas for better and safer therapeutic approaches, and physicians will glean information about pharmacological limitations in altering disease progression and complications. This reference on the translational realization of the burgeoning findings in immunology provides a go-to reference for experienced professional clinicians, researchers, industry scientists, and those seeking more information on the field. - Delivers comprehensive coverage of seminal human immunology discoveries and the resulting impact on therapeutic strategies - Presents potential novel targets and approaches for clinical applications in organ specific and systemic autoimmunity, transplant rejection, cancer, and vaccine development - Discusses lessons learned from successful and failed clinical trials with specific interventions, including pharmacological issues and limitations, and complications due to immunosuppression - Provides information on new strategies and outstanding issues that should be addressed in future research

Section B

Emerging Pharmacological Targets

Chapter 5

Th17 Cells

Jianfei Yang GlaxoSmithKline, Cambridge, MA, United States

Abstract

Th17 cells and Th17 cytokines play important roles in the pathogenesis of a variety of autoimmune inflammatory diseases, including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, chronic obstructive pulmonary disease, and asthma. Interleukin-6 (IL-6), IL-1β, and TGFβ1 are important for the differentiation of Th17 cells, while IL-23 is critical for the generation of pathogenic Th17 cells. Th17 cells express the proinflammatory cytokines IL-17, IL-17 F, IL-21, IL-22, and IL-26. RORγt is the master transcription factor for the differentiation of Th17 cells and is required for the expression of Th17 cytokines. Currently, there are two approaches targeting Th17 cells for the treatment of autoimmune inflammatory diseases: targeting the Th17 lineage such as anti-IL-23 antibodies or RORγt small molecule inhibitors; and targeting Th17 effector cytokines such as anti-IL-17 antibodies or anti-IL-17 receptor antibodies.

Keywords

Th17

IL-17

IL-23

RORgammat

Autoimmune inflammatory diseases

Antibodies

Small molecule inhibitor

Contents

1. Introduction 133

2. Th17 Cell Differentiation 135

3. Transcriptional Regulation of Th17 Cells 137

4. Pathogenic Th17 Cells 138

5. Th17 In Protective Immunity Against Infections 139

6. Th17 Cells in Autoimmune and Inflammatory Diseases 139

6.1. Multiple sclerosis 139

6.2. Systemic lupus erythematosus 140

6.3. Inflammatory bowel disease 141

6.4. Psoriasis and psoriatic arthritis 144

6.5. Rheumatoid arthritis 146

6.6. Ankylosing spondylitis 147

6.7. Chronic obstructive pulmonary disease 147

6.8. Asthma 148

7. Th17 Cells in Other Diseases 149

8. Targeting Th17 Cells and Th17 Cytokines for Autoimmune Inflammatory Diseases and Cancer 149

8.1. Anti-IL-23 antibodies 150

8.2. IL-6 signaling blockade 150

8.3. RORγt inverse agonists 151

8.4. Anti-IL-17 or IL-17R antibodies 151

9. Concluding Remarks 153

References 153

1 Introduction

Naïve CD4⁺ T helper (Th) cells are activated and differentiated to different subsets upon antigen stimulation via MHC class II on antigen presenting cells (APCs) and cytokine costimulation. In 1986, Mosmann and Coffman discovered that CD4⁺ T cells are divided into two subsets, Th1 and Th2 cells, based on their production of cytokines (Mosmann et al., 1986; Mosmann and Coffman, 1989). CD4⁺ Th cells are differentiated to Th1 cells in the presence of interleukin-12 (IL-12). Th1 cells produce interferon-γ (IFNγ) and are dependent on STAT4 and the master transcription factor T-bet (Tbx21). Th2 cells are differentiated upon activation of STAT6 and the master transcription factor GATA3 upon stimulation by IL-4. Th2 are marked by the expression of IL-4, IL-5, and IL13. Th1 cells play a critical role in host immunity to intracellular pathogens and viruses while Th2 cells are important for humoral immune responses. Overactivation or deregulation of Th1 or Th2 cells was thought to be the key cause of autoimmune and allergic inflammatory diseases (Mosmann and Coffman, 1989; Murphy and Reiner, 2002).

The Th1 cytokine IL-12 is composed of two subunits: IL-12 p35 and IL-12 p40. The critical role of IL-12 in Th cell development was discovered by Murphy and colleagues, showing that IL-12 induces the differentiation of Th1 cells (Hsieh et al., 1993). Indeed, IL-12 p40-deficient mice are defective in IFNγ production and type 1 cytokine responses (Magram et al., 1996). Genetically resistant mice lacking IL-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response (Mattner et al., 1996). Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), was believed to be a Th1-mediated neuroinflammation. MS-like prolonged and relapsing EAE in dark agouti rats is associated with a prolonged expression of proinflammatory cytokines including IL-12 (Issazadeh et al., 1996). Increased IL-12 production in progressive MS has been reported (Balashov et al., 1997). Mice treated with recombinant IL-12 in vivo after the transfer of antigen-stimulated lymph node cells developed a more severe and prolonged course of disease compared with vehicle-treated control animals. In contrast, treatment of mice with an antibody to murine IL-12 after cell transfer completely prevented paralysis, with only 40% of the mice developing mild disease (Leonard et al., 1995). In addition, DBA/1 mice deficient in IL-12 p40 showed reduced incidence and severity of collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis (RA) (McIntyre et al., 1996). In an inflammatory bowel disease (IBD) model, administration of monoclonal anti-IL-12 p40 antibodies to the TNBS-treated mice both early (at day 5) and late (at day 20) after induction of colitis led to a striking improvement in both the clinical and histopathological aspects of the disease and frequently abrogated the established colitis completely (Neurath et al., 1995). These observations indicate that the Th1 cytokine IL-12 and Th1 cells play a critical role in the pathogenesis of several autoimmune diseases.

However, Oppmann et al. discovered that IL-12 p40 is also a component of IL-23, in combination with its p19 subunit (Oppmann et al., 2000). Therefore, the effect of IL-12 p40-deficiency or anti-IL-12 p40 antibodies could be due to the loss of function of IL-23. In order to address this question, Cua and colleagues tested mice deficient in each of the three subunits (IL-12 p35^−/−, IL-12/IL-23 p40^−/−, and IL-23 p19^−/−) in a CIA model. IL-12/IL-23 p40-deficient or IL-23 p19-deficient mice protected from induction of CIA while IL-12 p35^−/− mice showed similar disease induction to wild-type mice (Murphy et al., 2003). Thus, IL-23 but not IL-12 plays a critical role in the pathogenesis of the autoimmune diseases such as CIA. Importantly, Cua and colleagues later demonstrated that IL-23 induces IL-17 (formerly known as IL-17A) expression by CD4⁺ T cells from lymph node cells immunized with MOG antigen. These cells were later named Th17 cells. The investigators discovered that IL-23-induced Th17 cells (Th_IL-17 or Th17 cells) transferred EAE disease much more efficiently than IL-12-induced Th1 cells (Langrish et al., 2005). Since then, Th17 cells have been demonstrated to be critical in protective immunity as well as autoimmune inflammatory diseases.

2 Th17 Cell Differentiation

As discussed above, IL-23 induces the generation of Th17 cells ex vivo. In vitro, the groups of Weaver and Dong demonstrated IL-23 induces the differentiation of Th17 cells from lymph node or spleen cells in the absence of IFNγ and IL-4 (Harrington et al., 2005; Park et al., 2005), demonstrating the IFNγ and IL-4 are negative regulators of Th17 cells. In addition to IL-17, Th17 cells also express IL-17F, IL-21, IL-22, and CCL20. The role of IL-23 in the differentiation of Th17 cells is complicated as IL-23 alone cannot induce the differentiation of Th17 cells from naïve CD4⁺ T cells (Bettelli et al., 2006). Instead, Bettelli et al. and Veldhoen et al. simultaneously discovered that IL-6 and TGFβ1 are critical factors for the differentiation of Th17 cells from naïve CD4⁺ cells (Bettelli et al., 2006; Veldhoen et al., 2006). Although TGFβ1 is believed to be a differentiation factor for the generation of inducible T regulatory cells, it is also required for the generation of Th17 cells. Significantly enhanced Th17 cells were observed from TGFβ1-transgenic mice immunized with MOG_33–35 peptide (Bettelli et al., 2006). In TGFβ1-deficient mice, the development of Th17 cells were significantly impaired (Mangan et al., 2006). Another cytokine, IL-21, has also been shown to induce the differentiation of Th17 cells in the presence of TGFβ1. Th17 cells themselves produce IL-21, which then plays an autocrine role in Th17 cell development (Bauquet et al., 2009; Nurieva et al., 2007). In addition to cytokines, high concentrations of sodium have been reported to promote the generation of Th17 cells (Wu et al., 2013).

In humans, IL-6 and TGFβ1 failed to induce Th17 cell differentiation in vitro. Instead, IL-1β/IL-6 or IL-1β/IL-23 can induce the differentiation of naïve CD4⁺ T cells into Th17 cells, indicating TGFβ1 is not required in human Th17 cell development. However, culture conditions contain serum in the medium, in which TGFβ1 may exist. Indeed, in serum-free medium, TGFβ1 is required for the differentiation of human Th17 cells. Th17 cells can be induced by costimulation with TGFβ1/IL1β/IL-6. Addition of IL-23 could further differentiate Th17 cells and maintain the phenotype of Th17 cells. In addition, TGFβ1 and IL-21 were also found to induce the generation of human Th17 cells (Korn et al., 2007; Yang et al., 2008b). For more details, the readers are referred to the review by Kuchroo and colleagues (Korn et al., 2009).

While IL-1β, IL-6, IL-23, and TGFβ1 are important for the differentiation of Th17 cells, several different cytokines inhibit the development of Th17 cells. Murine naïve ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Section A: Human Immunology
• Section B: Emerging Pharmacological Targets
• Section C: New Approaches
• Index