ASCT does not erase immune-markers in CSF

A board to discuss Revimmune as a potential therapy for multiple sclerosis

ASCT does not erase immune-markers in CSF

Postby Frank » Tue Sep 23, 2008 10:08 am

http://www.ncbi.nlm.nih.gov/pubmed/18223013

Bone-marrow transplantation fails to halt intrathecal lymphocyte activation in multiple sclerosis.
Department of Neurology, Erasmus University Medical School, Erasmus MC, 3000 CA Rotterdam, The Netherlands.

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.
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby patientx » Tue Sep 23, 2008 2:28 pm

I pm'd Chris on another subject, and in his reply he asked me to post this regarding Revimmune:


This is not, I repeat not Stem Cell Transplant. Not even close. You never ever receive any stem cells. Your body makes it's own.

Something along the way teaches healthy immune cells to start attacking. This treatment kills off all those bad cells, and your bone marrow send out the healthy cells. There are not any bad cells left to teach the new cells how to be bad, therefore the MS isn't active. In some they have relearned to be bad, but with Copaxone it may actually not happen again.

With Revimmune there is never a stem cell issued.
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Postby Frank » Tue Sep 23, 2008 4:09 pm

Hi Patientx / Chris,

tts true that HDC does not involve any SC transplant. But the thing both attempts have in common is the heavy immun-ablation at the beginning, that is intended to kill any aggressive immune cells in the body.

After that a "new" immunesystem is to be builded out of SCs.
Either the ones that remaind unharmed in the bonemarrow (HDC) or the transplanted ones (ASCT).

The point of this study is that the attempt to erase the whole malfunctious immune system does not seem to be successful because after immunerasive treatment pathological immune components are still found in the CSF.

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby rainer » Tue Sep 23, 2008 9:31 pm

What stage or type of MS did the patients they pooled their own with? Did those patients receive the exact same immunoablative protocol? Was this a blind study? Why no mention that MS patients who continue to show bands have also show stabilization and improvement in their EDSS?

If this study were "Bone-marrow transplantation halts intrathecal lymphocyte activation in multiple sclerosis" and treated all of 8 people, how much recognition to you think it'd get?

None of that's directed at Frank btw, just think standards should be the same in whether a treatment is accepted or dismissed.
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Postby mommasan » Wed Sep 24, 2008 5:55 am

I wonder if the results would be the same if the patients had been re-infused with embryonic stem cells or cord stem cells? Those auto-reactive buggers are almost impossible to be 100% wiped out from autologus bone marrow.

Still, Keri, you make a good point are those of us who have gone thru the Hopkins protocol truly free of disease? It's really difficult for us patients to make a true comparison of different treatments when the testing for efficacy is so different. Not that it would have changed our decision.

Sandy
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Postby cheerleader » Wed Sep 24, 2008 6:49 am

Hi all...
I think this is why copaxone has been introduced into the Revimmune equation. I was just mentioning this on the copax site re: lymph % on my husband's recent CBC- copax binds to lymphs and retrains naive ones-

http://www.thisisms.com/ftopict-6162.html

AC
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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More data on this study

Postby WilliamT » Wed Sep 24, 2008 10:56 am

I've pasted below the abstract of the primary results from the Rotterdam case studies posted earlier in this thread. As you'll see, the patients were all secondary progressive with fairly substantial disability and disease duration. Certainly a different profile from the patients selected for the Hopkins protocol. While there certainly are important differences from the Hopkins protocol, the concept of complete immunoablation is shared. In fact, the Rotterdam study uses a more aggressive conditioning, including radiation and other agents in addition to cyclophosphamide. Possibly a key is the profile of patient.

Here's the abstract:

Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis.
Department of Neurology, MS Centre ErasErasmus MC, Postbox 2040, 3000 CA Rotterdam, The Netherlands.
BACKGROUND: Certain stem cell transplantation procedures might slow down inflammatory pathology in multiple sclerosis (MS). AIMS: To halt disease progression in aggressive MS by a bone marrow transplantation (BMT) protocol aimed at maximum T cell suppression. METHODS: Autologous BMT was performed in 14 patients with rapid secondary progressive MS (median EDSS score at baseline, 6; median disease duration, five years). To accomplish rigorous T cell ablation, a strong conditioning protocol was chosen--cyclophosphamide, total body irradiation, and antithymocyte globulin. To minimise the possibility of reinfusing mature T cells in the graft, bone marrow, not peripheral blood, was used as the CD34+ stem cell source. RESULTS: Median follow up was 36 months (range, 7-36). Post-transplant haemopoietic recovery was successful in all patients. Early toxicity included Epstein-Barr virus related post-transplantation lymphoproliferative disorder. Longterm effects were development of antithyroid antibodies (three) and myelodysplastic syndrome (one). One patient died of progressive disease five years after transplantation. Treatment failure, defined by EDSS increase sustained for six months or more, was seen in nine patients and stabilisation or improvement in five. Other clinical parameters generally showed the same outcome. No gadolinium enhanced lesions were seen on post-treatment magnetic resonance imaging, in either cerebral or spinal cord scans. However, cerebrospinal fluid oligoclonal bands remained positive in most cases. CONCLUSIONS: This strong immunosuppressive regimen did not prevent clinical progression in patients with aggressive secondary MS. The lack of efficacy, together with some serious side effects, does not favour the use of similar rigorous T cell depleting protocols in the future.
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Postby rainer » Wed Sep 24, 2008 3:37 pm

I wonder if by giving them an autologous transfusion of stem-cells you may actually be jump-starting the MS process back in a way that just immunoablation avoids. Maybe an allogenic transplant would work better.
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Postby WilliamT » Thu Sep 25, 2008 8:51 am

Maybe reinfusing pre-collected stem cells could do that, although it seems like there would be no difference between the stems cells' "naiveity", whether they are collected prior to chemo or remain unharmed through cytoxan treatment.

Allogenic really opens a whole can of worms, its so difficult to find a matching donor, then there's graft vs. host rejection issues, so you'd have to be on immunosuppresants long term, etc.
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Postby rainer » Thu Sep 25, 2008 3:53 pm

My philosophy is find out it if it works then work out the kinks.

Maybe reinfusing pre-collected stem cells could do that, although it seems like there would be no difference between the stems cells' "naiveity", whether they are collected prior to chemo or remain unharmed through cytoxan treatment.


But how do we know they are unharmed? Maybe the cytoxan is effecting them and knocking back the ones with memory. A positive gain that ASCT diminshes faster.
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