Immunological questions on hematopoietic stem cell transplantation for multiple sclerosis PA Muraro and R Martin Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA Summary: Multiple sclerosis (MS) is considered an inflammatory autoimmune disorder. Approved immunotherapies are only moderately effective in reducing disease exacerba- tions and brain inflammation in a subset of patients. Autologous hematopoietic stem cell transplantation (HSCT) has emerged in recent years as the first opportunity to offer to patients a radical, potentially curative treatment. Here, we will summarize key im- munopathological aspects of MS and discuss important questions that need to be addressed to clarify the therapeutic role and mechanism of action of HSCT in this disorder. Bone Marrow Transplantation (2003) 32, S41–S44. doi:10.1038/sj.bmt.1704096 Keywords: multiple sclerosis; stem cells; hematopoietic stem cell transplantation MS: an inflammatory demyelinating and degenerative axonal disorder Multiple sclerosis (MS) is a chronic inflammatory demye- linating disorder of the central nervous system (CNS) that predominantly affects young adults. Approximately one million individuals worldwide are affected, over 200000 only in the US. 1 Females are affected twice as frequently compared to males. Impairment of motor function with paralysis and spasticity, incoordination (ataxia), loss of vision, sensitive disturbances, paroxysmal pain, sphincter dysfunction and cognitive impairment are the most common symptoms. The clinical course is very hetero- geneous, the most typical being a relapsing-remitting form with exacerbations followed by complete or partial recovery of neurological function. More advanced stages of the disease are characterized by accumulation of disability, either from incomplete recovery from relapses or by continuous progression (secondary progressive MS). Less commonly, the disease presents from the beginning with a slowly progressive course (primary progressive MS), with or without relapses. 2 MS pathology selectively affects the CNS. Focal lesions can be found in the white matter of the brain, of the brainstem, of the cerebellum and of the spinal cord. The pathological hallmark of MS is the demyelinated plaque, characterized by varying grades of myelin loss and gliosis. Prominent intraparenchymal and perivascular inflamma- tory cell infiltrates, predominantly lymphocytes and macro- phages, are commonly found in active lesions. Axonal damage has been recognized as an additional important component of MS pathology. 3 Different patterns of demyelination have recently been associated to distinct possible pathways of immune-mediated tissue destruction. 4 The interindividual heterogeneity of MS lesions suggests that different mechanisms may act in different patients, accounting for the variability of clinical courses, of immunological findings and of responses to treatments. The cause of MS is unknown and the pathogenic process is incompletely understood. Several features of the disease, which include the presence of immune cells in lesions, cerebrospinal fluid (CSF) abnormalities with intrathecal production of oligoclonal IgG, the response to immune- modifying treatments and the increased disease suscept- ibility of individuals with certain HLA class II haplotypes, point to an immune-mediated pathogenesis. Current knowledge supports a T-cell-dependent, T- and/or B-cell- mediated autoimmune pathogenesis targeting myelin com- ponents or myelin-producing cells. 5 Myelin proteins that could be involved as targets of the inflammatory immune response in MS include myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendroglia glyco- protein (MOG) and 2 0 ,3 0 -cyclic nucleotide 3 0 phosphodies- terase (CNPase) as well as other minor components. This hypothesis is supported by observations in experimental animals models. Immunization of susceptible animal strains with myelin antigens or transfer of myelin antigen-reactive T cells induces experimental autoimmune encephalo- myelitis (EAE), an inflammatory disorder of the CNS which resembles MS. EAE studies have demonstrated that inflammatory demyelinating CNS disorders can be mediated by CD4 + myelin-specific T cells. In this context, disease-inducing T cells are clearly biased toward Correspondence: Dr. PA Muraro, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bldg. 10, Room 5B16, 10 Center Dr MSC1400 Bethesda MD 20892-1400 USA Bone Marrow Transplantation (2003) 32, S41–S44 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt