Background: Autologous hematopoietic stem cell transplantation (AHSCT) is being explored in the treatment of severe multiple sclerosis (MS) as a means of high-dose immunosuppressive therapy followed by full immune recovery after the engraftment of the AHSC. AHSCT may be beneficial for the possible 'resetting' of the immune system, thereby becoming tolerant against self-antigens. While there is evidence that long-term suppression of inflammatory activity in MS patients (pts) who receive AHSCT are associated with profound immunological changes (Muraro eta/. , JEM 2005), very little is known about changes in the gene expression profile (GEP) induced by AHSCT. Aim of the study. To determine early and late GEP changes, investigating the whole blood from MS pts, before and after receiving AHSCT. Methods: We analyzed expression changes in 4 7 genes associated with cell survival functions, transduction signals, intercellular adhesion, immune regulation in 8 patients with secondary progressive or relapsing-remitting MS who underwent AHCT not responding to conventional therapies. Peripheral AHSC were obtained by leukaph eresis after mobilization with cyclophosphamide and G-CSF. BEAM +ATG conditioning was used according to EBMT guidelines. Serial samples of peripheral blood were collected before and at 1, 6, 12 and 24 months after AHSCT. The same samples were coll ected also on the day of AHSC infusion and on the day when complete engraftment was shown. We have used a TaqMan® Low Density Array based on comparative ddCT method to perform a global gene expression. Results: AHSCT was well tolerated by pts without transplant- related death. At 1 year follow-up (r. 5-39 months) 6 pts improved, one patient showed stabilization and only one patient experienced a deterioration of0,5 point of EDSS. Baseline GEP was similar in all pts. Immediately after transplant, in all pts there were profound modifications of many genes and at 6-24 months after AHSCT a subset of them remained modified. Particularly, CD52 was up-expressed before transplant and stayed markedly down-regulated until 12 and 24 months except in 2 pts, one of them worsening after HSCT. Conclusions: AHSCT improves clinical outcome in pts affected by severe MS. Our data demonstrates how AHSCT modulates the immune system particularly in responding pts. CD52 may have a central role in pathogenesis of severe MS. Further studies are needed in a larger controlled cohort of patients to better explain these mechanisms.
Autologous haematopoietic stem cell transplantation induces a prolonged and profound modification of gene expression profiles in patients with multiple sclerosis
Aguglia U;
2010-01-01
Abstract
Background: Autologous hematopoietic stem cell transplantation (AHSCT) is being explored in the treatment of severe multiple sclerosis (MS) as a means of high-dose immunosuppressive therapy followed by full immune recovery after the engraftment of the AHSC. AHSCT may be beneficial for the possible 'resetting' of the immune system, thereby becoming tolerant against self-antigens. While there is evidence that long-term suppression of inflammatory activity in MS patients (pts) who receive AHSCT are associated with profound immunological changes (Muraro eta/. , JEM 2005), very little is known about changes in the gene expression profile (GEP) induced by AHSCT. Aim of the study. To determine early and late GEP changes, investigating the whole blood from MS pts, before and after receiving AHSCT. Methods: We analyzed expression changes in 4 7 genes associated with cell survival functions, transduction signals, intercellular adhesion, immune regulation in 8 patients with secondary progressive or relapsing-remitting MS who underwent AHCT not responding to conventional therapies. Peripheral AHSC were obtained by leukaph eresis after mobilization with cyclophosphamide and G-CSF. BEAM +ATG conditioning was used according to EBMT guidelines. Serial samples of peripheral blood were collected before and at 1, 6, 12 and 24 months after AHSCT. The same samples were coll ected also on the day of AHSC infusion and on the day when complete engraftment was shown. We have used a TaqMan® Low Density Array based on comparative ddCT method to perform a global gene expression. Results: AHSCT was well tolerated by pts without transplant- related death. At 1 year follow-up (r. 5-39 months) 6 pts improved, one patient showed stabilization and only one patient experienced a deterioration of0,5 point of EDSS. Baseline GEP was similar in all pts. Immediately after transplant, in all pts there were profound modifications of many genes and at 6-24 months after AHSCT a subset of them remained modified. Particularly, CD52 was up-expressed before transplant and stayed markedly down-regulated until 12 and 24 months except in 2 pts, one of them worsening after HSCT. Conclusions: AHSCT improves clinical outcome in pts affected by severe MS. Our data demonstrates how AHSCT modulates the immune system particularly in responding pts. CD52 may have a central role in pathogenesis of severe MS. Further studies are needed in a larger controlled cohort of patients to better explain these mechanisms.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
