Bone Marrow transplants

Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, Carassiti D, Reynolds R, Salvetti M, Calabresi PA, Coles AJ, Battistini L, Martin R, Burt RK, Muraro PA Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis.Brain. 2013  [Epub ahead of print]

Autologous (your own) haematopoietic (bone marrow derived) stem cell transplantation has been tried as one experimental strategy for the treatment of patients with aggressive multiple sclerosis refractory to other immunotherapies. The procedure is aimed at ablating (depleting completely) and repopulating the immune repertoire by sequentially mobilizing (generating them to grow from their tissue niches) and harvesting (collecting) haematopoietic stem cells, administering an immunosuppressive conditioning regimen (depleting the immune cells), and re-infusing the autologous haematopoietic cell product (reconstituting the immune response). ‘Non-myeloablative’ conditioning regimens to achieve lymphocytic ablation without marrow suppression have been proposed to improve safety and tolerability (kill lymphoid white blood cells without destroying all white blood cells like macrophages/monocytes). 

One trial with non-myeloablative autologous haematopoietic stem cell transplantation reported clinical improvement and inflammatory stabilization in treated patients with highly active multiple sclerosis. The aim of the present study was to understand the changes in the reconstituted immune repertoire bearing potential relevance to its mode of action. Peripheral blood was obtained from 12 patients with multiple sclerosis participating in the aforementioned trial and longitudinally followed for 2 years. We examined the phenotype (markers expressed) and function of peripheral blood lymphocytes (white blood cells).

During immune reconstitution post-transplantation we observed significant though transient increases in the proportion of CD4+FoxP3+ T cells (T regulatory cells that prevent autoimmunity) and natural killer cell subsets, which are cell subsets associated with immunoregulatory function. CD8+,CD57+cytotoxic T cells were persistently increased after therapy and were able to suppress CD4+ T cell proliferation with variable potency. In contrast, a proinflammatory CD8+, CD161 T cell subset was depleted at all time-points post-transplantation. Phenotypic characterization revealed that the CD161, CD8+ T cells were mucosal-associated invariant T cells, a novel cell population originating in the gut mucosa but expressing the central nervous system-homing receptor CCR6 (a chemokine receptor that controls cell a postcode/zip finder that tells the cell which address to go to).

Detection of mucosal-associated invariant T cells (Mucosal associated invariant T cells (MAITs) are a special type of T cell, which have a canonical T cell receptor (Vα19-Jα33 in mice and Vα7.2-Jα33 in humans), and which appear to play a regulatory role in immunity. They are dependant on gut microbiota, being absent in germ-free micein post-mortem multiple sclerosis brain white matter active lesions confirmed their involvement in the disease pathology (May be involved but may just be bystanders dragged into the CNS during blood brain barrier problems). Intracellular cytokine staining demonstrated interferon γ and interleukin 17 production and lack of interleukin 10 production, a pro-inflammatory profile. Mucosal-associated invariant T cell frequency did not change in patients treated with interferon β; and was more depleted after autologous haematopoietic stem cell transplantation than in patients who had received high-dose cyclophosphamide (n = 7) or alemtuzumab (n = 21) treatment alone, suggesting an additive (e.g. 1 + 2 = 3) or synergistic (more than just addition e.g. 1 + 2 = 5) effect of the conditioning regime components.

We propose that a favourably modified balance of regulatory and pro-inflammatory lymphocytes underlies the suppression of central nervous system inflammation in patients with multiple sclerosis following non-myeloablative autologous haematopoietic stem cell transplantation with a conditioning regimen consisting of cyclophosphamide and alemtuzumab.

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  • Was cyclophosphamide and alemtuzumab the conditioning regime used for these patients prior to BM transplantation? I know cyclophosphamide (revimmune or cytoxan in the US) has been used on it's own, as has alemtuzumab for MS, but I hadn't heard of them being used together. A couple of big hitters and then transplantation? Has there been any research on just using the 2 drugs together?

  • I have spinal lesions which 7 different neurologists have said are or appear to be MS. However, I have been basically symptom free for over over 14 years. Unrelated to the lesions, I had a Autologous BMT for cancer. While I realize that the only truly reliable study as to the effect of a BMT on MS is a double blind study, one might do a large data review of people with asymptomatic MS and see if a disproportionate number of them have had BMT as opposed to persons with symptomatic MS.

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