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How Safe Could Intrathecal Transplantation of Mesenchymal Stem Cells Be Considered in Multiple Sclerosis?—Reply

How Safe Could Intrathecal Transplantation of Mesenchymal Stem Cells Be Considered in Multiple... In reply Karacostas and colleagues express their concerns about safety issues arising from our trial with MSCs in MS and ALS.1 Our detailed responses to each question raised follow. Concerning general safety issues, in our phase I/II study, our main goal was to investigate the feasibility and short-term safety of the treatment modality. We were able to rule out any short-term toxicity, as shown by the 6-month follow-up. Additionally, as mentioned in the manuscript, we followed up the patients for up to 3 years and were not confronted with any exceptional clinical change. We performed yearly MRI scans in all patients that did not reveal any unexpected pathology (up to at least 3 years) and continued to show stabilization and suppression of the disease (follow-up data not yet published). We definitely share the concerns regarding unknown long-term toxicities, especially because previous experience with other treatments of MS (natalizumab, linomide) has shown that small-scale trials are not sensitive enough to rule out all possible adverse effects. This is clearly underlined in our conclusions that “ . . . larger studies are warranted to establish the long term safety and efficacy of this modality. . . . ” Concerning the dangers of malignancy, there is indeed one study2 indicating a possible malignant transformation of MSCs in long-term cultures. However, this is the only one, of several studies, to show such a danger, and Røsland et al2 claim that the conditions of long-term in vitro cultures (for several months) may “provide stress-induced genomic instability, contributing to the malignant phenotype.” In our trial (and in most of the trials with MSCs in the literature), we used short-term cultures for expansion of MSCs, with only a single passage of the cells. According to most of the investigators and our previous articles, such short-term culture is highly unlikely to cause any transformation of the cells. Moreover, Røsland et al have shown that, when MSCs were transformed, their morphology and phenotypic characteristics changed completely. In our 5 years of experience with MSCs, we did not encounter any cells undergoing such phenotypical changes with the short-term culture and conditions used by our laboratory and protocol. Mesenchymal stem cells have been used for many years now in several clinical indications without any evidence of such in vivo malignant transformations. Two recent consensus articles (with the participation of leading experts in the fields of MS and stem cells research from all over the world) have summarized the safety data published in the literature and clearly state that MSCs are the most suitable and safe candidate stem cells for clinical experimentation in MS and that the existing data in the literature justify the performance of clinical studies with this type of cell.3,4 Concerning the possible danger of activation of Th17 cells by MSCs, which is based on a single in vitro study5 in which the researchers have shown that when stimulated with recombinant interleukin (IL) 1 (a situation much more reminiscent of the CNS inflammatory environment in MS), MSCs were potent suppressors of Th1/Th17. In general, in vitro immunological effects substantially differ from the in vivo more complicated interactions. In our experience (presented initially in the American Academy of Neurology), we were able to detect downregulation of Th17 responses. However, because these data are preliminary and the responses are highly variable, they will represent part of a more extensive immunological study that is under way. Moreover, it is now acknowledged that IL-17, which is produced by Th17 cells, may also enhance the regulatory function of regulatory T cells,6 and therefore their putative activation is not always necessarily detrimental. Moreover, the results of Th17 inhibition in human autoimmune diseases were highly variable.7 Anyhow, the fact that almost all of our patients with MS either stabilized or improved clinically, together with the significant downregulation of all other markers of inflammatory activation and with parallel upregulation of the regulatory lymphocytes (all evidenced in our study and presented in our article) indicate that it is unlikely that any adverse immunological effect has occurred in our patients or been induced by MSCs. Concerning the authors' skepticism about the intrathecal way of administration and its justification, this route of administration is not based only on our animal study but on many more studies using neuronal and other types of stem cells in experimental autoimmune encephalomyelitis, which have shown that this is probably the optimal way of maximizing the clinical effects of the cellular treatment.8-10 It was surprising to read that there is no evidence or indication for the migration of MSCs in our trial. It is obvious that, in human in vivo studies, there is no absolute way to provide clear-cut evidence of such migration. However, the MRI data shown in our study (following staining of the cells with Feridex) indicate such a migration. We all share the common determination as physicians and scientists, based on the Hippocratic oath, “not to harm.” However, we all certainly also want to progress in the research of new therapeutic approaches, aiming to improve our management of MS, especially when the conventional treatments fail and neurodegeneration causes progressive clinical deterioration. In our opinion, our role as physicians and scientists is, on one hand, to care and be concerned for the possible toxicities of novel treatments but, on the other hand, not jeopardize the efforts to bring new approaches for the management of neurodegeneration. Our study provides the data for only the first step in the exciting new field of regenerative medicine. Definitely, as mentioned in our manuscript, a lot more has to be done and investigated before such treatments become a part of our everyday arsenal of therapeutic options for MS. Back to top Article Information Correspondence: Dr Karussis, Department of Neurology and Multiple Sclerosis Center, Hadassah Hebrew University of Jerusalem, Jerusalem IL-91120, Israel (karus@cc.huji.ac.il). Financial Disclosure: None reported. This article was corrected for errors on July 18, 2011. References 1. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67(10):1187-119420937945PubMedGoogle ScholarCrossref 2. Røsland GV, Svendsen A, Torsvik A, et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009;69(13):5331-533919509230PubMedGoogle ScholarCrossref 3. Martino G, Franklin RJ, Van Evercooren AB, Kerr DA.Stem Cells in Multiple Sclerosis (STEMS) Consensus Group. Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol. 2010;6(5):247-25520404843PubMedGoogle ScholarCrossref 4. Freedman MS, Bar-Or A, Atkins HL, et al; MSCT Study Group. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-51020086020PubMedGoogle ScholarCrossref 5. Darlington PJ, Boivin MN, Renoux C, et al. Reciprocal Th1 and Th17 regulation by mesenchymal stem cells: implication for multiple sclerosis. Ann Neurol. 2010;68(4):540-54520661924PubMedGoogle ScholarCrossref 6. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490-50020559327PubMedGoogle ScholarCrossref 7. Steinman L. Mixed results with modulation of TH-17 cells in human autoimmune diseases. Nat Immunol. 2010;11(1):41-4420016509PubMedGoogle ScholarCrossref 8. Ben-Hur T, Goldman SA. Prospects of cell therapy for disorders of myelin. Ann N Y Acad Sci. 2008;1142:218-24918990129PubMedGoogle ScholarCrossref 9. Pluchino S, Gritti A, Blezer E, et al. Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol. 2009;66(3):343-35419798728PubMedGoogle ScholarCrossref 10. Pluchino S, Quattrini A, Brambilla E, et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003;422(6933):688-69412700753PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

How Safe Could Intrathecal Transplantation of Mesenchymal Stem Cells Be Considered in Multiple Sclerosis?—Reply

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Publisher
American Medical Association
Copyright
Copyright © 2011 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneurol.2011.162
Publisher site
See Article on Publisher Site

Abstract

In reply Karacostas and colleagues express their concerns about safety issues arising from our trial with MSCs in MS and ALS.1 Our detailed responses to each question raised follow. Concerning general safety issues, in our phase I/II study, our main goal was to investigate the feasibility and short-term safety of the treatment modality. We were able to rule out any short-term toxicity, as shown by the 6-month follow-up. Additionally, as mentioned in the manuscript, we followed up the patients for up to 3 years and were not confronted with any exceptional clinical change. We performed yearly MRI scans in all patients that did not reveal any unexpected pathology (up to at least 3 years) and continued to show stabilization and suppression of the disease (follow-up data not yet published). We definitely share the concerns regarding unknown long-term toxicities, especially because previous experience with other treatments of MS (natalizumab, linomide) has shown that small-scale trials are not sensitive enough to rule out all possible adverse effects. This is clearly underlined in our conclusions that “ . . . larger studies are warranted to establish the long term safety and efficacy of this modality. . . . ” Concerning the dangers of malignancy, there is indeed one study2 indicating a possible malignant transformation of MSCs in long-term cultures. However, this is the only one, of several studies, to show such a danger, and Røsland et al2 claim that the conditions of long-term in vitro cultures (for several months) may “provide stress-induced genomic instability, contributing to the malignant phenotype.” In our trial (and in most of the trials with MSCs in the literature), we used short-term cultures for expansion of MSCs, with only a single passage of the cells. According to most of the investigators and our previous articles, such short-term culture is highly unlikely to cause any transformation of the cells. Moreover, Røsland et al have shown that, when MSCs were transformed, their morphology and phenotypic characteristics changed completely. In our 5 years of experience with MSCs, we did not encounter any cells undergoing such phenotypical changes with the short-term culture and conditions used by our laboratory and protocol. Mesenchymal stem cells have been used for many years now in several clinical indications without any evidence of such in vivo malignant transformations. Two recent consensus articles (with the participation of leading experts in the fields of MS and stem cells research from all over the world) have summarized the safety data published in the literature and clearly state that MSCs are the most suitable and safe candidate stem cells for clinical experimentation in MS and that the existing data in the literature justify the performance of clinical studies with this type of cell.3,4 Concerning the possible danger of activation of Th17 cells by MSCs, which is based on a single in vitro study5 in which the researchers have shown that when stimulated with recombinant interleukin (IL) 1 (a situation much more reminiscent of the CNS inflammatory environment in MS), MSCs were potent suppressors of Th1/Th17. In general, in vitro immunological effects substantially differ from the in vivo more complicated interactions. In our experience (presented initially in the American Academy of Neurology), we were able to detect downregulation of Th17 responses. However, because these data are preliminary and the responses are highly variable, they will represent part of a more extensive immunological study that is under way. Moreover, it is now acknowledged that IL-17, which is produced by Th17 cells, may also enhance the regulatory function of regulatory T cells,6 and therefore their putative activation is not always necessarily detrimental. Moreover, the results of Th17 inhibition in human autoimmune diseases were highly variable.7 Anyhow, the fact that almost all of our patients with MS either stabilized or improved clinically, together with the significant downregulation of all other markers of inflammatory activation and with parallel upregulation of the regulatory lymphocytes (all evidenced in our study and presented in our article) indicate that it is unlikely that any adverse immunological effect has occurred in our patients or been induced by MSCs. Concerning the authors' skepticism about the intrathecal way of administration and its justification, this route of administration is not based only on our animal study but on many more studies using neuronal and other types of stem cells in experimental autoimmune encephalomyelitis, which have shown that this is probably the optimal way of maximizing the clinical effects of the cellular treatment.8-10 It was surprising to read that there is no evidence or indication for the migration of MSCs in our trial. It is obvious that, in human in vivo studies, there is no absolute way to provide clear-cut evidence of such migration. However, the MRI data shown in our study (following staining of the cells with Feridex) indicate such a migration. We all share the common determination as physicians and scientists, based on the Hippocratic oath, “not to harm.” However, we all certainly also want to progress in the research of new therapeutic approaches, aiming to improve our management of MS, especially when the conventional treatments fail and neurodegeneration causes progressive clinical deterioration. In our opinion, our role as physicians and scientists is, on one hand, to care and be concerned for the possible toxicities of novel treatments but, on the other hand, not jeopardize the efforts to bring new approaches for the management of neurodegeneration. Our study provides the data for only the first step in the exciting new field of regenerative medicine. Definitely, as mentioned in our manuscript, a lot more has to be done and investigated before such treatments become a part of our everyday arsenal of therapeutic options for MS. Back to top Article Information Correspondence: Dr Karussis, Department of Neurology and Multiple Sclerosis Center, Hadassah Hebrew University of Jerusalem, Jerusalem IL-91120, Israel (karus@cc.huji.ac.il). Financial Disclosure: None reported. This article was corrected for errors on July 18, 2011. References 1. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67(10):1187-119420937945PubMedGoogle ScholarCrossref 2. Røsland GV, Svendsen A, Torsvik A, et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009;69(13):5331-533919509230PubMedGoogle ScholarCrossref 3. Martino G, Franklin RJ, Van Evercooren AB, Kerr DA.Stem Cells in Multiple Sclerosis (STEMS) Consensus Group. Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol. 2010;6(5):247-25520404843PubMedGoogle ScholarCrossref 4. Freedman MS, Bar-Or A, Atkins HL, et al; MSCT Study Group. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-51020086020PubMedGoogle ScholarCrossref 5. Darlington PJ, Boivin MN, Renoux C, et al. Reciprocal Th1 and Th17 regulation by mesenchymal stem cells: implication for multiple sclerosis. Ann Neurol. 2010;68(4):540-54520661924PubMedGoogle ScholarCrossref 6. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490-50020559327PubMedGoogle ScholarCrossref 7. Steinman L. Mixed results with modulation of TH-17 cells in human autoimmune diseases. Nat Immunol. 2010;11(1):41-4420016509PubMedGoogle ScholarCrossref 8. Ben-Hur T, Goldman SA. Prospects of cell therapy for disorders of myelin. Ann N Y Acad Sci. 2008;1142:218-24918990129PubMedGoogle ScholarCrossref 9. Pluchino S, Gritti A, Blezer E, et al. Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol. 2009;66(3):343-35419798728PubMedGoogle ScholarCrossref 10. Pluchino S, Quattrini A, Brambilla E, et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003;422(6933):688-69412700753PubMedGoogle ScholarCrossref

Journal

Archives of NeurologyAmerican Medical Association

Published: Jul 11, 2011

Keywords: multiple sclerosis,transplantation,stem cell, mesenchymal

References

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