[Show abstract][Hide abstract] ABSTRACT: Objective
To confirm CXCL10 over production in bone marrow mesenchymal stem cells (MSCs) and circulating monocytes isolated from multiple sclerosis patients (MS) and identify predate cell molecular signature; to extend this analysis after autologous hematopoietic stem cell transplantation (AHSCT) to test if therapy has modifying effects on MSCs and circulating monocytes.MethodsMSCs and monocytes were isolated from 19 MS patients who undergone AHSCT before and seven of them at least 3 years after transplant. CXCL10 production was detected after LPS/IFN-γ stimulation. TLR4 signaling pathways were investigated by means of transcription factors phosphorylation/activation level. RT-PCR of activated transcription factors was performed to quantify their expression. All experiments were conducted in parallel with 24 matched healthy donors (HD).ResultsCXCL10 expression was significantly increased in both peripheral circulating monocytes and BM MSCs compared to HD. We showed that CXCL10 production is determined by an altered signaling pathway downstream TLR4, with the involvement of STAT-1, NF-κB, p38, JNK, and CREB. All upregulated transcription factors are more phosphorylated in MS patient sample. These features are not modified after AHSCT.InterpretationWe demonstrated that in MS two different cell lineages are characterized by significantly increased production of CXCL10, due to altered signaling pathways of innate immune reaction mediated by TLR4, probably associated with disease phenotype. This characteristic is not modified by AHSCT, suggesting that when T and B lymphocytes are reset, other possible components of MS pathology, such as CXCL10 over production, do not determine therapy outcome.
Annals of Clinical and Translational Neurology. 08/2014;
[Show abstract][Hide abstract] ABSTRACT: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase.
To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008.
Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8-126) months.
Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing-remitting course (31%) had a 6-12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression.
This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing-remitting phase of the disease.
[Show abstract][Hide abstract] ABSTRACT: To summarize recent evidence and current trends in the use of haematopoietic stem cell transplantation (HSCT) for autoimmune diseases.
Updates of published trials and data from the registries indicate a long-lasting, immunosuppression-free condition in about 50% of the patients who underwent an HSCT for a severe, progressive autoimmune disease. For all diseases, autologous HSCT is largely preferred for safety reasons, whereas allogeneic HSCT is to be considered only for carefully selected cases. Transplant-related mortality (TRM) has decreased in the past 5 years, due to both better selection of patients and the use of less intensive conditioning regimens. The most employed conditioning regimens in Europe are BCNU (carmustine), etoposide, ARA-C (cytosine arabinoside), M (melphalan) (BEAM)/anti-thymocyte globulin in multiple sclerosis and high-dose cyclophosphamide/anti-thymocyte globulin for all other diseases, with a trend for more intense regimens in North America. Multiple sclerosis and systemic sclerosis are currently the most frequent diagnoses. Prospective comparative trials are currently ongoing both in Europe and North America.
Recent reports confirm the evidence that HSCT is able to induce a high rate of sustained remissions in most severe autoimmune diseases, unresponsive to conventional treatments. Valuable information is expected by the finalization of the ongoing prospective, comparative trials.
Current opinion in hematology 12/2008; 15(6):594-600. · 4.05 Impact Factor