Saturday, 3 November 2012

Research: natalizumab reduces B cell activity in the CSF

Epub: Harrer et al. Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy. Mult Scler. 2012.

Background: Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated MSers has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. 


Aims: To try and confirm whether OCBs disappear from the CSF in MSers on natalizumab.

Methods: The investigators' pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood-CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MSers requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. 

Results: At the time of repeat lumbar puncture, local IgG production was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the MSers. 

Conclusion: The investigators' therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of MSers.



"In believe that B cells, the progenitors, of the factory or plasma cells that produce antibodies are pivotal in the pathogenesis of MS. Almost all MSers gave oligoclonal bands or IgG bands in their spinal fluid indicative of a B-cell and plasma cell response within the central nervous system. Finding out what these antibodies react with almost certainly be key to pinning down the cause of MS."

"More recently B cell activity has been linked to the development of grey matter lesions and progressive MS. The finding that natalizumab reduced the B and plasma cell response in MSers is important and supports the ASCEND trial, which is currently testing natalizumab in secondary progressive MS."


Eligibility:
  1. Ages Eligible for Study: 18 Years to 58 Years
  2. Genders Eligible for Study: Both
  3. Accepts Healthy Volunteers: No
Major Inclusion Criteria:
  1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
  2. Be between the ages of 18 and 58, inclusive, at the time of informed consent.
  3. SPMS defined as relapsing-remitting disease followed by progression of disability independent of or not explained by MS relapses for at least 2 years.
  4. EDSS score of 3.0 to 6.5, inclusive.
  5. MS Severity Score (MSSS) of 4 or higher.
  6. Documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment as defined in the Study Reference Guide.
Major Exclusion Criteria:
  1. RRMS or primary progressive MS as defined by the revised McDonald Committee criteria.
  2. Clinical relapse (within 3 months) prior to randomization.
  3. T25FW test of >30 seconds during the screening.
  4. Any value below the lower limit of normal for blood levels of leukocytes, lymphocytes, or neutrophils.
  5. Considered by the Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or any other testing required by local guidelines, or due to prior immunosuppressive or immunomodulating treatment.
  6. Subjects for whom MRI is contraindicated (i.e., have pacemakers or other contraindicated implanted metal devices, are allergic to gadolinium, or have claustrophobia that cannot be medically managed).
  7. History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal, or other major disease that would preclude participation in a clinical study.
  8. History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
  9. Known history of or positive test result for Human Immunodeficiency Virus (HIV).
  10. Positive test result for hepatitis C virus (test for hepatitis C virus antibody [HCV Ab]) or hepatitis B virus (test for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]).
  11. History of transplantation or any anti-rejection therapy.
  12. Presence of any infectious disease (e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to screening.
  13. History of PML or other opportunistic infections.
Treatment History:
  1. Any prior treatment with cell-depleting therapies, including total lymphoid irradiation, cladribine, rituximab, alemtuzumab, or bone marrow ablation.
  2. Any prior treatment with natalizumab.
  3. Treatment with mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, T cell or T cell receptor vaccination, fingolimod, daclizumab, or cytapheresis within 6 months prior to randomization.
  4. Treatment with IV or oral corticosteroids, intravenous immunoglobulin (IVIg), or plasmapheresis for treatment of MS within the 3 months prior to randomization.
  5. Treatment with glatiramer acetate or any interferon beta preparations within 4 weeks prior to randomization.
  6. Treatment with 4-aminopyridine within 30 days prior to randomization, unless a stable dose has been maintained for at least 30 days prior to randomization and will be continued for the course of this study.
Other posts of interest on B cells

15 Sep 2012
The germinal center (GC) model of EBV infection and persistence proposes that EBV gains access to the memory B cell compartment via GC reactions by driving infected cells to differentiate using the virally encoded LMP1 ...
24 Jul 2012
B cells are thought to contribute to MS pathogenesis by producing autoantibodies that amplify demyelination via opsonization of myelin. To analyze autoantibody-nondependent functions of B cells in an animal model of MS, ...
17 Jun 2012
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. We compared the expression of 1059 miRNAs in B lymphocytes from untreated and natalizumab treated relapsing-remitting multiple sclerosis ...
02 Jun 2012
BACKGROUND: BAFF (B-cell activating factor of the tumor necrosis factor family) and APRIL (a proliferation-inducing ligand) are two of the major survival factors for B cells. Many studies have shown that BAFF levels were ...

05 Apr 2012
B cells are important in the pathogenesis of MS and some of the effects are not dependent on maturation of B cells into immunoglobulin (Ig) producing plasmablasts and plasma cells (cell factories that make antibodies).

29 Mar 2012
A dual role of B cells in experimental autoimmune encephalomyelitis (EAE), the animal model of the human autoimmune disease multiple sclerosis (MS), has been established. In the first role, B cells contribute to the ...
15 Aug 2012
While the role of T cells has been studied extensively in multiple sclerosis (MS), the pathogenic contribution of B cells has only recently attracted major attention, when it was shown that B cell aggregates can develop in the ...
11 Mar 2012
Given the evidence for a role for B cells in MS, we hypothesized that MS associated genomic regions co-localized with regions which are functionally active in B cells. We used publicly available data on 1) MS associated ...

17 Feb 2012
Conversely, only patients free of disease activity showed a decrease in local IgM and, to a lesser extent, in IgG synthesis. They also showed lower percentages of B cells, particularly of CD5(+) and plasmablast subsets that ...
08 Nov 2011
BACKROUND: Atacicept is a recombinant fusion protein made to inhibit B cells. The designer protein combines the binding site for two cytokines that regulate maturation, function, and survival of B cells, B-lymphocyte ...
22 Dec 2011
Ectopic lymphoid follicles (place where antibody producing B cells are generated) are hallmarks of chronic autoimmune inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis, Sjögren's syndrome, and ...
07 Oct 2011
There seems to be some confusion on the role of B cells in progressive MS and the link between B cells and grey matter pathology. I have made several posts on this in the past. I suggest you re-read these if you have not ...

19 Dec 2011
Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells (cells ...
05 Oct 2011
The immune system forms and maintains the ectopic B-cell follicles in the brain & spinal cord by producing a cocktail of immune messengers called cytokines. One of these messengers is called lymphotoxin; if you inhibit or ...
08 Jun 2011
This study is also targeting the B cell within the central nervous system (CNS) in the hope of disrupting the ectopic B cell follicles and thereby trying to stop progressive cortical or grey matter disease progression. Rituximab is a ...
06 Nov 2011
BACKGROUND: B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients ...

04 May 2012
B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell-specific IL-6 deficiency showed less severe disease ...
06 Jun 2011
The B cell that make the antibodies are found in structures called "ectopic lymphoid follicle-like structures" in the coverings of the brain and spinal cord; the covering are called the meninges. These ectopic follicles are not ...
19 Aug 2012
We found that the number of newly produced T and B lymphocytes is increased because of a high release and of a low propensity of naïve subsets to migrate across endothelial cells. In some patients this resulted in an ...

CoI: Barts Health is a site for the ASCEND study; Dr Ben Turner is the principal investigator at our site.

4 comments:

  1. Does the natalizumab need to cross the bbb to work in this population? Could it do so through an active lesion? What other way might it work here?

    ReplyDelete
    Replies
    1. Maybe not it depends on your view of the problem, but could get in through active lesion.

      Delete
  2. Is the study still recruiting?

    ReplyDelete
  3. you still dont understand this disease at all

    ReplyDelete

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