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Low-dose Interleukin-2 in the Treatment of Autoimmune Disease
John Koreth, MBBS, DPhil, 1,4 Jerome Ritz, MD, 2,5 George C Tsokos, MD, 3,5 Alberto Pugliese, MD, 6 Thomas R Malek, PhD, 7
Michelle Rosenzwajg, MD, PhD 8 and David Klatzman, MD, PhD 9,10
1. Assistant Professor; 2. Professor, Dana-Farber Cancer Institute, Boston, Massachusetts, US; 3. Chief, Division of Rheumatology, Beth Israel Deaconess Medical
Center, Boston, Massachusetts, US; 4. Attending Physician; 5. Professor of Medicine, Harvard Medical School, Boston, Massachusetts, US; 6. Professor of Medicine,
Immunology, and Microbiology, Division of Diabetes, Endocrinology and Metabolism, and Head, Immunogenetics Program, Division of Diabetes Research Institute,
University of Miami Miller School of Medicine, Miami, Florida, US; 7. Professor and Vice-Chair, Department of Microbiology and Immunology, and Diabetes
Research Institute, University of Miami Miller School of Medicine, Miami, Florida, US; 8. Associate Professor of Immunology and Head of the Clinical Immunology
Laboratory, Biotherapy Department, Sorbonne University, Pierre and Marie Curie Medical School, Pitié-Salpêtrière Hospital, Paris, France; 9. Professor of Immunology
and Head of Department, Inflammation-Immunopathology-Biotherapy Department, Sorbonne University, Pierre and Marie Curie Medical School, Pitié-Salpêtrière
Hospital, Paris, France; 10. Head, U959 INSERM Research Unit, Paris, France
Abstract CD4 + regulatory T cells (Tregs) act to maintain peripheral immune tolerance. Decreased numbers or defective function of Tregs has been implicated
in the pathogenesis of various autoimmune diseases. Interleukin-2 (IL-2) at high doses is approved by the US Food and Drug Administration
(FDA) as an immune stimulant to induce anti-tumor cytotoxicity. However, at physiologic doses, IL-2 is necessary for the expansion and function
of Tregs. Treatment with low-dose IL-2 can selectively enhance Treg function while avoiding the activation of effector T cells and ameliorate
immune inflammation. Administration of low doses of IL-2 to patients suffering from chronic graft versus host disease (cGvHD) or chronic hepatitis
C-mediated vasculitis resulted in significant clinical benefit, which was linked to improved Treg cell function. Preclinical studies suggest that
low-dose IL-2 may offer benefit in other autoimmune diseases including systemic lupus erythematosus and type 1 diabetes. Ongoing preclinical
and clinical studies indicate a wider potential role for low-dose IL-2 based Treg therapeutics in human autoimmune diseases.
Keywords Autoimmune disease, interleukin-2, systemic lupus erythematosus, graft versus host disease, vasculitis, type-1 diabetes
Disclosure: John Koreth, MBBS, DPhil, has received research funding from Prometheus. Jerome Ritz, MD, has received research funding from Prometheus. Michelle Rosenzwajg,
MD, PhD, is an inventor of a patent application claiming low-dose interleukin-2 (IL-2) in autoimmune and inflammatory diseases, owned by her academic institutions and licensed
to ILTOO Pharma in which she holds shares. David Klatzman, MD, PhD, is an inventor of a patent application claiming low-dose IL-2 in autoimmune and inflammatory diseases,
owned by his academic institutions and licensed to ILTOO Pharma in which he holds shares. George C Tsokos, MD, Alberto Pugliese, MD, and Thomas R Malek, PhD, have no
conflicts of interest to declare.
Acknowledgments: Editorial assistance was provided by Katrina Mountfort, PhD, at Touch Medical Media, London, UK and funded by Prometheus.
Received: October 22, 2014 Accepted: November 6, 2014 Citation: Oncology & Hematology Review, 2014;10(2):157–63
Correspondence: John Koreth, MBBS, DPhil, D2029 Dana Faber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, US (E: firstname.lastname@example.org). George C Tsokos,
MD, 330 Brookline Avenue, CLS 937, Boston, MA 02115, US (E: email@example.com).
Support: The publication of this article was supported by Prometheus. The views and opinions expressed are those of the authors and do not necessarily reflect those of Prometheus.
Autoimmune diseases comprise more than 80 chronic conditions that
collectively affect approximately 5 to 8 % of the US population and are
a leading cause of death in young and middle-aged women. 1 Moreover,
the incidence and prevalence of autoimmune diseases are rising. The
age of onset of autoimmune diseases varies widely but many start
during childhood 2 and, being chronic and debilitating in nature, require
long-term therapy and invoke considerable medical costs, long-term
impaired quality of life, and constitute a significant burden to families and
society. Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus
erythematosus (SLE), and inflammatory bowel disease (IBD) account for
the majority of the patients with autoimmune diseases. Understanding
© To u ch MEd ica l MEdia 201 4
the dysregulated immune response underlying autoimmune diseases
will help the development of disease-specific therapeutics. In this short
review we will present an overview of the pathophysiology of autoimmune
diseases in the context of regulatory T cell (Treg) dysfunction with a focus
on the emerging role for interleukin-2 (IL-2) based Treg therapeutics in
restoring immune regulation and mitigating organ damage.
Pathophysiology of Autoimmune Disease—
The Role of Tregs
Autoimmune diseases are characterized by a breakdown of mechanisms
that allow the immune system to distinguish between self and nonself and