I have been asking myself about the non-myeablative HSCT and wondering how does it work?
It is often a combination of cyclophophamide and anti-thymocyte globulin.
Cyclophosphamide is a drug that can kill anything that divides and so it will hit activated T cells but it is also pretty good at depleting B cells, because many of them have a high natural turnover. This causes the CD34+ stem cells to mobilize from the bone marrow into the blood, where they are harvested. They then get anti-thymocyte globulin. I thought that this would therefore target T cells, so to squeeze the memory B cell idea into the mix the cyclophosphamide would have to kill memory B cells.
Indeed in a paper the reduction was by about 70% CD19 B cell compared to about 25% for T cells. Switched memory B cells depleted by about 40% and unswitched by about 60%. Memory CD4 cells were down by about 20% and CD8 memory were not affected.
Anti-thymocyte globulin (ATG) is an infusion of horse or rabbit-derived antibodies against human T cells, which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia. I saw Dr Burt from Chicago and he said to me the anti-thymocyte globulin depletes B cells. This came as a bit of a shock but thinking about it, it makes perfect sense as T and B cells share loads of molecules that can be targeted by the antibody.
Mondria T1, Lamers CH, te Boekhorst PA, Gratama JW, Hintzen RQ Bone-marrow transplantation fails to halt intrathecal lymphocyte activation in multiple sclerosis.J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1013-5. doi: 10.1136/jnnp.2007.133520. Epub 2008 Jan 25.
.BACKGROUND:Given the presumed key role for autoreactive lymphocytes in multiple sclerosis (MS), treatment strategies have been developed to ablate lymphocyte activity. Intrathecal lymphocyte activation can be measured by CSF-soluble(s)CD27.
OBJECTIVE:To determine the effect of maximum whole-body immune ablation on two different markers that detect lymphocyte activation in CSF-oligoclonal IgG bands and levels of CSF-sCD27.
DESIGN, SETTING AND PATIENTS: The study quantified sCD27 levels and assessed the presence of oligoclonal IgG bands in CSF samples of secondary progressive patients with MS treated by autologous bone-marrow transplantation. In eight individuals, CSF was taken before and 6-9 months after conditioning. CSF-sCD27 levels were compared with other MS and non-inflammatory neurological disease controls. Regarding the effect of stem-cell transplantation on CSF oligoclonal bands, the study analysed pooled data of this and four other international studies on stem-cell transplantation in MS.
RESULTS:CSF-sCD27 was significantly lower after the extremely immunoablative protocol. However, levels remained elevated compared with non-inflammatory controls and stayed within the range observed in other MS controls. The joint analysis of CSF oligoclonal bands demonstrated persistence of this immune abnormality in 88% of the reported cases (n = 34).
CONCLUSIONS:The persistence of CSF lymphocyte activation markers sCD27 and intrathecal oligoclonal IgG bands after maximum immunoablative treatment indicates that complete eradication of activated lymphocytes from the CNS has not been established. This is paralleled by disease progression observed in several studies on the effect of stem-cell transplantation in MS