Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study

Burt, Richard K.; Loh, Yvonne; Cohen, Bruce A.; Stefosky, Dusan; Balabanov, Roumen; Katsamakis, George; Oyama, Yu; Russell, Eric J.; Stern, Judith M.; Muraro, Paolo A.; Rose, John; Testori, Alessandro; Bucha, Jurate; Jovanovic, Borko; Milanetti, Francesca; Storek, Jan; Voltarelli, Júlio César; Burns, William H.

doi:10.1016/s1474-4422(09)70017-1

Cited by 265 publications

(212 citation statements)

References 32 publications

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“…3,5,10,12 --14 Recently, it was reported that non-myeloablative autologous BMT to treat multiple sclerosis produced a positive outcome. 4 However, alemtuzumab that provides a beneficial outcome in multiple sclerosis patients was also included in the conditioning regimen. 27 Here, we carried out step-down irradiation dose experiments to assess the effect of antigen-specific BMT under non-myeloablative conditioning regimes.…”

Section: Discussionmentioning

confidence: 99%

Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice

Hosseini

Chan

et al. 2011

Gene Ther

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Myeloablative transplantation of bone marrow (BM) engineered to express myelin oligodendrocyte glycoprotein (MOG) establishes central intrathymic tolerance and completely prevents MOG-induced experimental autoimmune encephalomyelitis (EAE) in mice. Here we asked whether non-myeloablative transplantation of MOG expressing BM (pMOG-bone marrow transplantation (BMT)) can also provide the same protection. Using stepwise reduction of irradiation doses, 275 cGy irradiation with pMOG-BMT protected 100% of mice from EAE development even with two subsequent re-challenge with MOG. Irradiation doses o275 cGy produced dose-dependent partial protection with significant disease protection still evident at 50 cGy. Splenocytes from 275 cGy recipients proliferated to MOG stimulation in vitro, indicating that MOG-reactive cells are present in the periphery but failed to induce disease. MOG-stimulated splenocytes produced little or no interleukin-17, interferon-g, granulocyte-monocyte colony stimulating factor and tumor necrosis factor-a compared with EAE control. Adoptive transfer of CD4 T cells from EAE-resistant mice into Rag2 À/À mice devoid of MOG expression resulted in MOG-induced EAE in B74% of mice. Treatment of EAE-resistant mice with anti-programmed death 1 (PD-1) monoclonal antibody-induced EAE in 67% of mice. We conclude that nonmyeloablative transplantation of self-antigen expressing BM induces robust peripheral tolerance that completely prevented EAE development. Our findings implicate clonal anergy and the PD-1 pathway in the maintenance of peripheral tolerance.

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Section: Discussionmentioning

confidence: 99%

Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice

Hosseini

Chan

et al. 2011

Gene Ther

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“…Less intensive regimens, such as cyclophosphamide with ATG, have resulted in the reduction of signs of CNS inflammation; however, some of these patients breakthrough and experience ongoing relapses after HSCT. Clinical relapses or magnetic resonance imaging evidence of ongoing CNS relapse were seen in 38 % of recipients during the 3 years after HSCT [15,49]. The use of higher intensity conditioning regimens, such as BEAM with ATG or busulphan/cyclophosphamide with ATG, is effective at suppressing episodic CNS inflammation.…”

Section: Lesson 4: Hsct Is More Likely To Be Effective For Ms Patientmentioning

confidence: 99%

Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Top 10 Lessons Learned

Atkins

Freedman

2013

Neurotherapeutics

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Reports from more than 600 hematopoietic stem cell transplants (HSCT) have appeared in the medical literature for the last 1 and one-half decades. The patient's own stem cells are harvested and stored temporarily while high doses of chemotherapy and biologics are used to destroy the auto-destructive immune system. The immune system is regenerated from the infused autologous hematopoietic stem cells. Increasing clinical experience has refined patient selection criteria and management in the peri-transplant period leading to a reduction in treatment-related complications. HSCT, when used to treat patients with aggressive highly active multiple sclerosis, can reduce or eliminate ongoing clinical relapses, halt further progression, and reduce the burden of disability in some patients, in the absence of chronic treatment with disease-modifying agents. The top 10 lessons learned from the growing experience using HSCT for the treatment of multiple sclerosis are discussed.Keywords Hematopoietic stem cell transplantation . Multiple sclerosis . Autoimmunity . Immune ablation There are published reports of more than 600 bone marrowbased transplants performed primarily for the treatment of multiple sclerosis (MS). This review will focus on why and how the hematopoietic stem cell transplantation (HSCT) procedure is used and discuss some of the lessons that can be gleaned from the experience of using HSCT to treat MS.MS is an organ-specific autoimmune disease that results in exclusive central nervous system (CNS) demyelination and axonal damage. Early on, multifocal localized pockets of inflammation lead to transient neurologic dysfunction manifesting as a series of relapses followed by remissions, usually with complete recovery owing to adequate CNS repair. However, as the damage accumulates, repair becomes inadequate and leads to incomplete resolution of disability, culminating in a neurodegenerative process amid a sea of smoldering and changing inflammation. This is probably the underlying state for the clinical stage of secondary progressive MS (SP-MS), a phase characterized by relentless and progressive accumulation of neurological disability with dwindling evidence of discrete relapses [1].Targeting inflammation with interferon-β, glatiramer acetate, natalizumab, fingolimod, and other immune-modulating agents reduces the frequency of relapses, but the impact on delaying the onset, preventing or slowing the tempo of SP-MS remains uncertain [2][3][4]. Several other drugs are in late stage clinical trials and may provide new alternatives for some patients with relapsing-remitting MS (RR-MS). However, despite these therapeutic advances, a subset of patients seem refractory and rapidly develop severe neurological impairment, whereas other patients may have a slower progression of illness that ultimately results in marked functional disabilities. Only a single agent, mitoxantrone, has been shown to temporarily halt or slow the tempo of SP-MS [5,6], but even then, this occurs only in SP-MS patients who have highly act...

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“…For instance, cell numbers appeared to recover more rapidly in the Muraro et al [16] study in 2005 than in the Cole et al [22] study in 2008. There also appears to be a higher proportion of patients achieving progression-free survival with AHSCT at a 3-year follow-up, although these are still preliminary results [8,22]. Yet, this lays the ground for a fundamental question: How does transplantation of CD34 + HSCs following a lymphoablative conditioning regimen alter the reconstitution and reprogramming of the immune system?…”

Section: Ahsct Mechanism Of Action: Reconciling Hypothesismentioning

confidence: 99%

“…Although the efficiency of AHSCT in MS is increasingly being validated [8], the immune mechanisms that account for its therapeutic effects are still largely unknown (see Table 1). Two basic hypotheses have been proposed to explain the beneficial effects of AHSCT.…”

Section: Introductionmentioning

confidence: 99%

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

Gosselin

Rivest

2011

Neurotherapeutics

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A recent phase I/II clinical trial drew serious attention to the therapeutic potential of autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis. However, questions were raised as to whether these beneficial effects should be attributed to the newly reconstituted immune system per se, or to the lymphoablative conditioning regimeninduced immunosuppression, given that T-cell depleting combinational drug therapies were used in the study. We discuss here the possibility that both AHSCT and T-cell depleting therapies may re-program alternatively the immune system, and why transplantation of CD34 + hematopoietic stem cells may offer AHSCT a possible advantage regarding longterm remission.

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Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study

Cited by 265 publications

References 32 publications

Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice

Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice

Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Top 10 Lessons Learned

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

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