Action of treosulfan in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis and human lymphocytes

Weissert, Robert; Wiendl, Heinz; Pfrommer, Heike; Storch, Maria K.; Schreiner, Bettina; Barth, Silvia; Seifert, Thomas; Melms, Arthur; Dichgans, J.; Weller, Michael

doi:10.1016/j.jneuroim.2003.08.028

Cited by 25 publications

(14 citation statements)

References 35 publications

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“…Therefore, the model described here can be considered to be highly relevant for the preclinical testing of novel strategies for the treatment of MS. Furthermore, it might contribute to a better understanding of the pathogenesis of MS. 29,[32][33][34] In agreement with earlier studies we demonstrate that BMT leads to disease attenuation and protects from further induced relapses with the disease-inducing antigen, strongly suggesting that this therapy is a promising option for the treatment of MS in humans. [17][18][19][20][21][22][23][24] For the first time we demonstrate in direct comparisons that protection can be achieved by MHC-matched allogeneic, syngeneic, and BM grafts from EAE-diseased DA rats.…”

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confidence: 90%

Tolerance induction by bone marrow transplantation in a multiple sclerosis model

Herrmann

Gaertner

Stadelmann

et al. 2005

Blood

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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...

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confidence: 90%

Tolerance induction by bone marrow transplantation in a multiple sclerosis model

Herrmann

Gaertner

Stadelmann

et al. 2005

Blood

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“…10,15,29 The stable engraftment and high rate of early complete chimerism achieved in our patient collective indicate that the conditioning agents fludarabine and treosulfan possess pronounced stem cell toxicity as well as immunosuppressive features, which have both been recently attributed to treosulfan in in vitro studies and rodent models. [30][31][32][33][34][35] In contrast to busulfan, which preferentially depletes primitive stem cells, treosulfan was found to deplete committed progenitors as well as primitive stem cells in vitro. 31 In addition, agar colony assays demonstrated that the stem cell toxicity of treosulfan is superior to that achieved by busulfan or cyclophosphamide.…”

Section: Discussionmentioning

confidence: 99%

Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma

Schmidt‐Hieber

Blau

Trenschel

et al. 2007

Bone Marrow Transplant

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In recent years, reduced-intensity conditioning (RIC) regimens before allogeneic stem cell transplantation (SCT) are increasingly used in patients not eligible for conventional conditioning. We did a retrospective, multicenter analysis to assess the feasibility of conditioning with fludarabine and treosulfan before allogeneic SCT in multiple myeloma patients. Thirty-four patients with a median age of 51.5 years were included in the analysis. All patients underwent myeloablation after conditioning followed by stable engraftment, and 29 of 31 evaluable patients (94%) showed early complete hematopoietic chimerism. Non-hematological toxicities were limited and encompassed mainly fever in neutropenia and infections. Grade II-IV acute and chronic graft-versushost disease was observed in 33 and 39%, respectively. With a median follow-up of 708 days (range 60-1729 days), the median progression-free survival was 180 days. The treatment-related mortality was 10% on day 100 and 25% after 1 year. The median overall survival has not yet been reached. Our data indicate that conditioning with fludarabine and treosulfan before allogeneic SCT is feasible in intensively pretreated multiple myeloma patients and leads to stable engraftment and complete hematopoietic chimerism. Randomized trials are warranted to determine if this approach might be incorporated in an algorithm of multiple myeloma treatment.

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“…To test whether irradiation of the cerebellum was instrumental in the fusion process, we repeated some of the above experiments by conditioning mice with Treosulfan and Fludarabine instead of total body irradiation. Treosulfan is a derivative of busulfan that did not show appreciable CNS toxicity (Scheulen et al, 2000;Weissert et al, 2003), whereas neurotoxic effects of Fludarabine were observed only at higher doses and spared the cerebellum (Spriggs et al, 1986). To further rule out the possibility that these drugs induced direct damage to the cerebellum and particularly to Purkinje cells, sections from animals killed 5 d after treatment were labeled for different markers of Purkinje cell stress or death, such as c-Jun, activated caspase 3, and NADPH-diaphorase histochemistry (Zagrebelsky et al, 1998).…”

Section: Cerebellar Irradiation Is Dispensable To Fusion Of Purkinje mentioning

confidence: 99%

Induction and Survival of Binucleated Purkinje Neurons by Selective Damage and Aging

et al. 2007

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Fusion of bone marrow-derived cells with adult Purkinje cells in the cerebellum gives rise to binucleated Purkinje cells. Whether fusion can be modulated by epigenetic factors and whether fused neurons are stable has remained unclear. Here, we show that in mice and rats, partial ablation of Purkinje cells and local microglial activation in the absence of structural damage to the cerebellum increase the rate of fusion. Moreover, mouse Purkinje cells once fused with bone marrow-derived cells are viable for at least 7 months. We also show that cerebellar irradiation is unnecessary for the generation of binucleated Purkinje cells after bone marrow grafting. Moreover, binucleated Purkinje cells can be found in aged mice that did not receive any treatment, suggesting that fusion events occasionally occur throughout the whole lifespan of healthy, unmanipulated individuals. However, in aged chimeric mice that, after bone marrow transplant, have the majority of their nucleated blood cells fluorescent, the number of binucleated fluorescent Purkinje cells is two orders of magnitude less than the total number of binucleated Purkinje cells. This suggests that, in the majority of heterokaryons, either the incoming nucleus is quickly inactivated or fusion is not the only way to generate a binucleated Purkinje cell.

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Action of treosulfan in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis and human lymphocytes

Cited by 25 publications

References 35 publications

Tolerance induction by bone marrow transplantation in a multiple sclerosis model

Tolerance induction by bone marrow transplantation in a multiple sclerosis model

Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma

Induction and Survival of Binucleated Purkinje Neurons by Selective Damage and Aging

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