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Defective expression of apoptosis-related molecules in multiple sclerosis patients is normalized early after autologous hematopoietic stem cell transplantation

Abstract

Defective apoptosis might be involved in the pathogenesis of multiple sclerosis (MS). We evaluated apoptosis-related molecules in MS patients before and after autologous hematopoietic stem cell transplantation (AHSCT) using BEAM or cyclophosphamide (CY) based conditioning regimens. Patients were followed for clinical and immunological parameters for two years after AHSCT. At baseline, MS patients had decreased proapoptotic BAD, BAX and FASL, and increased A1 gene expression when compared with healthy counterparts. In the BEAM-group, BAK, BIK, BIMEL, FAS, FASL, A1, BCL2, BCLXL, CFLIPL and CIAP2 genes were upregulated after AHSCT. With exception of BIK, BIMEL and A1, all genes reached levels similar to controls at D+720 post-transplantation. Furthermore, in these patients, we observed increased CD8+Fas+ T-cell frequencies after AHSCT, when compared to baseline. In the CY-group, we observed increased BAX, BCLW, CFLIPL, CIAP1, and decreased BIK and BID gene expressions after transplantation. At D+720 post-AHSCT, the expression of BAX, FAS, FASL, BCL2, BCLXL and CIAP1 was similar to that of controls. Protein analyses showed increased Bcl-2 expression before transplantation. At one year post-AHSCT, expression of Bak, Bim, Bcl-2, Bcl-xL and cFlip-L was decreased when compared to baseline values. In summary, our findings suggest that normalization of apoptosis-related molecules is associated with the early therapeutic effects of AHSCT in MS patients. These mechanisms may be involved in the reestablishment of immune tolerance during the first two years post-transplantation. (AU)

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