Effect of Human Mesenchymal Stem Cells on Xenogeneic T and B Cells Isolated from Lupus-Prone MRL.Fas^lpr Mice

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease, which is characterized by hyperactivation of T and B cells. Human mesenchymal stem cells (hMSCs) ameliorate the progression of SLE in preclinical studies using lupus-prone MRL.Faslpr mice. However, whether hMSCs inhibit the functions of xenogeneic mouse T and B cells is not clear. To address this issue, we examined the in vitro effects of hMSCs on T and B cells isolated from MRL.Faslpr mice. Naïve hMSCs inhibited the functions of T cells but not B cells. hMSCs preconditioned with IFN-γ (i) inhibited the proliferation of and IgM production by B cells, (ii) attracted B cells for cell–cell interactions in a CXCL10-dependent manner, and (iii) inhibited B cells by producing indoleamine 2,3-dioxygenase. In summary, our data demonstrate that hMSCs exert therapeutic activity in mice in three steps: first, naïve hMSCs inhibit the functions of T cells, hMSCs are then activated by IFN-γ, and finally, they inhibit B cells.

Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Faslpr mice

“…hB cells were isolated from lymphocytes using a human B cell isolation kit (Miltenyi Biotec, Auburn, CA, USA). mB cells were purified from spleen cells of MRL .Fas lpr mice by a negative depletion method using mouse B cell isolation kit (Miltenyi Biotec) 9 . Purity of hB and mB cells was typically >90%.…”

“…Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have emerged as a promising therapy for the treatment of SLE. Adoptive transfer of MSCs to lupus-prone MRL .Fas lpr mice increased their survival and decreased anti-dsDNA antibody level and nephritis 3 - 9 . In clinical studies, MSCs improved renal functions and decreased autoantibody production 10 - 15 .…”

Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System

“…Furthermore, they produce IL-6 and IL-8, which are known to be associated with MSC tissue repair potential [ 148 ]. Subsequently, MSCs control the inflammatory state as evidence of the reduced expression of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and CRP [ 140 ]. Then, the STAT6 pathway is activated by IL-4, which then stimulates the MSCs to secrete TGF-β.…”

“…Moreover, Lee et al noted that the xenogeneic transplantation of human MSCs (hMSCs) in SLE mice models only inhibited the T cells but not the B cells. However, hMSCs that are primed with IFN-γ have increased CXCL10 and IDO expression, which effectively attracts B cells for contact inhibition [ 140 ].…”

“…IFN-γ is one of the cytokines released by T cytotoxic cells during inflammation. Therefore, in Th17 centered inflammatory response, MSC treatment would require the addition of Treg to successfully regulate the inflammation [ 140 , 172 ]. Lim et al found that combination of MSCs and Treg has shown promising results in IFN-γ knockout mice with reduced inflammation and IL-7 production [ 172 ].…”