The Immunosuppressive Role of Mesenchymal Stem Cells in Systemic Lupus Erythematosus Through Induction of Tolerogenic Dendritic Cells via FLT3L
Introduction. Systemic lupus erythematosus (SLE) is an autoimmune disorder occurring in 20-150 cases per 100,000 population.1 SLE is increasingly prevalent in people of African ancestry and it usually affects women of reproductive age, with a female-to-male ratio being 9:1.1 In SLE, all pathways lead to production of endogenous interferon α (IFN-α), which promotes the maturation of conventional myeloid dendritic cells (DCs).2 Mature DCs break self-tolerance while immature DCs promote tolerogenicity.2 Current treatments with B cell selective monoclonal antibodies inhibiting T and B lymphocytes are ineffective because they non-specifically suppress the immune system and lead to infections.3 In treating SLE, a disease with autoantigens in several cell types, mesenchymal stem cells (MSCs) can induce DC tolerogenicity.3 Methods. Twenty-one patients refractory to SLE underwent umbilical cord-derived MSC transplantation (UC-MSCT). Peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls were isolated to compare conventional DCs (CD1c+DCs) using flow cytometry.3 Human Fms-related tyrosine kinase 3-ligand (FLT3L) stimulated with IFN-γ was added to PBMCs and analyzed by PCR.3 Mice with SLE underwent human adipose tissue derived mesenchymal stem cell (ASC) transplantation to measure anti-dsDNA and CD138 levels.4 PBMCs from healthy mice treated with FLT3L for 21 days were analyzed using flow cytometry.5 Results. Compared to healthy controls, patients with SLE have decreased numbers of CD1c+DCs.3 ASCs led to decreased production of anti-dsDNA and CD138.4 FLT3L injection in mice resulted in 16 to 234 fold increase in DCs starting on day 5 and peaked on day 14.5 In patients with SLE, UC-MSC injected with FLT3L up-regulated CD1c+DCs production.3 Stimulation of UC-MSCs with IFN-γ enhanced FLT3L expression via JAK-STAT pathway.3 Furthermore, systemic lupus erythematosus disease activity index (SLEDAI) score was negatively correlated to CD1c+DCs.3 Conclusions. MSC transplantation demonstrated therapeutic efficacy in animal models.4,5 Moreover, MSC transplants were well tolerated by patients and treatment-related mortality or adverse events did not occur.3 Dendritic cell tolerogenicity is critical in treating autoimmunity in SLE by upregulating the expression of immunomodulatory molecules, immunosuppressive cytokines, and regulatory T cells while decreasing the expression of pro-inflammatory cytokines.6 Increasing CD1c+DCs, which are decreased in SLE patients, is critical via MSC transplantation.3 Stimulating UC-MSCs with IFN-γ enhances production of FLT3L via JAK/STAT pathway.3 Consequently, FLT3L increases production of CD1c+DCs, thus promoting DC tolerogenicity and decreasing SLEDAI score.3 These findings demonstrate the MSCs as a promising therapeutic tool to suppress immunity in SLE patients in a more controlled and specific manner.
- Tsokos, G. Systemic Lupus Erythematosus. The New England Journal of Medicine. 2011; 2110-2121. doi: 10.1056/NEJMra1100359
- Bertsias, G, Cervera, R, Boumpas, D. Systemic Lupus Erythematosus: Pathogenesis and Clinical Features. Eular textbook on rheumatic diseases. 2012; 476-505.
- Yuan, X, Qin, X, Wang, D. et al.Mesenchymal stem cell therapy induces FLT3L and CD1c+ dendritic cells in systemic lupus erythematosus patients. Nature Communications. 2019; 10 (2498). https://doi-org.srv-proxy2.library.tamu.edu/10.1038/s41467-019-10491-8
- Choi, E, Lee, M, Song, J, et al. Mesenchymal stem cell transplantation can restore lupus disease-associated miRNA expression and Th1/Th2 ratios in a murine model of SLE. Scientific Reports. https://doi.org/10.1038/srep38237
- Breton, G, Lee, J, Zhou, Y, Schreiber, J. Circulating precursors of human CD1c+ and CD141+dendritic cells. Rockefeller University Press. 2015; 212 (3): 401–41. https://doi.org/10.1084/jem.20141441
- Kaewraemruaen, Ch, Ritprajak, P, Hirankarn, N. Dendritic cells as key players in systemic lupus erythematosus. Asia Pacific Journal of Allergy and Immunology. 2019. Doi: 10.12932/AP-070919-0639