Tolerance induction by bone marrow transplantation in a multiple sclerosis model

Abstract

Experimental autoimmune encephalomyelitis (EAE) in rats is a highly valuable model of multiple sclerosis (MS) because it mimics major hallmarks of the human disease. EAE induced with myelin-oligodendrocyte-glycoprotein (MOG) in DA rats is relapsing/ remitting, and lesions in the central nervous system show inflammation, demyelination, and axonal and neuronal loss. Recently, bone marrow transplantation (BMT) was introduced as a novel strategy to treat MS, but its efficiency and the underlying mechanism are debatable. In MOG-induced EAE we found that BMT at the peak of EAE but not in the chronic phase leads to disease attenuation. In both settings, rats receiving bone marrow (BM) transplants were protected from subsequently induced relapses. These findings could be confirmed by histopathology in which rats receiving BM transplants did not have lesions compared with controls not receiving transplants. Importantly, the protective effect was achieved by allogeneic, syngeneic, and BM grafts from diseased rats. BMT resulted in increased numbers of CD4 ؉ CD25 bright regulatory T cells, increased IntroductionMultiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) that is characterized by demyelinating plaques and axonal loss. 1 Although MS is highly prevalent in Northern Europe and the United States, 2 no cure is presently available and the clinical management of the disease is unsatisfactory. 1 The etiology of MS is unknown. However, it is generally believed that both genetic and environmental factors contribute to the development of its pathology. 3 The onset of MS is presumably characterized by autoreactive T cells crossing the blood brain barrier (BBB) and initiating an inflammatory response that results in an opening of the BBB. This allows influx of additional immune cells such as granulocytes, macrophages, natural killer (NK) cells, and B cells as well as antibodies and complement. 4 Subsequently, this process leads to myelin destruction, induction of oligodendrocyte death, axonal degeneration and, ultimately, to the functional deficits seen in MS patients. 5 Experimental autoimmune encephalomyelitis (EAE) is a frequently used animal model for MS that can be induced in rodents and monkeys. 6 In particular, myelin-oligodendrocyte-glycoprotein (MOG)-induced EAE in DA rats mimics major hallmarks of the human disease. These include the relapsing/remitting type of disease course, the occurrence of demyelinated plaques in the brain and spinal cord, axonal loss, and the involvement of both antibodies and complement in the pathogenesis. [7][8][9][10][11] Autologous bone marrow transplantation (BMT) and hematopoietic stem cell transplantation (HSCT) are presently discussed as novel options for the treatment of patients with MS with fast progressive disease courses that do not respond to conventional treatment. 12,13 Clinical trials were to some extent inconclusive because they arrived at divergent results. [14][15][16] Preclinical studies were performed in EAE that assessed...

Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG

“…46 Recently, one of these latter studies was published using CY/rATG and it reported no deaths among 21 patients with relapsing-remitting MS. 31 There is a controversy regarding the analysis of the immune system modifications as increases in naive CD4 þ T cells over memory cells 20 and the fact that more intensive regimens seem to present better results than less intensive regimens. 19,26,47 On the other hand, some studies have shown that non-myeloablative conditioning regimens containing CY þ /Àanti-T-cell antibodies induce deep changes in the immune system of patients with autoimmune diseases, with an increase in regulatory subsets of cells and of naive T cells, improvement in TCR diversity and re-establishment of the auto-tolerant state. 48,49 The implications of these findings in clinical studies are still to be seen.…”

“…13,[18][19][20] Since the first HSCT reported by Fassas et al, 21 in 1997, more than 300 HSCTs have been performed in MS patients worldwide. [22][23][24] The EBMT (European Group for Blood and Marrow Transplantation) has published the largest samples.…”

Abstracts from Scientific Programme

“…This prompted others and us to hypothesize that restoration of self tolerance could be mediated by the normalization of immune regulatory mechanisms. In an animal model of multiple sclerosis, there was an increase of CD4+CD25+ T cells after syngeneic bone marrow transplantation and this was seen in connection with attenuation of active disease and protection from induction of relapses (5). In humans, enumeration of CD4+CD25[high] T cells in juvenile idiopathic arthritis patients after AHSCT showed recovery of the pre-treatment frequency of Tregs at 6 months post-transplant, and a continued increase for the remaining 12-month follow-up period (6).…”

“…4 In this respect there has been increasing recognition that total myeloablation may not necessarily provide the best balance between benefi ts and risks, and that autologous HSCT could be used to support safer, better tolerated forms of intensive immuno-ablation. 5 In addition, there has been considerable discussion about the role of TBI based regimens in certain diseases where radiation may exacerbate specifi c conditions and generic late effects. 6 Ultimately, the results of phase III trials should be available in scleroderma, multiple sclerosis and Crohn's disease to prove initial proof of principle of the future role of autologous HSCT in these diseases.…”

“…Haematopoietic stem cells transplantation (HSCT) has been used for the treatment of autoimmune disorders based on results obtained in animal models [1,2]. Allogeneic transplantation was shown to have the potential to transfer the autoimmune disorder in healthy animals [3,4], but was also able to induce long lasting remission in affected animals [5,6]. Nevertheless autologous transplantation has been proved to determine clinical remission in induced diseases, even if a minor rate when compared to allogeneic [7].…”