Thymosin-induced immunoregulation: clinical potentials for allergy and asthma endotypes

KEYWORDS:

• Allergy
• asthma
• immunoregulation
• regulatory T cells
• thymosin

1. Introduction

The incidence, prevalence and severity of allergic diseases continue to increase around the world. Although allergic patients typically have high morbidity and low mortality with their illness, the increasing percentages of severe conditions such as asthma has prompted a great deal of research into etiology and development of effective therapies. More recent work has demonstrated that similar clinical presentations may result from distinct immune mechanisms commonly referred to as endotypes [1]. This has brought better understanding as to why patients presenting with similar clinical symptoms may respond very differently to the same therapeutic interventions.

In the classical sense, the term allergy is defined as an overreaction of the host immune system whereby excessive amounts of antigen – specific IgE, one of five classes of antibody produced by humans – are produced against typically innocuous, nonpathogenic proteins from a variety of sources such as pollens, saphrophytic mold spores, animal dander, dust mite proteins and others. The specific IgE, when bound to dendritic cells, mast cells and/or eosinophils, initiates and propagates various inflammatory pathways leading to signs and symptoms of the allergic disease process. The exact clinical syndromes vary depending upon whether the patient has nasal, pulmonary, gastrointestinal, cutaneous and/or systemic (anaphylaxis) manifestations.

2. Asthma and immunoregulation

Besides anaphylaxis, asthma is the syndrome with the highest morbidity and mortality. Asthma is characterized as episodic reversible airway obstruction typically accompanied by expiratory wheeze, bronchial hyperreactivity and airway inflammation. Classically considered a single disease entity, recent studies have shown that clinical asthma is actually a syndrome resulting from multiple immune mechanisms. Thus, asthma is now commonly thought of in terms of phenotypes (early onset, allergic, obese, exercise induced, eosinophilic, etc.) resulting from differing endotypes (Th2High, Th2 low, etc.) that are responsible for these symptoms [2]. The incidence, prevalence and severity of asthma continue to increase in western society for reasons not well understood. These facts demand an increasingly sophisticated approach to a therapy that focuses on controlling the altered immune mechanisms responsible for clinical conditions such as asthma.

The major pathophysiological mechanisms responsible for the inflammatory patterns of asthma involve at least two major components – an alteration of the normal immune balance between CD4 + T-cell subpopulations (commonly referred to as Th1 and Th2) and an apparently deficient number and/or function of immunoregulatory pathways; particularly, those of the CD4+CD25^HIGHFoxP3+ regulatory T-cell (T_REG) populations. These aberrations result in inflammatory mechanisms – high mast cell and eosinophil activity – thought to be primarily responsible for the morbidity of asthma and other allergic conditions [3].

Recently, biological therapy has become increasingly utilized for more difficult to treat, severe asthma patients targeting inflammatory pathways fundamental to TH2 dominant pathways. This ‘TH2 high’ endotype is the most prevalent category in younger and/or more allergic asthma patients who show elevated levels of serum IgE, eosinophils and the cytokines IL-4, IL-5 and/or IL-13. There are multiple drugs currently available that target circulating IgE, IL-5 and Il-5 receptors as well as drugs in active development that target IL4/IL13 receptors and other molecules in the inflammatory cascade. There is also a significant number of asthma patients who do not fall into this ‘Th2 high’ endotypic category and are collectively known as ‘Th2 low’ asthma. This group tends to be older, more resistant to steroids, has greater disease severity and is more difficult to control. Such patients tend to be less responsive to many of the currently available biologics and represent a patient population with unmet therapeutic needs. To date, virtually all of the successful therapies have targeted the ‘TH2 high’ endotype. There is very little progress in effective therapies for the ‘TH2 low’ patients [4].

Yet as in all asthma endotypes, there appears to be an inadequate level of immune regulation that results in these increased adverse effects of inflammation on the lungs [5]. There is a robust, ongoing research effect that is bringing biologically derived therapies for asthma; these therapies target various inflammatory components of the cascade. However, there is a large treatment gap in therapeutic develop that actively targets restoring normal immune regulation in these afflicted patient populations

3. Potential for Thymosins as immunomodulatory therapy for asthma

Thymosins define a family of polypeptides originally derived and characterized from bovine thymus and have been studied for decades to identify and characterize their immune restorative and immune modulating properties in normal and diseased individuals [6]. From the earliest days of thymosin fraction 5 characterization, induction of regulatory networks has been postulated and demonstrated. In early attempts to define the role of thymosin in T-cell ontogeny, our group studied the effects of thymosin fraction 5 (TF5) on development of cytotoxic T lymphocytes in congenitally athymic nude (nu⁺/nu⁺) mice. We could not generate cytotoxic T lymphocytes (CTL) with thymosin but did induce the formation of what was then called suppressor T-cells [7] demonstrating the experimental ability of TF5 to induce immunoregulatory cells in a murine model.

Since those early studies, thymosin research has made vast leaps in progress. Individual components of TF5 have been extensively characterized both chemically and biologically. Two major components have emerged as having significant clinical potential and are discussed extensively through this issue. These molecules, thymosin α1 (thymalfasin) and thymosin β4 (Tβ4), have been studied for their immunomodulatory properties including both immune enhancement and regulation. Interestingly, the same compounds appear to have efficacy in clinical conditions requiring immune restoration as well as immune regulation [8,9]. Thymalfasin has demonstrated therapeutic roles in treatment of acute cytomegalovirus infection, acute respiratory distress syndrome, chronic hepatitis C (in combination with interferons), peritonitis and tuberculosis. Tβ4 has been evaluated for its clinical potential for wound healing, various ocular inflammatory conditions, fatty liver disease and post-myocardial infarction myocyte repair. Many of these conditions are associated with disregulated inflammatory responses which provide at least a theoretical rationale for further investigation.

4. Expert opinion

Allergic diseases, being part of the hypersensitivity disease spectrum, can generally be characterized by their poorly regulated immune responses (whether due to deranged specificity, duration, intensity or all). Data that have demonstrated the spectrum of specific immune mechanisms responsible for the various endotypes of asthma have resulted in a quite useful therapeutic paradigm for those asthma patients with the Th2 High endotype. Extreme clinical challenges remain for those patients characterized as Th2 ‘Low’. When examining the immunopathophysiology of the various endotypes, most investigators and clinicians agree on defective immunoregulation being a central component of the adverse clinical states. Thus, it seems rational to explore therapeutic options aimed at this arm of the host immune response. Because various thymosin peptides have been characterized in different experimental systems (including clinical) for their immune effects and several have shown evidence of immunoregulatory activities, it is intriguing to postulate that at least some of these thymosin peptides could have therapeutic utility particularly in the ‘TH2 low’ asthma population for which there is currently no well characterized therapeutic successes for biologic agents. This approach will not be either easy or without risk. A careful assessment of the effects of administering various doses of thymosin peptides in various treatment schedules (previously shown to be critical for all types of biological therapy for inflammatory diseases) will be required. However, if successful, such a therapy has the potential to have a major positive impact on a significant proportion of asthma patients for whom no currently available therapies have been found to be useful. Whether this could progress to a disease modifying instead of just disease controlling modality is speculative but provocative to consider in terms of ultimate patient benefit.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Acknowledgments

This paper has been published as part of a supplement issue covering the proceedings of the Fifth International Symposium on Thymosins in Health and Disease and is funded by SciClone Pharmaceuticals.

Additional information

Funding

This paper has been published as part of a supplement issue covering the proceedings of the Fifth International Symposium on Thymosins in Health and Disease and is funded by SciClone Pharmaceuticals.