Background Our previous studies in the (NZBxNZW) F1 model provide strong rationales for an IL-2 based immunotherapy of lupus in order to restore regulatory T cell (Treg) mediated tolerance that is impaired due to an acquired IL-2 deficiency (Humrich et al, 2010). However, because of its pleiotropy, other cells than Treg can be activated by IL-2 in a dose dependent manner, which may induce unwanted side effects or even trigger autoimmunity.

Objectives To determine an optimal regimen for an IL-2 based immunotherapy that is capable to induce a sufficient expansion of CD4+Foxp3+Treg in vivo while only marginally affecting other cells, and that most efficiently influences active disease in the (NZBxNZW) F1 model for lupus.

Methods Recombinant mouse IL-2 at various single doses was injected subcutaneously either into young or diseased (NZBxNZW) F1 mice every day for the duration of five days as induction therapy. After the induction phase, IL-2 injections were continued every 4 days until the end of the experiment. Control animals received an equal amount of PBS (carrier). Cells from lymphoid organs and peripheral blood were analysed by flow cytometry at different time points throughout the study. In addition survival and clinical parameters (weight, proteinuria, leukozyturia, autoantibodies) were analysed during IL-2 therapy of diseased mice for regimens with the single dosages of 5 ng/g and 25 ng/g body weight.

Results We found that the low-dose IL-2 regimen with a single dose of 5 ng/g body weight sufficiently promoted the expansion of CD4+Foxp3+Treg, while not or only marginally affecting CD4+ conventional T cells (Tcon) and other potentially harmful cells. Although higher doses of IL-2 resulted in a more pronounced proliferation and expansion of Treg, this was accompanied by a considerable increase in CD4+ memory/effector Tcon and NK/NKT cells. Clinically, regimens with both 5 ng/g and 25 ng/g were almost equally sufficient to influence nephritis and to decrease mortality in mice with established disease.

Conclusions These studies show that a low-dose IL-2 regimen selectively targets Treg and is clinically effective and also safe in murine lupus providing essential rationales for the clinical introduction of an IL-2 based immunotherapy in SLE.

References

1. Humrich, JY et al, (2010). Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc Natl Acad Sci USA 107, 204–9.