Autologous hematopoietic stem cell transplantation modifies specific aspects of systemic sclerosis-related microvasculopathy

Abstract

Objective: Autologous hematopoietic stem cell transplantation (AHSCT) is a therapeutic option for patients with severe and progressive systemic sclerosis (SSc). Here, we aimed to investigate how AHSCT affects the vasculopathy of SSc patients. Methods: Twenty-seven SSc patients were retrospectively assessed, before and after AHSCT, for vessel morphology (nailfold capillaroscopy), skin expression of endothelial markers and serum levels of markers of inflammation, angiogenesis and endothelial activation. Skin biopsies were analyzed by immunohistochemistry (IHC) for expression of CD31, VE-cadherin, E-selectin, angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), Tie-2, vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), and endothelin-1 before and 12 months post-AHSCT. Serum samples from SSc patients were assessed before and up to 36 months after AHSCT for IL-6, von Willebrand factor (vWF), CXC Motif Chemokine Ligand 8 (CXCL8), Endothelin-1, epidermal growth factor (EGF), VEGFA, Pentraxin-3, Intercellular Adhesion Molecule 1 (ICAM-1), E-selectin, P-selectin, Thrombomodulin and IL-18 levels, and compared to healthy control samples. Results: On nailfold capillaroscopy, the number of capillaries increased at 1 year, while giant capillaries decreased at 6 months and 1 year after AHSCT. In the skin biopsies, expression of E-selectin notably decreased and Ang1 increased after AHSCT. At baseline, all vascular markers evaluated in the serum were significantly higher in SSc patients when compared to healthy controls, except for ICAM-1. When compared at different time points after AHSCT, Thrombomodulin, Pentraxin-3, vWF, and IL-18 levels remained generally stable at high levels until 36 months after AHSCT. Conclusion: Our results suggest that AHSCT contributes to improvements of the vessel morphology and dermal microvasculopathy, but does not normalize elevated levels of serum vascular markers in SSc patients. Additional vascular therapeutic approaches might contribute to more effectively treat the endothelial injury.

Reconstitution of the immune system and clinical correlates after stem cell transplantation for systemic sclerosis

“…Along with immune monitoring from blood samples, analyses of tissues affected by the disease, such as skin and lungs, may provide more insights into the local effects of auto-HSCT ( 83 ). Transplantation was able to reduce collagen deposition in the skin of SSc patients ( 73 , 89 ), improved the microvascular morphology ( 63 , 72 , 90 ) and decreased lung infiltrates ( 91 ). In addition, the expression of IFN-α and CD123 + (pDC markers) is associated with fibrosis in dcSSc ( 92 ).…”

“…A remaining question is how the auto-HSCT rebalances the communication/interaction between innate immune cells, endothelial cells, and fibroblasts, which could explain the positive effects of transplantation in the fibrosis and vasculopathy pathological axes ( 83 ). SSc patients treated with auto-HSCT have improved microvascular morphology and significantly reduced endothelial activation in the dermis ( 72 ). Auto-HSCT can also induce connective tissue remodeling and decrease inflammation markers in the skin, such as S100 calcium-binding protein A9 (S100A9) and NF-κB ( 73 ).…”

“…Several T cell-related cytokines are implicated in SSc pathogenesis and associated with fibrosis and vascular damage ( 18 , 114 , 125 , 126 ). Auto-HSCT changes serum levels of inflammatory and pro-fibrotic cytokines by regenerating the immune system ( 39 , 64 , 65 , 72 , 73 ). High serum levels of tumor necrosis factor-alpha (TNF-α), IL-6, and soluble interleukin 2 receptor (sIL-2R) are found at baseline in the SSc patients, with a significant decrease after auto-HSCT ( 64 ).…”

“…Santana-Gonçalves et al. evaluated serum levels of markers of inflammation, angiogenesis, and endothelial activation before and until 36 months post-transplant ( 72 ). IL-6, von Willebrand factor (vWF), CXC Motif Chemokine Ligand 8 (CXCL8), Endothelin-1, epidermal growth factor (EGF), VEGFA, Pentraxin-3, Intercellular Adhesion Molecule 1 (ICAM-1), E-selectin, P-selectin, Thrombomodulin and IL-18 levels were significantly higher at baseline in SSc patients when compared to healthy controls, except for ICAM-1.…”

“…IL-6, von Willebrand factor (vWF), CXC Motif Chemokine Ligand 8 (CXCL8), Endothelin-1, epidermal growth factor (EGF), VEGFA, Pentraxin-3, Intercellular Adhesion Molecule 1 (ICAM-1), E-selectin, P-selectin, Thrombomodulin and IL-18 levels were significantly higher at baseline in SSc patients when compared to healthy controls, except for ICAM-1. After auto-HSCT, all biomarkers remained stable at high levels until 36 months of follow-up, indicating persistence of the vascular injury ( 72 ).…”