Given the crucial role of the homeostatic γc cytokines in the steady state as well as in immune pathologies, the objectives of this CRPP project CYTIMM-Z are (i) to gain detailed insight into these processes in patients with HLH and SLE, and (ii) to translate this knowledge into improved treatments aimed at the modulation and durable re-establishment of immune balance. Within the following work packages the laboratories of Jana Pachlopnik Schmid and Onur Boyman are approaching these objectives in a stepwise, translational manner.
a) Studies of the IL-2–IL-2R system in hemophagocytic lymphohistiocytosis (HLH; preclinical and translational)
Using murine models and patient samples of HLH, we will study selective modulation of IL-2 signals in specific immune cell subsets by using biased IL-2/anti-IL-2 mAb complexes (cx), with the aim of stimulating regulatory vs. effector-type immune cells. Lymphocyte homeostasis, cellular cytotoxicity, and disease severity will also be evaluated. We will compare these data with HLH patient samples stimulated with these cytokine-directed reagents in vitro and assessed for cytokine receptor expression on immune cell subsets and receptor signaling.
b) Charact-IL-2 clinical trial in systemic lupus erythematosus (SLE) patients (phase II clinical):
In this work package, we will focus on qualitative homeostasis by modulating the ratio of effector to regulatory-type immune cells in SLE. We will investigate the effects on these immune cell subsets and homeostatic cytokine–cytokine receptors before and after low-dose IL-2 treatment of SLE patients within an investigator-initiated phase II clinical trial at the Department of Immunology, University Hospital Zurich (USZ). Comparison of B and T cell repertoires including transcriptional profiles will be carried out before and after IL-2 treatment. Particular attention will also be given to activation of the phagocytic and APC systems.