Its Popper time….more bad news for the CD4 hypothesis


To take our minds off COVID-19, I’m sticking to regular business. We have been talking about experiments and that you can’t prove an idea but you can disprove it. Yes it was online for 30minutes yesterday, but why play second fiddle to the boss’s posts.

The clinical study is the ultimate human experiment and the drug trial tells us a lot. One of the most informative drugs is natalizumab. It doesn’t deplete it’s target, it blocks them. The word in the lab says that natalizumab blocks T cells from migrating into the CNS. Sure it does but what else does it block. When the natalizumab idea was first shown in 1990’s the antibody was blocking the ability of U937 to bind to inflammed vessels…No this is not a German submarine, but it is also not a T cell. It is in fact a monocyte/macrophage like cell.

Now there are some interesting observations with natalizumab

You give natalizumab and it stops MS for most people, so it is blocking the relapsing disease causing cells.

You stop natalizumab and you get disease rebound within 8-12 weeks. Therefore, the disease causing cells are around and seem to be held in check.

Natalizumab targets the cell that causes relapsing MS. What are they?

It matters to know. This is because you can mitigate risk of problems, like infections, if only remove the cells causing the problem. At the moment many people are looking at the CD4 T cells as if it is a bad black, red-eyed cat. However, are they white fluffy cats and the menace is behind you? If you are not looking in the right place, you miss it and may suffer the consequences of being hit by a half-eaten dinosaur thigh….. or a relapse.

Great question 1

What is an effective treatment to stop rebound and what cells are being targeted?

One answer is anti-CD20 B cell therapy to block rebound. It works within a few weeks based on MRI studies in clinical trials. CRAB drugs are not that great.

What about the T cell therapies?..Well there aren’t any good enough. Use alemtuzumab and if the person has sub-clinical PML (JC virus brain disease), then there is a risk the recipient will die from uncontrolled infection. Dimethyl fumarate which blocks CD8s is not that good at blocking rebound (calabrese et al. J Neurol Neurosurg Psychiatry. 2017;88:1073).

Answer: The cell driving MS is either a B cell (Memory B cells are depleted) or resides in the 2% of CD4 cells affected or the 6% of CD8 cells affected by CD20 depletion.

T cell immunologist will therefore have to side on the hard to understand, 2%, view to keep their Popperian experience going.

JC virus causes PML and that can be deadly in people with reduced immune systems.

Many people are infected by JC virus and this is normally controlled by the immune system. People treated with natalizumab have a high risk of PML so people are often swopped from natalizumab onto something else after about 24 months of treatment if they have the JC virus and have had previous immunosuppresssive treatment. This is part of a risk mitigation scheme to reduce the risks of PML.

The folks at Biogen have also looked into the effect of changing the dosing scheme. This was first shown by Docs in the US and subsequently supportive data was mined from the Biogen Natalizumab vaults. The approach is called EXTENDED INTERVAL DOSING. So rather than you get your fix once a month (STANDARD INTRVAL DOSING) you get it every six weeks. Long enough interval to protect you from MS, but short enough to protect you from the effect of rebound and importantly it was suggested that this reduces your risk of PML. So you may start of at once a month and then after 12 months switch to EID.

That is good news if we can keep Natalizumab working and make it safer. OK it may take more work for more definitive data

Hower this creates a great experiment.

Great question 2

What is allowed to enter the CNS to ensure there is no JC virus in there to cause PML, but what is kept out of the CNS to ensure that MS is kept at bay?

The answer is the cellular cause of relapsing MS!!!!!!

What has happened.

Extended dosing reduces risk of PML (top left) I guess more studies are needed.

but there is less antibody around (bottom left)

Standard dosing inhibits CD4, CD8 and B cells from entering the CNS (Top right)

CD4 T and and monocytes express high levels of CD49d (alpha 4 integrin the target of natalizumab), memory B cells and CD8 cells express less target so it should be easier to inhibit them than T cells that need more antibody. (Middle right)

Sera from EID patients seems to block CD8 binding to blood vessels better than CD4 T cells. (Bottom right) in an online meeting report (At the limits. Jan 2020)

In the cerebrospinal fluid of people treated with EID there are the presence of CD4 T call and monocytes. CD8 T cells and B cells are still blocked. (Bottom left) in an online meting report (At the limits. Jan 2020)

Apply the logic of mister Popper to the data and you have a suggestion of what does not cause relapsing MS.

Some T cell immunologists may not like this. Let’s see how long it takes for the idea and the data to surface, it was presented but has not been peer reviewed, if it ever does in this format. OK you have to ask how is the virus controlled and it does not say that it isn’t CD8 or antibodies that are useful. However

The idea of the importance of memory B cells in this process is not disproved and lives for another day.

Therefore if you want to treat relapsing MS, where are you going to put your effort in CD4 T cells or not? The answer for some is yes, yes, yes

Memory CD4+ T Cells in Immunity and Autoimmune Diseases. Cells. 2020;9(3). pii: E531

CD4+ T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4+ Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4+ T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4+ tissue-resident memory T cells and of CD4+ memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4+ T cell-mediated autoimmune diseases.

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