Translational Autoimmunity, Volume 2: Treatment of Autoimmune Diseases

By Nima Rezaei

Translational Autoimmunity: Treatment of Autoimmune Diseases, Volume Two in the Translational Immunology series, focuses on advances in therapeutic modalities in autoimmune diseases. Efficacy and safety of not only the current biologic therapies, but also novel drug targets are discussed. Therapeutic targeting of B regulatory cells, T regulatory cells, as well as the immunomodulation effects of nanoparticles and organisms are also covered, along with our understanding and future challenges of prognostic significance of treatments in autoimmune diseases.

• Covers the clinical aspects and treatment of autoimmunite diseases
• Meets the needs of basic scientists, clinicians and translational scientists and industry partners
• Mentions each and every key concept after background is drawn
• Supported by a systematic appraisal of the most recent evidence
• Helps students at all academic levels, but is also applicable to scientists who work with autoimmunity

• Language: English
• Publisher: Academic Press
• Release date: Jan 5, 2022
• ISBN: 9780323859752

Book preview

Chapter 1: Introduction on therapeutic opportunities for autoimmunity

Nima Rezaeia,b,c,⁎; Niloufar Yazdanpanaha,c    a Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

b Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

c Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

* Corresponding author

Abstract

Autoimmune diseases have induced a huge burden on individuals, families, economy, and the healthcare system. Considering their wide spectrum of manifestations and systemic involvement in some of the cases, different complications are associated with these diseases. On the other hand, since most of the current treatments systematically target the immune system, patients might experience a variety of adverse effects. Despite the progress in finding new targets and treatment strategies in animal studies, the development of treatments in clinical application is not seen to the same extent. One important explanation regarding this issue is the difference between the animal and human physiological systems. Moreover, the genetic and epigenetic differences between individuals potentially result in different disease manifestations even with the same underlying pathology besides different spectra of response to treatment. Therefore, finding proper treatment for autoimmune diseases by conducting translational studies that facilitate the application of current evidence from laboratory, animal studies, and preclinical findings in clinical practice is of interest. In this chapter, a brief review of currently available treatments for autoimmune diseases and existing challenges in this field are provided.

Keywords

Immunology; Immunity; Autoimmunity; Treatment; Translational studies

1: Introduction

Affecting about 5% of the population [1], a considerable burden of society and healthcare service is attributed to autoimmune diseases. In spite of the efforts and time devoted to the discovery of an appropriate treatment for autoimmune diseases, multiple challenges exist in the treatment of these patients. For instance, unexpected side effects, several remissions or disease flare after the period of taking the treatment, and complications resulting from the nonselectivity of therapeutic agents are of the major foresaid challenges.

Considering the recent attempts in understanding the pathophysiology and multifactorial etiology of autoimmunity, it might be expected to witness a great progress in the discovery of novel promising therapeutic approaches. Meanwhile, regardless of how deep is the current knowledge about underlying mechanisms of autoimmunity, many challenges exist in linking the laboratory and preclinical findings to clinical benefits. In this chapter, current therapeutic strategies as well as challenges in the field of drug discovery are discussed.

2: From the very first known treatment to the recent developments in therapeutic strategies

The first rationale for the treatment of autoimmune diseases has been based on suppressing the immune system. In spite of the variety of side effects and complications resulting from the nonselectivity of the immune suppression, this approach is still the gold standard in the treatment and control of autoimmune diseases [2]. The most noticeable side effect of the nonselective immunosuppressive drugs is inducing an increased vulnerability to infections and emergence of malignancies that might progress to life-threatening conditions since they disturb nonrelevant pathways and cell functions. Meanwhile, as in other types of diseases, conservative therapies with the aim of reducing the symptoms of the patients had had their role in the management of autoimmune patients [3]. In the following sections, different therapeutic agents involved in the management of autoimmune diseases are briefly discussed.

2.1: Corticosteroids

Glucocorticoid therapy was primarily suggested in the 1950s by Philip Hench and his colleagues [4]. Undoubtedly, it was a milestone in the management of autoimmune reactions in autoinflammatory and rheumatoid diseases. In addition, these immunosuppressant antiinflammatory agents are favorable in transplant rejection, allergic reactions, ambulatory care service, and as a part of chemotherapy process in oncology [5]. Although several side effects have been reported for corticosteroids due to their systemic effects, they are still part of treatment strategies concerning their fast mechanism of action that potentially covers the gap between the administration of other therapeutic agents and the start of their effects [6–9]. Furthermore, these drugs are beneficial in the maintenance therapy as well [6, 8]. Considering the vast spectrum of corticosteroids’ targets and different mechanisms of action, long-term and high-dose administration is associated with serious side effects. For instance, psychiatric complications, gastric problems, osteoporotic fractures, adrenal suppression, metabolic problems and undesired weight gain, hypertension, and cardiovascular complications as well as increased susceptibility to infections due to the global suppression of the immune system [5, 10]. Since all the cells possess the same glucocorticoid receptors, their modulatory effects on inflammation and their metabolic effects are inseparable. To reduce these adverse effects and optimize the use of corticosteroids, different aspects of corticosteroid therapy have been investigated. One important finding might be the optimal pattern of administration as it has been revealed that administration with an alternate-day pattern potentially decreases the adverse effects and autoantibodies’ level compared to daily administration [11, 12]. It has been reported that local (inhaled or topical corticosteroids) administration potentially reduces the systemic side effects. However, local prescription of corticosteroids is accompanied with different side effects as well. Although the local side effects are not as dangerous as the systemic complications, the presence of these side effects could potentially decrease the patients’ compliance with the treatment that could result in detrimental consequences [13] such as the flare-up of the disease and prednisolone withdrawal symptoms in the case of the abrupt stop in taking the drug. That being so, regardless of all the benefits of the corticosteroids that make them an important part of the management strategies of autoimmune diseases, there are still considerable challenges remained to be solved.

2.2: Disease-modifying antirheumatic drugs

Disease-modifying antirheumatic drugs (DMARDs) are therapeutic agents that modulate or suppress the immune system. DMARDs are classified into conventional such as methotrexate, sulfasalazine, and hydroxychloroquine, and biological consists of monoclonal antibodies and the antagonist of different factors in the immune system [14]. In contrast to the nonspecific targeting of corticosteroids, biological DMARDs target a specific pathway or component of the immune system. Hence, the adverse effects related to this group of drugs might be less serious and observed at lower rates. However, they are not completely safe since a number of side effects have been reported for DMARDs. Gastrointestinal problems, increased risk of infection, hepatotoxicity, bone marrow suppression, and hypersensitivity reactions are demonstrated as side effects in patients treated with conventional DMARDs [15, 16]. While these effects have been reported in most of the conventional DMARDs administration, hydroxychloroquine has represented milder complications such as allergic reactions and diarrhea [17, 18]. On the other hand, ophthalmological complications (drug-induced retinopathy or maculopathy) have been reported as rare but serious side effects exclusively for hydroxychloroquine prescription [19]. The most remarkable and common undesirable effect of biological DMARDs is predisposing individuals to different infections, while a spectrum of different rare adverse effects has been reported as well [14, 20].

2.3: Targeting the different immune components

Moreover, the medical society has witnessed developments in the treatment of autoimmune diseases by discovering promising alternative targets. Since both the innate and adaptive immune systems are involved in autoimmunity, a broad spectrum of medications has been approved and indicated for specific conditions. B cells, T cells, T regulatory (Treg) cells, complement pathways, costimulatory molecules and receptors, Toll-like receptors (TLRs), cytokines, immunoglobulins, JAK enzymes, and tolerance mechanisms have been the target of different treatment strategies so far [2, 3, 21, 22].

As a comprehensive concept, immunotherapy is a therapeutic method having the manipulated components of the immune system as its tools. Monoclonal antibodies, receptor fusion proteins, cytokines, and immune cells are functional tools in immunotherapy [21]. Although many of these tools have shown promising results in animal models, their efficacy for human cases has faced several challenges. The complexity of the human immune system, the issue of applying the animal and laboratory finding to the human system, and the crucial matter of preoccupation with safety in human immunotherapy studies are some of the most prominent obstacles in this field [21, 23, 24]. The dynamic progressive route of scientific discoveries results in finding novel targets for immunotherapy in autoimmune diseases. For instance, investigating the diversity and unique functional pathways of antigen-presenting cells (APCs), discovery of the cytokine alteration in the immune environment action sites, and the immune cells’ interaction with the resident cells in different tissues led to the conceptualization of plasticity in the differentiation process of T cells into various subtypes [25–28]. Therefore, these kinds of findings might reveal potential novel treatment targets such as T helper 17 (Th17) cells and inducible Treg (iTreg) cells [27, 28].

2.4: Targeting cytokines

Due to the wide spectrum of biological effects of cytokines, they have attracted special attention as treatment targets. Inhibition of proinflammatory cytokines either by special monoclonal antibodies or by soluble receptors, interfering in the pathways related to the function of cytokines, and impairing the function of the cytokines’ receptors by both monoclonal antibodies and receptor antagonists are the strategies applied to tackle autoimmune diseases by means of cytokines [29–33]. Furthermore, provoking the immune system to produce autoantibodies against cytokines by novel methods of anticytokine vaccination [34, 35] and the introduction of cytokine traps that have represented promising results in vitro and in vivo [36, 37] are other potential treatment strategies targeting cytokines. On the other hand, administration of antiinflammatory cytokines such as TGF-β, IFN-β, IL-4, and IL-10 to attenuate the autoimmune responses might be beneficial as well [33]. In addition to immune mediators, infiltration of immune cells plays a significant role in the induction of chronic inflammation. Hence, targeting the related pathways’ components such as chemokines and adhesion molecules might be beneficial for the management of chronic conditions in autoimmune diseases [38–41].

2.5: Targeting immune cells

OKT3 (Ortho Kung 3) or muromonab, a CD3-recognizing antibody, was the first monoclonal antibody of murine origin [42]. Furthermore, rituximab, an anti-CD20 antibody, one of the successful applied targeted B cell therapies in autoimmune patients highlighted the possible efficacy of the therapeutic agents targeting immune cells as promising groups of medications for autoimmune diseases [43]. Rituximab selectively targets CD20+ cells such as pre-B cells and B cells through different mechanisms, while it does not affect bone marrow stem cells and evolved plasma cells. This is counted as one of the best aspects of rituximab whereas some of the B- and T-cell targeting agents function nonselectively, which in turn enhances the risk of developing cancer and opportunistic infection [44]. However, assessment of the balance between risks and benefits has always remained a challenge [45]. An example in the field of immunotherapy for autoimmune diseases might be the application of alemtuzumab, an anti-CD52 antibody that nonselectively inhibits B cells, T cells, natural killer (NK) cells, and monocytes, in multiple sclerosis patients. Promising impressive results have been observed in the related trials; however, due to its broad spectrum of effects on different immune cells, different deleterious side effects have been reported for it. Progressive multifocal leukoencephalopathy and even other autoimmune conditions such as idiopathic thrombocytopenic purpura (ITP) are of the mentioned unwanted adverse effects [46, 47].

Besides the aforementioned therapeutic agents that mostly inhibit the function of immune cells, immune-related receptors, proinflammatory cytokines, and leukocyte infiltration, some agents do not inhibit or negate a function, but modulate, convert, or induce a function. For instance, stimulation or induction of regulatory immune cells, altering the antigen recognition process, and conversion of the immune responses to protective ones.

2.6: Vaccination

In 1911, by demonstrating how hay fever potentially resolved after a patient’s inoculation with the related antigen, the first antigen-specific immunotherapy (SIT) was suggested [48]. Considering the concept of inducing antigen-specific Treg cells to target the underlying pathological mechanisms of autoimmunity rather than treating the symptoms of the diseases, therapeutic vaccination for autoimmune diseases emerged [49, 50]. Antigen-presenting cells (APCs) facing the stimulating antigens in a proinflammatory environment (in the presence of proinflammatory cytokines and innate immunity receptors) potentially results in the progress of the immune response through the Th1 and Th2 mediated pathways that might induce autoreactive immune cells [51, 52]. Meanwhile, encounter of APCs with antigens in a nonproinflammatory environment stabilizes these cells and leads to induction of regulatory cells and responses as they confront T cells in the periphery in a noninflammatory state [49, 51]. Deletion and anergy processes have been suggested as the main action mechanism of APCs (e.g., dendritic cells or DCs) [53, 54]. However, how administration of a peptide component of one antigen could stop the immune response against another antigen still remained a challenge. Bystander suppression has been suggested as an explanation for this observation [55, 56]. To further elucidate the action mechanism of this method of immunotherapy in autoimmune diseases, it has been observed that frequent exposure of the APCs with the synthetic antigen results in the production of IL-10 secreting regulatory cells. It has been demonstrated that these regulatory cells originate from naïve T cells without the expression of FOXP3, but with approximately equivalent regulatory potency as CD4+ CD25+ Treg cells [57, 58]. An antigen potent to bind MHC molecules and simulate the characteristics of naturally processed antigens to be capable of inducing tolerance in the involved immune cells might be a proper option to develop autoimmune therapeutic vaccination. In addition, the proposed antigen might be nonstimulating for the innate immune system so that an appropriate environment is provided to result in the induction of regulatory immune responses [49]. To avoid the local inflammation and facilitate the APCs to arrive in the peripheral lymphoid tissues, the designed antigen must be soluble [49, 59]. It is worth mentioning that DCs can be used either as cellular vaccines after ex vivo manipulations or can be the target of in vivo peptide delivery system [60, 61]. Although promising results have been achieved for the application of antigen-specific immunotherapy in animal studies, translation of these results to clinical studies and usage is still the main challenge in this field.

Oral tolerance has been known as a physiologic route to reduce inflammation and autoimmune reactions. The advantage of oral tolerance is its potential specificity for defined antigens and rare chance of toxicity that is due to its administration route that resembles a physiologic process [62]. Whether the antigen fed is in low or high dose, it could lead to the emergence of Treg cells or the stimulation of clonal anergy/clonal deletion, respectively [62, 63]. Furthermore, there are different factors affecting the initiation and maintenance of the oral tolerance including the administrated dosage of the antigen and the characteristics of it, age and gender of the patient, and the variation in genetic background of patients [64]. Considering the integration of these complex factors besides the difference between the human and animal physiologic systems, further investigations are necessary to translate the current finding regarding the efficacy of oral tolerance, which is mostly from animal and preclinical studies, to clinical practice in humans [64, 65].

2.7: Gene therapy

Gene therapy, defined as a novel therapeutic strategy in which the impaired genes are inactivated or substituted in the targeted cells, could offer a treatment opportunity for autoimmune diseases [66]. The existing records of the efficacy of gene therapy in attenuating the autoimmune reactions and complications in animal models have attracted considerable attention whether this method is applicable in humans as well [67]. Meanwhile, with the introduction of appropriate vectors for gene delivery, the investigations regarding gene therapy in autoimmune diseases have been strengthened [68]. Adjustment of the activation and function of autoreactive immune cells, expression level and the function of immune systems’ immunomodulatory molecules, and immune tolerance are of the focused fields in animal models for the improvement of gene therapy strategies [68]. In spite of the recent advancements in gene therapy studies, there are few approved clinical trials with limited number of participants due to the safety and efficacy concerns, since there are major differences between animal and human physiologic systems [68, 69].

2.8: Cell therapy

Cell therapy, which is the method of reconfiguration of the immune system to the naïve and self-tolerant nonautoreactive cells, holds great promises in the treatment of autoimmune diseases [70]. Although it has been established to combat malignancies, recent promising reports concerning the application of this method on severe forms of autoimmune diseases, and in cases with poor or no response to targeted therapies [71]. The initial translational study that has constructed the basic concept of the application of HSCT in autoimmunity using murine model was conducted by Ikehara et al. in 1985 [72]. They have suggested the bone marrow as the root of autoimmune diseases and claimed that bone marrow transplantation could be beneficial in reconfiguration of the immune system while thymus transplantation might not be effective [72]. Hematopoietic stem cell transplantation (HSCT), regulatory T cell therapy, and mesenchymal stromal cell therapy are different cells employed in methods of cell therapy. The integration of different processes, such as restriction of the autoreactive B cells and T cells besides impeding the aging process in the remained normal cell repertoires, maintaining the immune system’s defense potency against environmental treats by saving memory cells, and reinstating the regulatory process of the immune system, results in the effectiveness of the cell therapy in autoimmune diseases [71].

2.9: Microbiota manipulation and probiotic application

Drastically developing data on the association of microbiota and the immune system function has highlighted the potentials of the application of microbiota manipulation for the treatment of autoimmune diseases [73]. Some of the resident normal flora bacteria in the gut and airways trigger the formation of T helper 17 (Th17) cells by affecting the normal response of dendritic cells, which Th17 is one of the pivotal components of the autoimmune reactions in some autoimmune diseases [74, 75]. However, the microbiota perform antiinflammatory roles by facilitating the Treg responses by means of secreting substances such as polysaccharide A or short-chain fatty acids [75, 76]. Several approaches have been established for the modulation of microbiota for therapeutic purposes. For instance, antimicrobial interventions, fecal transplantation, prebiotics diets, and the administration of selective bacterial candidates [77]. Furthermore, dietary treatments, with the goal of microbiota change, could be a promising alternative treatment due to its reasonable economical costs, feasibility, and noninvasiveness [78].

2.10: Immunometabolism

The mutual connection between the immune system and the metabolism, as the two most vital components of survival, is detectable in health and disease. To go into further detail, the inflammatory processes are responsible for the physiopathology of metabolic syndromes [79]. Meanwhile, the metabolic processes determine the proliferation, differentiation, and function of the immune cells [79, 80]. The observations concerning the fat tissue’s secretion of TNF-α in a murine model of obesity [81] in addition to the widely accepted notion that malnutrition leads to immunosuppression [82] have strengthened the link between metabolic alteration and immune system function. Indeed, each type of the immune cells represents specific metabolic characteristics in different steps of their life span and they acquire specific features and undergo reprogramming as they enter different tissues [79, 83]. With regard to these observations, modification of the function of immune cells by manipulating their microenvironment of the infiltrated tissue or their origin tissue, which in turn results in the metabolic reprogramming of these cells, has opened new chapters in investigating new treatment methods for autoimmune diseases. Since this method could potentially target specific components of the immune system according to their distinct metabolic features, it could be a favorable alternative to systemic immunosuppression. It is worth mentioning that some of the immune cells’ metabolic pathways have already been targeted in the classic treatment. For instance, methotrexate potentially affects the JAK-STAT pathway as one of its action mechanisms [84]. However, specifically targeting immunometabolic targets to optimize the treatment results and reduce the undesired adverse effects of conventional medications requires further research.

3: Conclusion

As reviewed throughout this chapter, there are different treatment strategies established for the management of autoimmune diseases during the recent decades, however, no definite long-lasting treatment is available so far. In spite of the considerable progress in the animal studies aiming to elucidate the etiopathogenesis and contributing factors to the initiation and progress of autoimmune diseases, the advancement in clinical practice is not to that extent. This inequivalent progress is due to the difference between animal and human systems besides the restrictions in conducting human studies with large number of participants. Hence, the importance of translational studies in the attempt to apply the laboratory, preclinical, and animal studies finding in clinical practice is highlighted once more.

References

[1] Jacobson D.L. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 1997;84(3):223–243.

[2] Rosenblum M.D. Treating human autoimmunity: current practice and future prospects. Sci. Transl. Med. 2012;4(125):125sr1.

[3] Chandrashekara S. The treatment strategies of autoimmune disease may need a different approach from conventional protocol: a review. Indian J. Pharmacol. 2012;44(6):665–671.

[4] Burns C.M. The history of cortisone discovery and development. Rheum. Dis. Clin. North Am. 2016;42(1):1–14 vii.

[5] Sarnes E. Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review. Clin. Ther. 2011;33(10):1413–1432.

[6] Hellmich B. 2018 update of the EULAR recommendations for the management of large vessel vasculitis. Ann. Rheum. Dis. 2020;79(1):19.

[7] Fanouriakis A. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann. Rheum. Dis. 2019;78(6):736.

[8] Mukhtyar C. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann. Rheum. Dis. 2009;68(3):310.

[9] Smolen J.S. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis. 2020;79(6):685.

[10] McDonough A.K., Curtis J.R., Saag K.G. The epidemiology of glucocorticoid-associated adverse events. Curr. Opin. Rheumatol. 2008;20(2):131–137.

[11] Chaia-Semerena G.M. The effects of alternate-day corticosteroids in autoimmune disease patients. Autoimmune Dis. 2020;2020:8719284.

[12] Suda M. Safety and efficacy of alternate-day corticosteroid treatment as adjunctive therapy for rheumatoid arthritis: a comparative study. Clin. Rheumatol. 2018;37(8):2027–2034.

[13] Roland N.J., Bhalla R.K., Earis J. The local side effects of inhaled corticosteroids: current understanding and review of the literature. Chest. 2004;126(1):213–219.

[14] Benjamin O., Lappin S.L. Disease modifying anti-rheumatic drugs (DMARD). In: StatPearls. StatPearls Publishing; 2019 [Internet].

[15] Wang W., Zhou H., Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. Eur. J. Med. Chem. 2018;158:502–516.

[16] Katchamart W. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann. Rheum. Dis. 2009;68(7):1105–1112.

[17] Srinivasa A., Tosounidou S., Gordon C. Increased incidence of gastrointestinal side effects in patients taking hydroxychloroquine: a brand-related issue?. J. Rheumatol. 2017;44(3):398.

[18] Sharma A.N., Mesinkovska N.A., Paravar T. Characterizing the adverse dermatologic effects of hydroxychloroquine: a systematic review. J. Am. Acad. Dermatol. 2020;83:563–578.

[19] Melles R.B., Marmor M.F. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132(12):1453–1460.

[20] Hansel T.T. The safety and side effects of monoclonal antibodies. Nat. Rev. Drug Discov. 2010;9(4):325–338.

[21] Feldmann M., Steinman L. Design of effective immunotherapy for human autoimmunity. Nature. 2005;435(7042):612–619.

[22] Barrat F.J., Coffman R.L. Development of TLR inhibitors for the treatment of autoimmune diseases. Immunol. Rev. 2008;223(1):271–283.

[23] Roep B.O., Atkinson M., von Herrath M. Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes. Nat. Rev. Immunol. 2004;4(12):989–997.

[24] Blumberg R.S. Unraveling the autoimmune translational research process layer by layer. Nat. Med. 2012;18(1):35–41.

[25] O'Shea J.J., Hunter C.A., Germain R.N. T cell heterogeneity: firmly fixed, predominantly plastic or merely malleable?. Nat. Immunol. 2008;9(5):450–453.

[26] Veldhoen M. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 2008;9(12):1341–1346.

[27] Chen W. Conversion of peripheral CD4 + CD25- naive T cells to CD4 + CD25 + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 2003;198(12):1875–1886.

[28] Harrington L.E. Interleukin 17–producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 2005;6(11):1123–1132.

[29] Cargill M. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 2007;80(2):273–290.

[30] Duerr R.H. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314(5804):1461–1463.

[31] Lubberts E. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 2004;50(2):650–659.

[32] Pesu M. Therapeutic targeting of Janus kinases. Immunol. Rev. 2008;223:132–142.

[33] Adorini L. Cytokine-based immunointervention in the treatment of autoimmune diseases. Clin. Exp. Immunol. 2003;132(2):185–192.

[34] Semerano L., Assier E., Boissier M.-C. Anti-cytokine vaccination: a new biotherapy of autoimmunity?. Autoimmun. Rev. 2012;11(11):785–786.

[35] Delavallée L. Vaccination with cytokines in autoimmune diseases. Ann. Med. 2008;40(5):343–351.

[36] Economides A.N. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat. Med. 2003;9(1):47–52.

[37] Zamecnik C.R. An injectable cytokine trap for local treatment of autoimmune disease. Biomaterials. 2020;230:119626.

[38] Bonecchi R. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med. 1998;187(1):129–134.

[39] Godessart N. Chemokine receptors: attractive targets for drug discovery. Ann. N. Y. Acad. Sci. 2005;1051:647–657.

[40] McMurray R.W. Adhesion molecules in autoimmune disease. Semin. Arthritis Rheum. 1996;25(4):215–233.

[41] Oppenheimer-Marks N., Lipsky P.E. Adhesion molecules as targets for the treatment of autoimmune diseases. Clin. Immunol. Immunopathol. 1996;79(3):203–210.

[42] Kung P. Monoclonal antibodies defining distinctive human T cell surface antigens. Science. 1979;206(4416):347–349.

[43] Strand V., Kimberly R., Isaacs J.D. Biologic therapies in rheumatology: lessons learned, future directions. Nat. Rev. Drug Discov. 2007;6(1):75–92.

[44] Balagué C., Kunkel S.L., Godessart N. Understanding autoimmune disease: new targets for drug discovery. Drug Discov. Today. 2009;14(19–20):926–934.

[45] Yasunaga M. Antibody therapeutics and immunoregulation in cancer and autoimmune disease. Semin. Cancer Biol. 2020;64:1–12.

[46] Hirst C.L. Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis. J. Neurol. 2008;255(2):231–238.

[47] Calabrese L.H., Molloy E.S. Progressive multifocal leucoencephalopathy in the rheumatic diseases: assessing the risks of biological immunosuppressive therapies. Ann. Rheum. Dis. 2008;67(Suppl. 3):iii64–5.

[48] Noon L. Prophylactic inoculation against hay fever. Lancet. 1911;177(4580):1572–1573.

[49] Larché M., Wraith D.C. Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nat. Med. 2005;11(4):S69–S76.

[50] Van Brussel I. Tolerogenic dendritic cell vaccines to treat autoimmune diseases: can the unattainable dream turn into reality?. Autoimmun. Rev. 2014;13(2):138–150.

[51] Jonuleit H. Induction of interleukin 10–producing, nonproliferating CD4 + T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 2000;192(9):1213–1222.

[52] Anderton S.M. Influence of a dominant cryptic epitope on autoimmune T cell tolerance. Nat. Immunol. 2002;3(2):175–181.

[53] Wraith D.C. Therapeutic peptide vaccines for treatment of autoimmune diseases. Immunol. Lett. 2009;122(2):134–136.

[54] Anderson R.P., Jabri B. Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr. Opin. Immunol. 2013;25(3):410–417.

[55] Faria A.M., Weiner H.L. Oral tolerance: mechanisms and therapeutic applications. Adv. Immunol. 1999;73:153–264.

[56] Weiner H.L. Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol. Today. 1997;18(7):335–343.

[57] Vieira P.L. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4 + CD25 + regulatory T cells. J. Immunol. 2004;172(10):5986–5993.

[58] Nicolson K.S. Antigen-induced IL-10 + regulatory T cells are independent of CD25 + regulatory cells for their growth, differentiation, and function. J. Immunol. 2006;176(9):5329–5337.

[59] Metzler B. Kinetics of peptide uptake and tissue distribution following a single intranasal dose of peptide. Immunol. Invest. 2000;29(1):61–70.

[60] Hilkens C.M., Isaacs J.D., Thomson A.W. Development of dendritic cell-based immunotherapy for autoimmunity. Int. Rev. Immunol. 2010;29(2):156–183.

[61] Gross C.C., Wiendl H. Dendritic cell vaccination in autoimmune disease. Curr. Opin. Rheumatol. 2013;25(2):268–274.

[62] Weiner H.L. Oral tolerance. Immunol. Rev. 2011;241(1):241–259.

[63] Faria A.M.C., Weiner H.L. Oral tolerance. Immunol. Rev. 2005;206(1):232–259.

[64] Mayer L., Shao L. Therapeutic potential of oral tolerance. Nat. Rev. Immunol. 2004;4(6):407–419.

[65] Sricharunrat T., Pumirat P., Leaungwutiwong P. Oral tolerance: recent advances on mechanisms and potential applications. Asian Pac. J. Allergy Immunol. 2018;36(4):207–216.

[66] Dunbar C.E. Gene therapy comes of age. Science. 2018;359(6372):eaan4672.

[67] Sloane E. Anti-inflammatory cytokine gene therapy decreases sensory and motor dysfunction in experimental multiple sclerosis: MOG-EAE behavioral and anatomical symptom treatment with cytokine gene therapy. Brain Behav. Immun. 2009;23(1):92–100.

[68] Shu S.A. Gene therapy for autoimmune disease. Clin. Rev. Allergy Immunol. 2015;49(2):163–176.

[69] Leung P.S. Gene therapy in autoimmune diseases: challenges and opportunities. Autoimmun. Rev. 2010;9(3):170–174.

[70] Alexander T. Hematopoietic stem cell therapy for autoimmune diseases—clinical experience and mechanisms. J. Autoimmun. 2018;92:35–46.

[71] Dazzi F. Cell therapy for autoimmune diseases. Arthritis Res. Ther. 2007;9(2):1–9.

[72] Ikehara S. Rationale for bone marrow transplantation in the treatment of autoimmune diseases. Proc. Natl. Acad. Sci. U. S. A. 1985;82(8):2483–2487.

[73] Fitzgibbon G., Mills K.H.G. The microbiota and immune-mediated diseases: opportunities for therapeutic intervention. Eur. J. Immunol. 2020;50(3):326–337.

[74] Ivanov I.I. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–498.

[75] Belkaid Y., Hand T.W. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121–141.

[76] Kim M. Microbial metabolites, short-chain fatty acids, restrain tissue bacterial load, chronic inflammation, and associated cancer in the colon of mice. Eur. J. Immunol. 2018;48(7):1235–1247.

[77] Balakrishnan B., Taneja V. Microbial modulation of the gut microbiome for treating autoimmune diseases. Expert Rev. Gastroenterol. Hepatol. 2018;12(10):985–996.

[78] Richards J.L. Dietary metabolites and the gut microbiota: an alternative approach to control inflammatory and autoimmune diseases. Clin. Transl. Immunol. 2016;5(5):e82.

[79] Makowski L., Chaib M., Rathmell J.C. Immunometabolism: from basic mechanisms to translation. Immunol. Rev. 2020;295(1):5–14.

[80] Galgani M., Bruzzaniti S., Matarese G. Immunometabolism and autoimmunity. Curr. Opin. Immunol. 2020;67:10–17.

[81] Hotamisligil G.S., Shargill N.S., Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91.

[82] Ibrahim M.K. Impact of childhood malnutrition on host defense and infection. Clin. Microbiol. Rev. 2017;30(4):919–971.

[83] Stathopoulou C., Nikoleri D., Bertsias G. Immunometabolism: an overview and therapeutic prospects in autoimmune diseases. Immunotherapy. 2019;11(9):813–829.

[84] Thomas S. Methotrexate is a JAK/STAT pathway inhibitor. PLoS One. 2015;10(7):e0130078.

Chapter 2: Innate lymphoid cells as therapeutic targets in autoimmune diseases

Prince Amoah Barniea,b,c; Xia Linb; Su Zhaolianga,b,⁎    a The Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China

b International Genome Center, Jiangsu University, Zhenjiang, China

c Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana

⁎ Corresponding author

Abstract

The recent identification of a complex group of innate lymphocyte cells, now collectively termed innate lymphoid cells (ILCs), has been implicated in the pathogenesis of inflammatory disorders. Basically, three classes of ILCs have been described according to how they function and develop as well as the type of cytokines they produce and how the interactions between innate and adaptive immune cells are influenced during inflammatory disorders. Data from clinical and experimental animal models suggest that ILCs modulate various autoimmune diseases. The ILCs play this role possibly through their ability to produce cytokines, which influence the activities of important cells, particularly the effector CD4+ cells. Due to their identified functions in the pathogenesis of autoimmune diseases, researchers have proposed that they may be viable therapeutic targets. This review outlines the biology and functions of ILCs in autoimmune diseases and attempts to further identify their potential as therapeutic targets.

Keywords

ILC; Autoimmune diseases; Inflammatory bowel disease; IBD; Multiple sclerosis; MS; Systemic lupus erythematosus; SLE

1: Introduction

Innate lymphoid cells (ILCs) represent a group of recently identified innate immune cells, which play important roles in innate and adaptive immunity [1]. They were previously identified and associated with mucosal immunity [2] but more functions have been discovered. Their recent discovery attracted considerable attention and led to the initiation of different research activities to better characterize their roles. They have been reported to share many phenotypic and functional characteristics with CD4+ and CD8+ T cells [3]. The roles of some innate and adaptive immune cells and their interplay have received much attention lately. Our understanding of the important roles of ILCs in autoimmune diseases has increased due to the recent investigations. It is interesting to note that more innate cells, particularly ILCs, have been added to the list of immune cells that play vital roles in autoimmune diseases such as inflammatory bowel disease (IBD) [4], psoriasis [5], rheumatoid arthritis (RA) [6], atopic dermatitis (AD) [7], systemic lupus erythematosus (SLE) [8], and multiple sclerosis (MS) [9]. The quest of the researchers in this field to obtain knowledge and further understand the roles of ILCs in autoimmune diseases is gradually making progress, however, there is more to be explored. Research activities have provided enough evidence to support the speculation that ILCs can act in response to microbiota through communication with both epithelial cells and intestinal mononuclear phagocytes via cytokine signaling [10]. However, little information is known about how the functions of cytokines from ILCs and their effects on other cells in the pathogenesis of autoimmune diseases can be targeted for therapeutic aims. As a group of cells related to the development, ILCs are involved in providing immunity and tissue development as well as remodeling [11]. Notably, ILCs are innate immune cells that are commonly distributed in lymphoid and nonlymphoid tissues. They are known to be enriched at mucosal and barrier surfaces and are rapid and potent in cytokine production, which participates in a variety of immune responses [12, 13]. These ILCs are emerging as important effectors of innate immunity and have been found to play a central role in tissue remodeling. Three main features are known to define the ILC family: the lack of recombination activating gene (RAG)-dependent rearranged antigen receptors; absence of markers typical of myeloid and dendritic cells (DCs); and the morphology of their lymphoid origin. The ILC populations exhibit a typical illustration of natural killer (NK) cells and lymphoid tissue-inducer (LTi) cells. Immunologically, NK cells have been found to mediate early immune responses against viruses (pathogens) and cancer cells [14]. LTi cells are essential for the formation of lymph nodes during embryogenesis and also for the formation of secondary lymphoid tissues [15]. Despite the functional differences between NK cells and LTi cells, they are developmentally related because both cell types require common cytokine receptor γ-chain (γc; also known as IL-2Rγ) and the transcriptional repressor inhibitor of DNA binding 2 (ID2) for their development. Based on recent findings, ILC populations have been shown to demonstrate significant effector functions against microorganisms as well as contribution to tissue repair during the early stages of immune responses. Actually, ILCs lack the expression of antigen-specific receptors and do not directly mediate antigen-specific responses as compared with T helper (Th) subsets [16, 17]. Instead, they act as central organizers of immune responses by coordinating signals from the epithelium, the microbiota, pathogens, and other immune cells via the expression of an array of cytokines, cytokine receptors, and eicosanoid receptors [18, 19]. In autoimmune diseases, ILC’s signature cytokines influence the pathophysiology of autoimmune diseases such as IBD and psoriasis. This chapter reviews the biology and diverse role of ILCs in autoimmune diseases and discusses how ILCs contribute to the pathogenesis of various autoimmune diseases. A clear understanding of the role of these cells in the pathogenesis of various autoimmune diseases could offer new treatment strategies targeting autoimmune