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The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases

Key Points

  • Interleukin-2 (IL-2) was discovered as a cytokine that supports the proliferation and differentiation of effector T cells. IL-2 initially entered clinical development based on this activity, in settings such as cancer and infectious diseases.

  • When used at high doses in patients with melanoma or renal cell carcinoma, IL-2 induces relatively rare (around 7%) but durable complete responses, at the expense of severe side effects. IL-2 has been approved by the US Food and Drug Administration for these indications.

  • Surprisingly, knockout of the genes encoding IL-2 or IL-2 receptor in mice led to severe autoimmunity, rather than the predicted immune deficiency. This was later explained by a defect in regulatory T (TReg) cells, and the discovery that IL-2 is the key cytokine for TReg cell function and survival.

  • Further studies showed that IL-2 also favours the development of activated CD4+ T cells towards the T helper 1 (TH1), TH2, TH9 and peripherally induced TReg (pTReg) cell lineages, rather than the TH17 and T follicular helper (TFH) cell lineages. Thus, IL-2 contributes to tipping the immune balance towards regulation rather than inflammation, notably by favouring the differentiation of pTReg cells over TH17 cells; helps to control autoantibody generation by favouring T follicular regulatory cells over TFH cells; and helps to control autoreactive CD8+ effector T cells.

  • Proof-of-concept clinical trials have shown that at a low dose, IL-2 is well tolerated, induces TReg cells and mediates clinical improvements in autoimmune and inflammatory diseases; these findings have been confirmed in additional trials.

  • These trials and additional experimental work also showed that IL-2 mediates immunoregulation without immunosuppression. This opens the door for broad investigation of the therapeutic potential of low-dose IL-2 in a large number of autoimmune and inflammatory diseases.

Abstract

Depletion of regulatory T (TReg) cells in otherwise healthy individuals leads to multi-organ autoimmune disease and inflammation. This indicates that in a normal immune system, there are self-specific effector T cells that are ready to attack normal tissue if they are not restrained by TReg cells. The data imply that there is a balance between effector T cells and TReg cells in health and suggest a therapeutic potential of TReg cells in diseases in which this balance is altered. Proof-of-concept clinical trials, now supported by robust mechanistic studies, have shown that low-dose interleukin-2 specifically expands and activates TReg cell populations and thus can control autoimmune diseases and inflammation.

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Figure 1: Pleiotropic effects of interleukin-2 in controlling autoimmunity.
Figure 2: Effector T cells and regulatory T cells show differential use of signalling pathways and differential sensitivity to interleukin-2.
Figure 3: Effects of interleukin-2 in patients with autoimmune or inflammatory diseases.
Figure 4: Possible administration schemes for interleukin-2.

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Acknowledgements

The work of D.K. is funded by French state funds within the Investissements d'Avenir programme (ANR-11-IDEX-0004-02; LabEx Transimmunom); the European Research Council Advanced Grant (ERC-2012-AdG, TRiPoD, Agreement number 322856); the Assistance Publique – Hopitaux de Paris, France; the Sorbonne University, Pierre and Marie Curie Medical School, Paris, France; the Institut National de la Santé et de la Recherche Médicale (INSERM); and Le Centre National de la Recherche Scientifique (CNRS).

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Correspondence to David Klatzmann or Abul K. Abbas.

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D.K. is an inventor of a patent application claiming low-dose IL-2 for therapy of autoimmune diseases, owned by his academic institution, and licensed to ILTOO Pharma, which he advises and in which he holds shares. A.K.A. declares no competing interests.

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Main clinical and biological findings from high- to low-dose IL-2 clinical trials (PDF 269 kb)

Glossary

T follicular regulatory cells

(TFR cells). Cells that are derived from thymus-derived regulatory T cells and share phenotypic characteristics with T follicular helper (TFH) cells, including the expression of the B cell follicle-homing receptor CXC-chemokine receptor 5. TFH cells control germinal centre B cells undergoing somatic hypermutation and selection that results in antibody affinity maturation. TFR cells reduce TFH cell and germinal centre B cell numbers.

Type 2 innate lymphoid cells

(ILC2s). ILCs are rare cells from the lymphoid lineage — comprising the ILC1, ILC2 and ILC3 subsets — that produce many of the same cytokines as T cells but lack T cell antigen receptors. They have diverse roles in immune responses and inflammation. ILC2s produce type 2 cytokines, such as interleukin-5 (IL-5) and IL-13, and have key roles in anthelminthic responses and allergic lung inflammation.

IL-2 international units

(IL-2 IU). The interleukin-2 (IL-2) IU is a biological activity determined by the ability to support the growth of an IL-2-dependent cell line. In practice, as the manufacture of IL-2 is standardized, 1.1 mg of IL-2 corresponds to 18 million IU.

Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome

(IPEX syndrome). This rare genetic autoimmune disease is caused by mutations in the FOXP3 gene (which encodes forkhead box P3). Affected males present with early-onset severe enteropathy that is usually accompanied by insulin-dependent diabetes (type 1). Other autoimmune manifestations include hypothyroidism, anaemia, thrombocytopenia and neutropenia. Increased serum IgE levels and dermatitis are often also present.

IL-2–antibody complex

(IL-2c). A complex of interleukin-2 (IL-2) and IL-2-specific antibody that has a prolonged half-life compared with IL-2. Its biological activity depends on the antibody. Some complexes preferentially stimulate effector T cells, whereas others preferentially stimulate regulatory T cells.

Vascular leak syndrome

(VLS). VLS (also known as capillary leak syndrome, systemic capillary leak syndrome or Clarkson disease) is characterized by a leakage of fluid from the circulatory system into the interstitial space, resulting in hypotension, haemoconcentration and hypoalbuminaemia.

Cytokine storm

Also known as hypercytokinaemia. The systemic expression of a vigorous immune response resulting in the release of inflammatory mediators into the bloodstream, including cytokines, oxygen free radicals and coagulation factors. The primary symptoms of a cytokine storm are high fever, swelling and redness caused by vascular leak, extreme fatigue and nausea.

Graft-versus-host disease

(GVHD). A common complication of allogeneic stem cell transplantation, in which immune cells from the graft recognize the recipient cells as foreign and attack them. The main target tissues are the liver, skin and gastrointestinal tract. It can be acute (within 100 days of transplantation) and life-threatening, or chronic.

Hepatitis C virus-induced vasculitis

(HCV-induced vasculitis). 10–15% of patients with chronic HCV infection develop systemic cryoglobulinaemic vasculitis. Cryoglobulins are cold-insoluble immune complexes containing rheumatoid factor and polyclonal IgG that deposit on vascular endothelium, causing vasculitis in organs such as the skin and kidneys, and in peripheral nerves.

Adverse events

Medical occurrences that are temporally (but not necessarily causally) associated with the use of a medicinal product. The severity of adverse events is graded from 1 to 4, with the grades representing mild, moderate, severe and potentially life-threatening events, respectively. Any adverse event that causes death, is life threatening, requires hospitalization, or results in persistent or significant disability or incapacity is considered a serious adverse event.

Alopecia areata

A prevalent autoimmune disease (affecting 1.7% of the general population) that leads to hair loss on the scalp and other areas of the body. Infiltration of CD4+ and CD8+ T cells around hair follicles is associated with the condition.

TRANSREG clinical trial

An open-label Phase II clinical trial investigating the stimulation of regulatory T cells by low-dose interleukin-2 in 11 autoimmune diseases: rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet disease, Wegener granulomatosis, Takayasu disease, Crohn disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis (ClinicalTrials.gov identifier: NCT01988506).

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Klatzmann, D., Abbas, A. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 15, 283–294 (2015). https://doi.org/10.1038/nri3823

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