Background Low-dose IL-2 therapy was shown to restore regulatory T cell (Treg) homeostasis and to decrease disease activity in early phase clinical trials in patients with SLE.1,2,3 However, the mechanisms of action of IL-2 therapy beyond Treg targeting are still poorly understood. Here, we assessed the changes of lymphocyte subsets in the peripheral blood that are considered to be involved in the regulation of germinal-center reactions during an open-label, uncontrolled, phase 1/2a single-center trial with low-dose IL-2 therapy in patients with active SLE.
Methods 12 patients with active and refractory SLE (SLEDAI ≥ 6) were treated with four separate 5-day treatment cycles consisting of daily subcutaneous injections of IL-2 between 0.75 and 3.0 million IU. Cells from peripheral blood were analyzed by flow cytometry before and one day after each treatment cycle.
Results Significant decreases in the numbers of CD3-CD56-CD19+ B cells were observed after most treatment cycles and at the end of the treatment period. Subtyping of the B cell population revealed that in particular proportions and numbers of CD20+IgD+CD27+ marginal-zone B cells were reduced. Transient and moderate decreases in the proportions and numbers of CD20+IgD-CD27- memory B cells were also apparent during the treatment cycles, whereas there were no relevant changes in CD20+IgD+CD27- naïve B cells. In addition we noted moderate decreases in the proportions of common CXCR5+ T follicular helper cells (Tfh) and of CD45RO+CCR7-CXCR5+PD1+ Tfh cells among CD3+CD4+FoxP3- T cells during the treatment period. Yet, more pronounced decreases were observed in the proportions of CXCR5+ cells among CD3+CD4+FoxP3+ regulatory T cells.
Conclusions These findings suggest that low-dose IL-2 therapy interferes with the regulation and fine tuning of immune responses that take place in the germinal-centres of lymphatic tissues.
Funding German Research Foundation (DFG).
Humrich JY, von Spee-Mayer C, Siegert E, Alexander T, Hiepe F, Radbruch A, Burmester GR, Riemekasten G. Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann Rheum Dis. 2015; 74; 791–792.
von Spee-Mayer C, Siegert E, Abdirama D, Rose A, Klaus A, Alexander T, Enghard P, Sawitzki B, Hiepe F, Radbruch A, et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2016; 75; 1407–1415.
Humrich JY, von Spee-Mayer C, Siegert E, Bertolo M, Rose A, Abdirama D, Enghard P, Stuhlmüller B, Sawitzki B, Huscher D, et al. Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial. Lancet Rheumatol. 2019; 1; e44–e54.
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