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Induction of Tolerance in Autoimmune Diseases Rather Than Cure of Cancer by Interleukin-2 Therapy

Clinical Department of Internal Medicine, Division of General Internal Medicine, Innsbruck Medical University, Innsbruck, Austria

Michael Schirmer

General Hospital of the Elizabethenians, Klagenfurt, Austria

To the Editor:

Once interleukin-2 (IL-2) was discovered, it was quickly used for the in vitro stimulation of lymphocytes and it was administered to cancer patients in order to expand antitumor effector cells.¹ Unfortunately, IL-2-based immunotherapy lacked response in approximately 80% of patients.² Cesana et al² demonstrated that treatment with IL-2 resulted in an increased prevalence of peripheral blood CD4⁺CD25^hi regulatory T cells (TREGs) in a subset of patients with renal cell carcinoma and metastatic melanoma, which lack clinical response. TREGs may suppress antitumor immune responses and exogenous IL-2 may therefore lead to progression, rather than cure of cancer.³

The selective manipulation of TREGs is of growing interest for rheumatologists as reduced prevalences and functional defects of TREGs have been implemented in the pathogenesis of various autoimmune diseases. Indeed, TREGs were successfully activated by CD28-superagonist antibodies in vivo, and polyclonally expanded TREGs significantly reduced inflammation in animal models of arthritis ex vivo.^4,5 Tolerance induction by exogenous IL-2 would also be an interesting therapeutic strategy for autoimmune diseases, as IL-2 deficient mice display a profound reduction of TREGs and develop fatal lymphoproliferative disease with multiorgan autoimmunity.¹ Similarly, the neutralization of circulating IL-2 for a limited period of time can elicit autoimmune disease in wildtype mice by reducing natural TREGs.⁶

In addition to the effects on TREG homeostasis, however, IL-2 enhances immune responses in vitro and effector T cells become resistant to TREG-mediated suppression.⁵ Some cancer patients developed autoimmune diseases under treatment with high dosages of IL-2.⁷ The clinical outcome of IL-2 therapy could be modulated by the cytokine milieu at target sites or by the presence or absence of danger signals, such as toll-like receptor signaling, which abrogate TREG-mediated suppression.⁵ Besides, high doses of IL-2 induce transient lymphopenia and it was shown in mice, that under lymphopenic conditions both effector T cells causing autoinflammation and protective TREGs could be induced by the same antigen in dependence of IL-2.^2,8

In patients with established tumors, effector T cells and TREGs directed against tumor antigens may coexist with effector T cells being suppressed by TREGs.⁹ Induction of lymphopenia by IL-2 therapy may thus promote the proliferation of TREGs that recognize tumor antigens and keep effector T cells in quiescence.^1,10

In patients with autoimmune diseases, TREG-resistant effector T cells directed against self-antigens have been suggested to dominate the immune response.⁵ It is conceivable that lymphopenia and exogenously provided IL-2 would then further stimulate TREG-resistant effector cells, at least in the acute phase. Interestingly, mouse studies showed evidence, that following lymphopenia, IL-2-stimulated effector T cells caused autoimmunity, and that after this acute phase, antigen-specific TREGs expanded in an IL-2 dependent manner restoring immune homeostasis.⁸ Although these animals kept under germ-free conditions may not accurately reflect established human autoimmunity, this model suggests that IL-2 can induce tolerance in autoimmunity, albeit with delayed kinetics. In contrast, IL-2 depletion by specific monoclonal antibodies and induction of lymphopenia would rather be promising in cancer patients causing a slow but progressive response against tumor antigens.⁸

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

This letter was supported by the Foundation to Support Training and Research of South Tyroleans at the University of Innsbruck (C. Dejaco) and the Tyrolean Research Funds (C. Duftner).

REFERENCES

1. Antony PA, Restifo NP: CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2. J Immunother 28:120-128, 2005[Medline]

2. Cesana GC, DeRaffele G, Cohen S, et al: Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol 24:1169-1177, 2006[Abstract/Free Full Text]

3. Viguier M, Lemaitre F, Verola O, et al: Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol 173:1444-1453, 2004[Abstract/Free Full Text]

4. Beyersdorf N, Hanke T, Kerkau T, et al: Superagonistic anti-CD28 antibodies: Potent activators of regulatory T cells for the therapy of autoimmune diseases. Ann Rheum Dis 64:91-95, 2005 (suppl 4)

5. Dejaco C, Duftner C, Grubeck-Loebenstein B, et al: Imbalance of regulatory T-cells in autoimmune diseases. Immunology 107:289-300, 2006

6. Fehervari Z, Yamaguchi T, Sakaguchi S: The dichotomous role of IL-2: tolerance versus immunity. Trends Immunol 27:109-111, 2006[CrossRef][Medline]

7. Acres B, Paul S, Haegel-Kronenberger H, et al: Therapeutic cancer vaccines. Curr Opin Mol Ther 6:40-47, 2004[Medline]

8. Knoechel B, Lohr J, Kahn E, et al: Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med 202:1375-1386, 2005[Abstract/Free Full Text]

9. Hiura T, Kagamu H, Miura S, et al: Both regulatory T cells and antitumor effector T cells are primed in the same draining lymph nodes during tumor progression. J Immunol 175:5058-5066, 2005[Abstract/Free Full Text]

10. Stockinger B, Kassiotis G, Bourgeois C: Homeostasis and T cell regulation. Curr Opin Immunol 16:775-779, 2004[CrossRef][Medline]

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