Low-Dose Il-2 Therapy Selectively Expands Regulatory T Cells And Suppresses Murine Lupus

BackgroundOur 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, although Treg appear to be the major target of IL-2 in vivo, because they constitutively express the high-affinity IL-2 receptor,other cells that potentially trigger autoimmunitycan also be activated by IL-2 in a dose dependent fashion.ObjectivesTo determine an optimal dose and regimen for a therapy with IL-2 that induces 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. In addition, the underlying cellular mechanisms and side effects were studied.MethodsRecombinant mouse IL-2 at different single doses (1, 5, 25, 50 ng/g body weight) 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 analyzed by flow cytometry at days 5, 7, 14 and 21. 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 and 25 ng/g body weight.ResultsWe found that the low-dose IL-2 regimen with a single dose of 5ng/g body weight sufficiently promoted the expansion of CD4+Foxp3+Treg, while not or only marginally affecting CD4+ effector T cells and other 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 CD44hi memory/effector CD4+ T cells and NK cells. Clinically, regimens with both 5ng/g and 25 ng/g were nearly equally sufficient to influence nephritis and to decrease mortality. In addition, we did not observe any signs of intolerability or other clinical side effects in the treated animals, even at higher dosages of 50ng/g body weight.ConclusionsThese studies provide the first evidence that low-dose IL-2 therapy selectively targets Treg and is clinically effective and also safe in murine lupus. This knowledge is very important for the future design of a clinical study with IL-2 in SLE.ReferencesHumrich, 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, 204-9Disclosure of InterestNone Declared