James Risinger

Introduction. Systemic sclerosis (SSc) is an immune-mediated that is uncommon, but has a high morbidity and mortality¹. The common clinical presentation of SSc includes perioral soft tissue loss, sclerodactyly, facial telangiectasis, dilated nail-fold capillaries, extensive calcinosis cutis¹. Interstitial lung disease (ILD) is a common complication of systemic sclerosis and the leading cause of morbidity and mortality². SSc-ILD is thought to be the result of the interplay between fibrosis, autoimmunity, inflammation, and vascular injury². The initial event is proposed as injury to the alveolar epithelium or vasculature followed by aberrant activation of the immune system, which promotes fibroblast recruitment/activation, ECM overproduction, and scarring². Etiology of SSc has genetic components but is also associated with exposure to vinyl chloride, silica, certain hydrocarbons⁸. No effective or established treatment thus far that can cure or stop the progression of the disease⁹. Recent studies suggest that MSCs can suppress the activation of T cells via Programmed death-ligand 1 (PD-L1)/PD-1 pathway^4,6, supporting the potential use of mesenchymal stem cells (MSCs) to treat SSc¹. Methods. To mimic human pulmonary fibrosis in mice, bleomycin was treated intravenously in humanized mice generated from Rag2−/−γc−/− mice by reconstitution of human peripheral blood mononuclear cells (PBMCs) or CD4+ or CD8+ T cell-depleted PMMCs ⁴. MSCs or PD-L1-blocked MSCs were injected into humanized mice intravenously at day 2 after bleomycin treatment. Pulmonary fibrosis severity in vivo was assessed via Ashcroft score and % trichrome area (a dye for collagen) as well as via associated weight loss⁴. T-cells were activated with anti-CD3/28 antibodies and co-cultured with MSCs in transwells with or without anti-PD-1/PD-L1 antibodies⁶. Patients received 3-cyclophosphamide and 1-MSC injections on days 1,3,5, and 8, respectively⁷. Results. Human T cells play a major role in the induction of pulmonary fibrosis in humanized mice^3,4,5. MSC administration alleviated pulmonary fibrosis in humanized mice while PD-L1-blocked MSCs showed no beneficial effect ^3,4,5. In vitro studies also demonstrated that MSCs via their secretion of PD‐1 ligands suppressed the activation of T-cells through PD‐1‐mediated blockade of the AKT Pathway, thereby inducing T cell hyporesponsiveness⁶. Consistent with these findings, recent clinical trials show promising therapeutic effects of MSC treatment⁷. Conclusion. MSCs suppress the activation of T-cells responsible for the disease’s leading cause of morbidity and mortality, pulmonary fibrosis. Mechanistically, PD-1/PD-L1 pathway contributed to the T cell hyporesponsiveness by human MSCs. Future investment and research in larger clinical trials is needed to see if the treatment is effective at scale.

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2. Perelas, A., Silver, R., Arrossi, A. and Highland, K., 2020. Systemic sclerosis-associated interstitial lung disease. The Lancet Respiratory Medicine, 8(3), pp.304-320.
3. Zhao, W., Wang, X., Sun, K. and Zhou, L., 2018. α-smooth muscle actin is not a marker of fibrogenic cell activity in skeletal muscle fibrosis. PLOS ONE, 13(1), p.e0191031.
4. Ni, K., Liu, M., Zheng, J., Wen, L., Chen, Q., Xiang, Z., Lam, K., Liu, Y., Chan, G., Lau, Y. and Tu, W., 2018. PD-1/PD-L1 Pathway Mediates the Alleviation of Pulmonary Fibrosis by Human Mesenchymal Stem Cells in Humanized Mice. American Journal of Respiratory Cell and Molecular Biology, 58(6), pp.684-695.
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7. Zhang, H., Liang, J., Tang, X., Wang, D., Feng, X., Wang, F., Hua, B., Wang, H. and Sun, L., 2017. Sustained benefit from combined plasmapheresis and allogeneic mesenchymal stem cells transplantation therapy in systemic sclerosis. Arthritis Research & Therapy, 19(1).
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