The Ameliorating Effects of MSCs in Controlling Treg-mediated B-Cell Depletion by Indoleamine 2, 3-dioxygenase Induction in PBMC of SLE Patients
DOI:
https://doi.org/10.3889/oamjms.2022.7487Keywords:
Mesenchymal stem cells, Indoleamine 2, 3-dioxygenase, B cells, T-reg, Systemic lupus erythematosusAbstract
BACKGROUND: Mesenchymal stem cells (MSCs) have potent immunosuppressive properties to control systemic lupus erythematosus (SLE) disease by releasing several anti-inflammatory molecules, particularly indoleamine 2, 3-dioxygenase (IDO), and increasing regulatory T cells (Treg) to control innate and adaptive immune cells. However, how MSCs release IDO to modulate Treg in controlling B is poorly understood. Therefore, investigating IDO, Treg, and B cells following MSC administration in SLE is needed.
AIM: This study aimed to investigate the ameliorating effects of MSCs in controlling B cells mediated by an increase of IDO-induced Treg in PBMC of SLE patients.
METHODS: This study used a post-test control group design. MSCs were obtained from human umbilical cord blood and characterized according to their surface antigen expression and multilineage differentiation capacities. PBMCs isolated from SLE patients were divided into five groups: Sham (placebo group), control, and three treatment groups. The treatment groups were treated by coculturing MSCs to PBMCs with a ratio of 1:10, 1:25, and 1:40 for 72 h incubation. Treg and B-cell levels were analyzed by flow cytometry with cytometric bead array (CBA) while the IDO levels were determined by ELISA.
RESULTS: This study showed that the percentages of B cells decreased significantly in groups treated by dose-dependent MSCs, particularly in T1 and T2 groups followed by increased Treg cell percentages. These findings were aligned with the significant increase of the IDO levels.
CONCLUSIONS: MSCs regulated B cells through an increase of IDO-induced Treg in SLE patients’ PBMC.
Downloads
Metrics
Plum Analytics Artifact Widget Block
References
Yaniv G, Twig G, Shor DB, Furer A, Sherer Y, Mozes O, et al. A volcanic explosion of autoantibodies in systemic lupus erythematosus: A diversity of 180 different antibodies found in SLE patients. Autoimmun Rev. 2015;14(1):75-9. https://doi.org/10.1016/j.autrev.2014.10.003 PMid:25449682
Malkiel S, Barlev AN, Atisha-Fregoso Y, Suurmond J, Diamond B. Plasma cell differentiation pathways in systemic lupus erythematosus. Front Immunol. 2018;9:427. https://doi.org/10.3389/fimmu.2018.00427 PMid:29556239
Yap DY, Chan TM. B cell abnormalities in systemic lupus erythematosus and lupus nephritis-role in pathogenesis and effect of immunosuppressive treatments. Int J Mol Sci. 2019;20(24):6231. https://doi.org/10.3390/ijms20246231 PMid:31835612
Prechl J. A generalized quantitative antibody homeostasis model: Antigen saturation, natural antibodies and a quantitative antibody network. Clin Transl Immunol. 2017;6(2):e131. https://doi.org/10.1038/cti.2016.90 PMid:28496977
Barbado J, Tabera S, Sánchez A, García-Sancho J. Therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis. Lupus. 2018;27(13):2161-5. https://doi.org/10.1177/0961203318804922 PMid:30290717
Putra A, Ridwan FB, Putridewi AI, Kustiyah AR, Wirastuti K, Sadyah NA, et al. The role of TNF-α _induced MSCs on suppressive inflammation by increasing TGF-β _and IL-10. Open Access Maced J Med Sci. 2018;6(10):1779-83. https://doi.org/10.3889/oamjms.2018.404 PMid:30455748
Darlan DM, Munir D, Putra A, Jusuf NK. MSCs-released TGFβ1 generate CD4+CD25+Foxp3+ in T-reg cells of human SLE PBMC. J Formos Med Assoc. 2020;120(1):602-8. https://doi.org/10.1016/j.jfma.2020.06.028 PMid:32718891
Ikhsan R, Putra A, Munir D, Darlan DM, Suntoko B, Kustiyah AR, et al. Mesenchymal stem cells induce regulatory T-cell population in human SLE. BJMS. 2020;19(4):743-8.
Baghaei K, Hashemi SM, Tokhanbigli S, Asadi Rad A, Assadzadeh-Aghdaei H, Sharifian A, et al. Isolation, differentiation, and characterization of mesenchymal stem cells from human bone marrow. Gastroenterol Hepatol Bed Bench. 2017;10(3):208-13. PMid:29118937
Gebler A, Zabel O, Seliger B. The immunomodulatory capacity of mesenchymal stem cells. Trends Mol Med. 2012;18(2):128-34. https://doi.org/10.1016/j.molmed.2011.10.004 PMid:22118960
Crop MJ, Baan CC, Korevaar SS, Ijzermans JN, Pescatori M, Stubbs AP, et al. Inflammatory conditions affect gene expression and function of human adipose tissue-derived mesenchymal stem cells. Clin Exp Immunol. 2010;162(3):474-86. https://doi.org/10.1111/j.1365-2249.2010.04256.x PMid:20846162
Dorraji SE, Hovd AK, Kanapathippillai P, Bakland G, Eilertsen GØ, Figenschau SL, et al. Mesenchymal stem cells and T cells in the formation of tertiary lymphoid structures in lupus nephritis. Sci Rep. 2018;8(1):7861. https://doi.org/10.1038/s41598-018-26265-z PMid:29777158
Haddad R, Saldanha-Araujo F. Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: What do we know so far? Biomed Res Int. 2014;2014:216806. https://doi.org/10.1155/2014/216806 PMid:25025040
Wu H, Gong J, Liu Y. Indoleamine 2, 3-dioxygenase regulation of immune response (Review). Mol Med Rep. 2018;17(4):4867-73. https://doi.org/10.3892/mmr.2018.8537 PMid:29393500
Comoli P, Ginevri F, Maccario R, Avanzini MA, Marconi M, Groff A, et al. Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation. Nephrol Dial Transplant. 2008;23(4):1196-202. https://doi.org/10.1093/ndt/gfm740 PMid:18029377
Shih TA, Roederer M, Nussenzweig MC. Role of antigen receptor affinity in T cell-independent antibody responses in vivo. Nat Immunol. 2002;3(4):399-406. https://doi.org/10.1038/ni776 PMid:11896394
Lentz VM, Manser T. Cutting edge: Germinal centers can be induced in the absence of T cells. J Immunol. 2001;167(1):15- 20. https://doi.org/10.4049/jimmunol.167.1.15 PMid:11418626
Chappell CP, Draves KE, Giltiay NV, Clark EA. Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J Exp Med. 2012;209(10):1825-40. https://doi.org/10.1084/jem.20120774 PMid:22966002
Iikuni N, Lourenço EV, Hahn BH, La Cava A. Cutting edge: Regulatory T cells directly suppress B cells in systemic lupus erythematosus. J Immunol. 2009;183(3):1518-22. https://doi.org/10.4049/jimmunol.0901163 PMid:19570829
Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14(1):117. https://doi.org/10.1186/s12974-017-0892-8 PMid:28599652
Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367-72. https://doi.org/10.1182/blood-2005-07-2657 PMid:16141348
Tabera S, Pérez-Simón JA, Díez-Campelo M, Sánchez-Abarca LI, Blanco B, López A, et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica. 2008;93(9):1301-9. https://doi.org/10.3324/haematol.12857 PMid:18641017
Downloads
Published
How to Cite
License
Copyright (c) 2022 Yan Wisnu Prajoko, Agung Putra, Bayu Tirta Dirja, Adi Muradi Muhar, Nur Dina Amalina (Author)

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0)
