Background:Lupus nephritis (LN) is a condition arising from abnormal immune responses to internal organs. Patients with LN suffer from severe morbidity and mortality1, 2. Despite the aggressive regimen, 20-40% of patients do not respond to current conventional therapy. CXCL5, as a potent chemoattractant and activator of neutrophils3, demonstrates strong immunosuppression in the pre-clinical mouse model of graft versus host disease (GvHD)4 and lupus nephritis (LN) by intravenous administration.Objectives:In this study, we aim to evaluate whether the therapeutic effect of conventional therapy could be further improved by combination therapy with CXCL5.Methods:Ten doses of exogenous CXCL5 (3ug/kg, biweekly) together with conventional therapy (methylprednisolone (MP, intravenous (IV) injection with 8.3mg/kg/day at day-1, day-2 and day-3) + cyclophosphamide (CP, IV injection with 0.5g/BSA at day-4, monthly for 5 doses)) were administered to 8-week-old Faslpr mice by IV injection. Mice were monitored for 64 weeks. Splenic immune profile at 3 weeks post treatment (PT) was measured by flow cytometry. Circulating cytokine profile were detected by Luminex technology. Renal function was evaluated by urinary spot albumin creatinine ratio. In situ renal immune cell infiltration and complement 3 deposition were detected by Haematoxylin and Eosin (H&E) and immunohistochemistry staining.Results:Comparing to control mice (dPBS: 0% at 28 weeks PT), mice survival was improved to 100% at 40 weeks PT and 55.6% at 64 weeks PT by combination therapy of CXCL5 and conventional therapy (MP + CP) (p<0.0001). The accumulation of autoantibody (anti-dsDNA) and proteinuria were reduced 61.2-fold at 32 weeks PT (p=0.004) and 83.5-fold at 28 weeks PT (p=0.03) respectively. Both autoantibody and proteinuria were maintained at low level for 64 weeks. The classification of LN was significantly reduced at 10 weeks PT and equivalent to the classes we observed in pre-onset mice (p=0.004). Although combination therapy was not able to promote Tregs, it reduced both innate (neutrophils and macrophages) and adaptive (TH1, TH2 and TH17 cells and B cells) immunities significantly. Concomitantly, the serum level of endogenous CXCL5 was boosted up by exogenous administration from 74.2 +/- 53.9 pg/ml to 254.1 +/- 147.1 pg/ml at 8 weeks PT (p=0.05) and this relative high concentration was maintained for 48 weeks.Conclusion:Combining CXCL5 with conventional therapy provides effective and durable immunosuppression in murine LN and it may provide a new option for LN therapy.References:[1]Almaani S, Meara A, Rovin BH. Update on Lupus Nephritis. Clin J Am Soc Nephrol. May 8 2017;12(5):825-835. doi:10.2215/cjn.05780616.[2]Touma Z, Gladman DD. Current and future therapies for SLE: obstacles and recommendations for the development of novel treatments. Lupus Sci Med. 2017;4(1):e000239. doi:10.1136/lupus-2017-000239.[3]Koltsova EK, Ley K. The mysterious ways of the chemokine CXCL5. Immunity. Jul 23 2010;33(1):7-9. doi:10.1016/j.immuni.2010.07.012.[4]Fan X, Guo D, Cheung AMS, et al. Mesenchymal Stromal Cell (MSC)-Derived Combination of CXCL5 and Anti-CCL24 Is Synergistic and Superior to MSC and Cyclosporine for the Treatment of Graft-versus-Host Disease. Biol Blood Marrow Transplant. Jun 5 2018;doi:10.1016/j.bbmt.2018.05.029.Disclosure of Interests:None declared
Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape