Rebound after natalizumab show memory cells are the major cell type(s) to target in MS

Larochelle C et al. Immunological and pathological characterization of fatal rebound MS activity following natalizumab withdrawal MSJ 2017 Jan;23(1):72-81

We have talked about this before

Our results underline the differences in immune cell populations between the CSF and the CNS parenchyma, and suggest that aggressive immunosuppressive therapy targeting both T and B lymphocytes is warranted to control the overwhelming CNS


  • The major T cell subset in MS and in EAE in animals is the Effector Memory Cell phenotype CD4/8, CD45RO, CCR7-

In this study the person was on for natalizumab for 2 years and switched to copaxone 1 month before discountinuation of natalizumab (NTZ), 4 months later the patient was hospitalised with a relapse. 

In the brain autopsy was performed within 1 hour of death and histologically there was demyelinating lesions, plasma cells and more T cells. The final pathological interpretation was severe MS rebound inflammatory demyelinating activity after NTZ withdrawal, with presence of numerous active demyelinating lesions.

CD4+ and CD8+ T lymphocytes in peripheral blood were mostly effector memory T lymphocytes (CD45RA neg, CD45RO+, and CCR7neg. As expected, CD19+ and CD20+ B lymphocytes as well as CD14+ monocytes/macrophages were less abundant than T lymphocytes in the peripheral blood compartment

CD4+ and CD8+ T lymphocytes in CSF were mostly effector memory T lymphocytes (CD45RAneg, CD45RO+, and CCR7neg, data not shown)

In CNS. A ratio of 1:2 was observed for CD4:CD8, concordant with pathological findings, but inverse to the blood and the CSF ratio. Most CD4+ (86%) and CD8+ (70%) cells were CD45RO+ and CD45RAneg, and were also CCR7neg. There were B cells in the CNS and they were mainly plasma cells

Therefore the dominant T cell response was of the memory effector type

This is consistent with animal studies the T cell accumulating in the CNS exhibit characteristics of a memory cell (CD45RO+. In animals CD45RBhigh) in particular an effector memory cell (CCR7-).

Its not always T cells. 

Massive exacerbation of multiple sclerosis after withdrawal and early restart of treatment with natalizumabLA Beume, R Dersch, H Fuhrer, O Stich, S Rauer 2015

They present a 46-year-old woman with a relapse of multiple sclerosis (MS) that began 3 months after withdrawal from long-term treatment with natalizumab. Shortly after restart of a single dose of natalizumab she developed a fulminant MS rebound with stupor and tetraparesis. Cerebral MRI showed massive progression in the number of lesions and tumefactive lesions with ring gadolinium-enhancement. Stereotactic brain biopsy evealed acute demyelination and B-cell dominated inflammation

In this case there were B cells in lesions in the biopsy, in the above case the disease had been going for some months plenty of time for B cells to turn into plasma (B) antibody-producing cells

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  • So would this research tie in with the next blog about the long term effects of alemtuzumab that it effects CD4/CD8 memory T cells that are forever reduced?

    • I had not thought of it this way, but it is somehow related, however I had thought of it another way. This we will evolve over the next week or so. The importance here is to think what is causing the problem, if it is a T cell. It must be in this population. Once you have this stored in you memory, we can start to think what happens to them following treatment.

  • seriously, the t cell, the b cell, the t and b cell business is doing my head in.

    it is midnight and i've just come home from a long day at the office. sometimes i come to this blog to switch off, rather than having the song that never ends play over and over and over and over again


    • Sorry, but I want to discuss this, so please bear with me for a little while whilst we rehearse some of the arguments.

      We need to provide context and background

    • Thank you. And it's ok, MouseDoctor2's you tube link will keep me entertained for at least 24, if not 28, hours

  • The biology is very interesting, but can some explain why a patient changed from Natalizumab to Copaxone? Who made that decision and why?

    • here is one, posted to a facebook group today:

      Person with MS‎ to Rituxan for MS
      5 hrs ·
      Thanks for the add! I had an awful awful relapse last weekend that led to 3 ER Visits, an ambulance, and a seizure. Oh, and a shit ton of sterroids. �� there was so much swelling in my brain! My doctor wants to start me on this as soon as possible and I can't wait to see what it can do! I've already done Copaxone, rebif, tysabri, and gilenya… my husband and I wanted to try to start a family so I switched back to Copaxone 3 months ago and my MS came back with a gnarly vengeance. �� unfortunatly my nuero doesn't want me to go back to gilenya because it shot my BP up so that's kind of a bummer but I'm just praying that I can get insurance to cover this stuff so I can get it where I live!

    • Also if Natalizumab was holding back this level of activity, what were the reactions like at the copaxone injection sites? I would expect sever reactions. Anything in the report on that?

  • Underscores why very early, intensive immunosuppressive therapy, only seen with HSCT, is important in controlling the disease. It is obvious that the focus strictly on T cells in MS has hindered progress; b cells are equally if not more important in the pathogenesis especially in progressive MS where they are more likely trapped behind the CNS and continue to cause damage. It's why I think neurologists have it backwards: treat early and aggressively instead of starting with low-efficacy DMDs (due to perceived risks). If time is brain, this is the wrong approach. It's why seven years after my diagnosis and three rounds of essentially the same ineffective generation 1 DMDs did nothing. Even eventually switching to Tysabri, my disease progressed to SPMS

    • "immunosuppressive therapy, only seen with HSCT"…there are other immunosuppressives but agree that the softly softly is not the approach I believe in.

  • Are U 'natalizumaber' currently? Ascend trial suggested U may have some benefit… (and U might have relapses if U have SPMS so natalizumab could inhibit these…)
    And finally age, magnitude of brain volume, and gender also cause transition to SPMS but 'hit hard & early' is very important neuros often are so conservative…

    • "(and U might have relapses if U have SPMS so natalizumab could inhibit these…)"

      Relapses are one thing but I thought also reduction of inflammation is what natalizumab..lemtrada..Ocrelizumab
      are good for..but then someone posts this below so I don't know anymore.

      "Ocrelizumab/rituximab are extremely effective in preventing Gad+ lesions, but this doesn't matter if you aren't making them anyways"

    • Yes, the ASCEND trial did suggest some very limited benefit but only in upper limb function. Why is that ? Are spinal lower limb axonal tracts too long and therefore not as amenable to treatment? Who knows? I think once immune suppression is not the primary problem, when it transitions to SPMS, likely mitochondrial metabolism is the driver in progressive, Hence why big pharma has to stop wasting research dollars on trying to repurpose anti inflammatory DMDs for progressive disease (also why ocrelizumab has such a weak effect in PPMS ). I think at the first sign of MS, CIS, HSCT SHOULD BE THE FIRST TREATMENT

  • What is the "alarm, beacon or tattletale" that is recalling the B-cells (or T-cells) to the area in the CNS and causing relapses and progression? What antigen presenting cell ("hot" microglia, A1 astrocytes, "infected" neuron) is screaming bloody murder and calling in the reinforcements- B or T-cells? Is that not the answer for what is causing relapses and progression of MS or even the cause of MS?

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