Amanda Duong

Introduction: Systemic Lupus Erythematous (SLE) is characterized by exaggerated B and T cell responses and loss of immune tolerance against self-antigens.¹ SLE is also characterized by remission and relapse phases rather than progressive like rheumatoid arthritis. It is the direct immune mediated tissue damage that leads to the morbidity and mortality in SLE.^2,3 The severity of lupus nephritis as well as the hematopoietic and central nervous system symptoms of SLE are related to type I interferon (IFN).⁴ The classical treatment for SLE is corticosteroids and immunosupressors, however, immunosuppressants are better than corticosteroids alone in preventing severe renal damage.^3,5 Hematopoietic stem cell transplants have been used for SLE treatments, however, it had a high mortality and relapse rate.⁵ Mesenchymal stem cells (MSCs) are ideal for treating SLE due to the inhibitory effect on dendritic cells and type I IFN.⁴ MSCs promote the differentiation and survival of Tregs and tolerogenic dendritic cells (TolDCs).⁶ TolDCs reduce both the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules, leading to a lower CD4+ T-cell priming. TolDCs pulsed with antigens can lead to antigen-specific T-cell hypo-responsiveness. This self-antigen selection is a central issue for the appropriate design of immunotherapy by using antigen-presenting cells in immune-mediated diseases such as SLE.⁷Methods: Twenty one patients underwent umbilical cord MSCs (UC MSC) transplantation with each recipient receiving UC MSCs from a single donor. Peripheral blood mononuclear cells (PBMCs) were isolated from active lupus patients and healthy controls and then cocultured with UC MSCs for up to 72 hours. SLE PBMCs were stimulated with different concentrations of recombinant human FLT3L (1, 10, 100 and 500 ng/ml). Flow cytometry, enzyme linked immunosorbent assay (ELISA), real-time PCR, Western blot analysis, and immunofluorescence were used to analyze the cells after culture. SLE PBMCs were stimulated with different concentrations of recombinant human FLT3L (1, 10, 100 and 500 ng/ml).⁸ Results: UC-MSCs ameliorate CD1c+DCs deficiency in SLE patients. MSCs increased tolerogenic CD1c+ DCs through FLT3L-FLT3 interactions. IFN-y increases FTL3L in US-MSCs. Patients who had higher levels of baseline IFN-y and lower levels of baseline IL-6 showed a better clinical response to the UC MSCs.⁸ Conclusion: Mesenchymal stem cell therapy shows promising results in SLE patients that have CD1c+DCs deficiency through increasing the dendritic cells through induction of FTL3L which can be enhanced by IFN-y.⁸ Unknown antigens as well as the great diversity of reported self-antigens in systemic autoimmune pathologies hinder the selection of the correct tissue-specific antigens in the therapeutic potential of TolDCs, especially considering that SLE is a heterogeneous disease composed of multiple clinical presentations.⁷

1. Kiriakidou M, Ching CL. Systemic Lupus Erythematosus. Ann Intern Med. 2020;172(11):ITC81-ITC96.
2. El-Jawhari JJ, El-Sherbiny Y, McGonagle D, Jones E. Multipotent Mesenchymal Stromal Cells in Rheumatoid Arthritis and Systemic Lupus Erythematosus; From a Leading Role in Pathogenesis to Potential Therapeutic Saviors? Front Immunol. 2021;12:643170.
3. Fava A, Petri M. Systemic lupus erythematosus: Diagnosis and clinical management. J Autoimmun. 2019;96:1-13.
4. Yang C, Sun J, Tian Y, et al. Immunomodulatory Effect of MSCs and MSCs-Derived Extracellular Vesicles in Systemic Lupus Erythematosus. Front Immunol. 2021;12:714832.
5. Li A, Guo F, Pan Q, et al. Mesenchymal Stem Cell Therapy: Hope for Patients With Systemic Lupus Erythematosus. Front Immunol. 2021;12:728190.
6. Mosanya CH, Isaacs JD. Tolerising cellular therapies: what is their promise for autoimmune disease? Annals of the Rheumatic Diseases. 2019;78(3):297-310.
7. Funes SC, Rios M, Gomez-Santander F, et al. Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice. Immunology. 2019;158(4):322-339.
8. Yuan X, Qin X, Wang D, et al. Mesenchymal stem cell therapy induces FLT3L and CD1c(+) dendritic cells in systemic lupus erythematosus patients. Nat Commun. 2019;10(1):2498.