Published: July 06, 2011 r2011 American Chemical Society 1488 dx.doi.org/10.1021/mp2001523 | Mol. Pharmaceutics 2011, 8, 1488–1494 REVIEW pubs.acs.org/molecularpharmaceutics Hematopoietic Stem Cell Gene Therapy as a Treatment for Autoimmune Diseases Frank Alderuccio,* ,† Zeyad Nasa, † Jieyu Chung, † Hyun-Ja Ko, † James Chan, ‡ and Ban-Hock Toh ‡ † Department of Immunology, Monash Central Clinical School, and ‡ Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Victoria, Australia ’ AUTOIMMUNITY Autoimmune diseases affect approximately 5À6% of the popu- lation and can be generalized as resulting from a chronic adaptive immune response that is fueled by self-antigens and leading ultimately to clinical disease. Over 60 autoimmune diseases have been defined and include diseases such as type 1 diabetes (TID), multiple sclerosis (MS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). 1 For each of these there is a well- defined and highly specific immune response associated with the disorder such that, for example, for T1D, the insulin secreting beta cells within the pancreatic islets of Langerhans are destroyed, leading to insulin deficiency and the need for insulin replacement. 2 Multiple sclerosis on the other hand is an autoimmune mediated disease that attacks the myelin sheath that surrounds and insulates axonal neurons of the central nervous system. 3,4 This can result in a range of motor, sensory, visual and cognitive system dysfunctions. 5,6 Contrary to general perception, auto- immunity is not restricted to the elderly. Type 1 diabetes can occur in the very young, and the mean age of onset for MS is 20À40 years of age. Therefore as a group, autoimmune diseases represent a major health and lifestyle burden on our society, and there are no cures for them. While there is a lot of activity in devising new treatments and therapeutics for autoimmune dis- eases, treatments are far from perfect and are associated with side effects, with the key issues being toxicity and specificity. For many autoimmune diseases, corticosteroids are still the major form of treatment, but in the aim of controlling immunity to self, the ability to combat pathogens is also compromised. ’ IMMUNITY AND IMMUNE TOLERANCE The basis of immunity involves the ability to recognize foreign bodies and mount appropriate offensive action. This is predo- minantly in the form of specialized receptors that have evolved or generated with the ability to identify pathogen-associated struc- tures. These can simplistically be divided into the innate and adaptive arms of the immune system. In the innate immune system, these receptors are generically termed pathogen recognition receptors (PRRs) and have evolved to recognize defined struc- ture on pathogens and collectively termed pathogen associated molecular patters (PAMPS). Pathogen recognition receptors can be found on a large range of innate immune cells including macrophages, dendritic cells and granulocytes. The targets of these receptors are often structures or molecules that are unique to the pathogens and important for survival such as terminal mannose residues that are characteristic of bacterial but not mammalian glycoproteins and double stranded RNA found in many viruses but not in mammalian cells. 7,8 The adaptive immune response, as the name suggests, is more aligned with generating a series of defense mechanisms that are Special Issue: Emerging Trends in Gene- and Stem-Based Combination Therapy Received: March 27, 2011 Accepted: July 6, 2011 Revised: June 15, 2011 ABSTRACT: A key function of the immune system is to protect us from foreign pathogens such as viruses, bacteria, fungi and multicellular parasites. However, it is also important in many other aspects of human health such as cancer surveillance, tissue transplantation, allergy and autoimmune disease. Autoim- munity can be defined as a chronic immune response that targets self-antigens leading to tissue pathology and clinical disease. Autoimmune diseases, as a group of diseases that include type 1 diabetes, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus, have no effective cures, and treatment is often based on long-term broad-spectrum immunosuppressive regimes. While a number of strategies aimed at providing disease specific treatments are being explored, one avenue of study involves the use of hematopoietic stem cells to promote tolerance. In this manuscript, we will review the literature in this area but in particular examine the relatively new experimental field of gene therapy and hematopoietic stem cell transplantation as a molecular therapeutic strategy to combat autoimmune disease. KEYWORDS: autoimmune disease, immune tolerance, experimental autoimmune encephalomyelitis, gene therapy, bone marrow transplantation