¹Universitätsklinikum Schleswig-Holstein, Klinik für Rheumatologie und klinische Immunologie, Lübeck

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Introduction: Natural killer (NK) cells are innate immune cells that a play crucial role in the initiation and perpetuation of acute and chronic immune responses. Apart from their cytotoxic and pro-inflammatory effector functions, distinct subsets of NK cells, particularly CD56bright (CD56br) NK cells, also exert inhibitory functions on immune responses and are capable to eliminate autoreactive immune cells, suggesting their interference with autoimmune processes. Similar to regulatory T cells (Treg), NK cells require the homeostatic cytokine interleukin-2 (IL-2) for their growth, differentiation and survival, which is known to be deficient in systemic autoimmune disease such as systemic lupus erythematosus (SLE). Correspondingly, in previous clinical trials low-dose IL-2 therapy was found to expand NK cells in patients with active SLE, although at a lower level compared to the expansion of the Treg population [1], [2], [3]. Here we investigated whether patients with SLE harbor a deficiency of CD56br NK cells and whether treatment with low-dose of IL-2 is capable to recover NK cells in particular those with immunoregulatory properties.

Methods: Frequencies of CD56+ and CD56br NK cells were determined by flow cytometry in peripheral blood mononuclear cells (PBMC) from patients with SLE (n=19) and age-matched healthy donors (HC, n=21). Changes in diverse NK cell subsets were analyzed by multi-color flow cytometry in 7 patients who participated in an investigator-initiated, phase 1/2 clinical trial using four separate treatment cycles of low-dose IL-2 therapy in active and refractory SLE (PRO-IMMUN)2. For statistical analyses, Kruskal-Wallis test was used for comparisons of differences between SLE patients and HC, and Wilcoxon signed rank test was used for comparing IL-2 induced changes in NK cells subsets within the clinical trial.

Results: Frequencies of NK cells and in particular of CD56br NK cells were drastically reduced in patients with SLE compared to HC (p<0.0001). Low-dose IL-2 therapy induced significant increases in the frequencies of CD56br NK cells among total CD3-CD56+ NK cells within the treatment cycles. Comparison of the CD56br and CD56dim NK cell subsets revealed increases in frequencies of CD56br NK cells co-expressing NKG2A, Perforin and Granzyme B, that was not observed for the CD56dim NK cell population.

Conclusion: Active SLE is marked by a reduction of NK cells, in particular of NK cells with immunoregulatory features. Apart from its known properties to efficiently boost Treg activity, low-dose IL-2 therapy is also capable to recover and expand NK cells with immunoregulatory potential in patients with active SLE. These findings point to a novel mechanism-of-action of low-dose IL-2 therapy aiming to correct a dysregulated state of NK cell biology in autoimmune diseases.

Literatur

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[2] Humrich JY, von Spee-Mayer C, Siegert E, Bertolo M, Rose A, Abdirama D, Enghard P, Stuhlmüller B, Sawitzki B, Huscher D, Hiepe F, Alexander T, Feist E, Radbruch A, Burmester GR, Riemekasten G. Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial. Lancet Rheumatol. 2019 Sep;1(1):e44-e54. DOI: 10.1016/S2665-9913(19)30018-9
[3] Humrich JY, Cacoub P, Rosenzwajg M, Pitoiset F, Pham HP, Guidoux J, Leroux D, Vazquez T, Riemekasten G, Smolen JS, Tsokos G, Klatzmann D. Low-dose interleukin-2 therapy in active systemic lupus erythematosus (LUPIL-2): a multicentre, double-blind, randomised and placebo-controlled phase II trial. Ann Rheum Dis. 2022 Dec;81(12):1685-94. DOI: 10.1136/ard-2022-222501