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

• Published in: Nature reviews. Immunology Vol. 15; no. 5; pp. 283 - 294
• Main Authors: Klatzmann, David, Abbas, Abul K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-05-2015; Nature Publishing Group
• Subjects: 631/250/127/1213; 631/250/249; 631/250/251/1574; 631/250/2520; Antineoplastic Agents - immunology; Antineoplastic Agents - therapeutic use; Autoimmune diseases; Autoimmune Diseases - drug therapy; Autoimmune Diseases - immunology; Biomedicine; Dosage and administration; Drug therapy; Human health and pathology; Humans; Immune system; Immunology; Inflammation; Inflammation - drug therapy; Inflammation - immunology; Interleukin-2; Interleukin-2 - immunology; Interleukin-2 - therapeutic use; Life Sciences; review-article; T-Lymphocytes, Regulatory - immunology; France
• ISSN: 1474-1733; 1474-1741; 1474-1741
• DOI: 10.1038/nri3823

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 (T
Reg
) cells, and the discovery that IL-2 is the key cytokine for T
Reg
cell function and survival.
Further studies showed that IL-2 also favours the development of activated CD4
+
T cells towards the T helper 1 (T
H
1), T
H
2, T
H
9 and peripherally induced T
Reg
(pT
Reg
) cell lineages, rather than the T
H
17 and T follicular helper (T
FH
) cell lineages. Thus, IL-2 contributes to tipping the immune balance towards regulation rather than inflammation, notably by favouring the differentiation of pT
Reg
cells over T
H
17 cells; helps to control autoantibody generation by favouring T follicular regulatory cells over T
FH
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 T
Reg
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.
The dominant role of interleukin-2 (IL-2) is in the maintenance of regulatory T cells rather than of effector T cells. This has led to clinical interest in the use of low-dose IL-2 to control autoimmune and inflammatory disorders, with promising initial results.
Depletion of regulatory T (T
Reg
) 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 T
Reg
cells. The data imply that there is a balance between effector T cells and T
Reg
cells in health and suggest a therapeutic potential of T
Reg
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 T
Reg
cell populations and thus can control autoimmune diseases and inflammation.