Therapeutic innovation from extinction of lupus in haemodialysis – ELuDial

Systemic lupus is a rare autoimmune disease leading to end stage renal disease (ESRD) in 25% of cases. It highlights the need for treatment innovation for systemic lupus and lupus nephritis. Despite important efforts made by the medical community, research groups, and pharmaceutical companies, randomized clinical trials failed to validate innovative treatment strategies for several decades.
After ESRD, lupus activity decreases to reach a stable extinct state in most patients. Our objective is to identify the mechanisms responsible for lupus extinction after ESRD and to propose new therapeutic options based on the replication of these mechanisms in non-dialysed patients with active lupus. We propose to investigate hypotheses based on previous findings of our consortium, or issued from clinical observations: the sexual dysfunction hypothesis and the ESRD-associated immune cells dysfunction hypothesis. In parallel, we will conduct an open screening of new mechanisms underlying the lupus extinction through the characterization of the differential gene expression profile associated with lupus extinction in patients undergoing haemodialysis.
First, we will assemble a multicentric French cohort of lupus patients, who started chronic haemodialysis between 2010 and 2017. Patients will be recruited from the national REIN registry, which prospectively collects data for all incident patients undergoing renal replacement therapy. This step will permit the identification of clinical parameters associated with lupus extinction and natural history of lupus extinction after ESRD.
Second, for biological investigations, we will recruit 64 dialysis patients with active or extinct lupus and a “control positive” group of patients with active lupus and no ESRD. Biologically relevant therapeutic targets will be hypothesised from biological characteristics associated with lupus extinction. Briefly, we will dose FSH, LH, prolactin, oestradiol, progesterone, anti-mullerian hormone, testosterone and prostaglandin; to evaluate the role of uremic toxins on lupus extinction and determine the immune cells phenotypes associated with lupus extinction we will determine the serum levels of several protein-bound uremic toxins by HPLC, IDO activity, and the global ability of patients’ serum to activate AhR (Callux test), the count of circulating pDCs, and DCs activation state will be measured, as well as the SHP1 phosphorylation of PBL and the basophil activation profile in each patient. Moreover, to extend the field outside those restricted hypotheses we will add an unbiased transcriptomic approach to provide additional and unsuspected information and identify which modules/pathways, up or down-regulated are associated with lupus extinction. Results will be correlated to clinical lupus activity to determine which pathophysiological pathways are involved in ESRD-associated extinction of lupus, and which ones should be further investigated as target of innovative therapies.
Third, we will test the ability of the targeting of those candidates ex vivo to turn off the lupus inflammatory signature of human inflammatory cells from active lupus patients. Lupus inflammatory signature will be assessed by flow cytometry analyses of DCs activation/maturation status, B? activation status, and the SHP1-based ITAMi/ITAMa status in Mo and PMN from patients with active lupus and no ESRD.
Finally, candidates selected from ex vivo experiments will be specifically tested in vivo as innovative treatments in animal models of severe lupus nephritis (a humanized mouse model Fc?RIIATg combined to pristane injection, and a non-genetic based lupus model on BALBc mice with pristane injection).
The ELUDIAL project will be conducted in a non-investigated field regarding treatment innovation. This originality and the high-level experience of the consortium in the field support its clinical relevance, its scientific robustness, and increase its chances of success.