New Target to Reduce MS Inflammation

A newly published single-center observational study in Neurology Neuroimmunology & Neuroinflammation reported that mesenchymal stem cells (MSCs) from patients with secondary progressive multiple sclerosis (SPMS) may promote inflammatory T-cell responses, contrasting with MSCs from healthy controls. The study authors also identified potential targets to reduce this effect.1

The study included 5 patients with SPMS and 7 healthy controls, from whom MSCs were obtained via bone marrow aspiration. Investigators tested the effects of these MSCs on autologous peripheral blood mononuclear cells (PBMCs), focusing on T-cell expression of IL-17, IFN-γ, and GM-CSF. All told, MSCs from healthy individuals reduced the proportion of T cells expressing IL-17 (Th17, P = .046), IFN-γ (Th1, P = .03), and GM-CSF (P = .012). By contrast, MSCs from patients with SPMS increased Th17 cells (P = .01) and GM-CSF–expressing T cells (P = .03), with no significant changes observed in Th1 cell abundance.

“The lack of the immunomodulatory potential in MS MSCs that is traditionally attributed to MSCs may be explained by an intrinsic deficit in immune regulation, as supported by the evidence of a numeric and/or functional Treg deficit and by the coexistence with other autoimmune disorders,” lead author Radu Tanasescu, MD, PhD, consultant neurologist at Nottingham University Hospitals NHS Trust, and colleagues wrote. “Alternatively, long exposure to an inflammatory milieu may cause the MS MSCs to lose immunomodulatory properties and become proinflammatory.”

Tanasescu et al continued, “This has implications for autologous MSC treatment of autoimmune diseases including MS. Possibly, the positive effects of MSCs on inflammation and tissue repair are counteracted or diminished by these paradoxical proinflammatory effects. This may explain the negative or only modest results of clinical trials of MSCs in MS. This study, however, also identifies some possible ways of abrogating these proinflammatory effects.”

Further analysis showed that unstimulated MSCs from patients with SPMS produced lower levels of the anti-inflammatory cytokine IL-10 (P = .03) and higher levels of osteopontin (OPN, P = .002) compared with MSCs from healthy controls. Gene expression profiling identified increased expression of ADAM-28 in MSCs from patients with SPMS, which was subsequently confirmed at the mRNA level by quantitative polymerase chain reaction (qPCR) and at the protein level by flow cytometry.

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The study also explored strategies to mitigate the proinflammatory effects of MS-derived MSCs. When MSCs from patients with SPMS were co-cultured with autologous PBMCs in the presence of natalizumab (Tysabri; Biogen), a monoclonal antibody that binds α4β1 and blocks its interaction with ADAM-28 and OPN, the proportion of Th17 cells decreased. Similarly, supplementing the co-cultures with IL-10 prevented the increase in Th17 cells observed in the absence of intervention. Overall, these findings suggested that blocking ADAM-28 and OPN interactions or increasing IL-10 levels can reduce the proinflammatory potential of MSCs from patients with SPMS.

All told, the study included a small number of donors, and limited PBMC availability restricted the number of experiments. Authors also noted that minor age differences existed between patients with SPMS and healthy controls, which could influence MSC or immune aging. However, researchers expressed that these differences were not statistically significant and there were no patients classified as older as defined for MSC purposes.2 The study did not examine effects on regulatory T cells because of cell limitations. In addition, molecules for targeted analysis were chosen based on functional pathway analysis rather than unbiased differential gene expression, though authors noted that multiple assays supported their relevance.

“In conclusion, we provide evidence for a proinflammatory effect of MSCs from [patients with] MS on autologous immune cells and further show that targeting some molecules that are differentially expressed between [patients with] MS and non-MS controls can counteract this proinflammatory effect. These observations can lead to the development of modalities for improving outcomes of MSC treatment of MS,” Tanasescu and colleagues noted.1