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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1514-1515.
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IMMUNOBIOLOGY
Comment on Zappia et al, page 1755
Finding a less toxic stem cell therapy for multiple sclerosis
Richard K. Burt
NORTHWESTERN UNIVERSITY FEINBERG SCHOOL OF MEDICINE
Unlike autologous hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) have an innate immune-modulating effect that suppresses autoimmunity without using a chemotherapy preparative regimen.
Autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis was first proposed based on the beneficial effect of bone marrow transplantation in experimental autoimmune encephalomyelitis (EAE) (see figure), an animal model of multiple sclerosis (MS).1 Autologous HSCT is a form of immune-suppressive therapy in which a conditioning regimen is used to suppress or "ablate" the immune system. Therefore, the beneficial effect of autologous HSCT is entirely a consequence of the conditioning regimen. Initial HSCT protocols were designed by medical oncologists and used myeloablative malignancy-specific regimens. These first-generation regimens consisted predominately of combinations of malignancy-specific agents that have nothing to do with the standard treatment of MS, such as busulfan, total body irradiation, BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), etoposide, cytosine, arabinoside, and melphalan. In general, these trials suffered from higher than anticipated treatment-related morbidity and mortality. In order to minimize regimen-related toxicity, second-generation HSCT conditioning regimens use MS-specific drugs that are currently used to treat MS (eg, the combination of cyclophosphamide and alemtuzumab).2 This regimen has little nonlymphopenic toxicity. As a result of diminished toxicity, cyclophosphamide and alemtuzumab conditioning is being used in a multicenter, multinational trial known as the Multiple Sclerosis International Stem Cell Transplant (MIST) Trial.2 In this issue of Blood, Zappia and colleagues suggest an even less toxic stem cell therapy for MS in which mesenchymal stem cells (MSCs) have an immune-modulating effect in EAE independent of chemotherapy (see figure).
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HSC (top) versus MSC (bottom) transplant for treatment of EAE. The top panel shows the therapeutic effect of HSCT in EAE requires an immune suppressive conditioning regimen. No response from infusion of only bone marrow (BMT) without a conditioning regimen. Reprinted from Burt et al.6(Fig1) The bottom panel shows the therapeutic effect of MSC occurs without any chemotherapy; see the complete figure in the article beginning on page 1755.
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MSCs are defined by their adherence capabilities.3 When bone marrow aspirates are placed in culture, hematopoietic cells float within the media and are removed with each passage while MSCs remain adhered to the flask. These adherent MSCs are morphologically heterogeneous and may be spindle, polygonal, or cuboidal in shape. MSCs are negative for hematopoietic markers such as CD34 and CD45, positive for adhesion molecules (CD44, CD62), and generally positive for stem cell antigen-1 (Sca-1), stromal-derived factor 1 (STRO-1), and CD105/endoglin (SH2, SH2 antibody).
For autoimmune diseases, unlike either autologous HSCT in which immune suppression is a consequence of chemotherapy or allogeneic HSCT in which engraftment with subsequent alteration of genetic susceptibility to disease requires administration of chemotherapy, MSCs have a direct immunomodulatory effect that occurs independent of any chemotherapeutic drug or cytotoxic agent.4 The paper from Italy by Zappia et al demonstrates that MSCs can ameliorate EAE without use of any chemotherapy or immune-suppressive medications. In fact, treatment of human immune-mediated diseases with MSCs has already begun, following a report of rapid resolution of grade IV acute graft-versus-host disease (GVHD) after intravenous infusion of MSCs from the patient's haploidentical mother.5
Nevertheless, many questions and concerns remain unanswered. (1) What are the late complications of MSC infusions? For example, will the MSCs lodge in tissue such as the pulmonary vascular bed resulting in local proliferation and differentiation into fibroblasts with late fibrosis? (2) What are the exact mechanisms of MSC-mediated immune suppression? Do MSCs normally suppress immune reactions in vivo, or is an immune-suppressive phenotype the consequence of extended passage in tissue culture? (3) Since MSCs are a heterogeneous population of cells, is there a unique identifiable MSC marker? (4) What is the best method to isolate, purify, and assay MSCs? (5) Are MSCs true stem cells that can be transplanted, isolated, and retransplanted in serial generations of recipients? (6) Is the immune suppressive effect of MSCs durable or will repeated injections be required? (7) Will immunologic sensitization or rejection occur with repeated exposure? Will nonspecific MSC-mediated immune suppression lead to increased opportunistic infections? These questions not withstanding, the application of MSCs for immune modulation may allow for MS-directed stem cell therapy that results in favorable immune modulation without exposure to chemotherapy or the use of combined allogeneic HSCs and MSCs for engraftment without GVHD. 
References
- Burt RK, Burns W, Hess A. Bone marrow transplantation for multiple sclerosis. Bone Marrow Transplantation. 1995;16: 1-6.[Medline]
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- Burt RK, Cohen B, Rose J, et al. Hematopoietic stem cell transplantation for multiple sclerosis. Archives of Neurology 2005;62: 860-864.[Free Full Text]
- Barry FP, Murphy JM. Mesenchymal stem cells: clinical applications and biological characterization. Intl J Biochem Cell Biol. 2004;36: 568-584.[CrossRef][Medline]
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- Zhao RC, Liao L, Han Q. Mechanisms of and perspectives on the mesenchymal stem cell in immunotherapy. J Lab Clin Med. 2004;143: 284-291.[CrossRef][Medline]
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- Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363: 1439-1441.[CrossRef][Medline]
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- Burt RK, Padilla J, Begolka WS, Canto MC, Miller SD. Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis. Blood. 1998;91: 2609-2616.[Abstract/Free Full Text]
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