Hyper-reactivity of CD8+ T cells and high expression of IL-3 correlates with occurrence and severity of Long-COVID, 2025, Renner et al.

Jonathan Edwards said:
For about twenty five years friends of mine have talked of manufacturing 'bispecific' monoclonal antibody drugs that in theory are very clever but have not broken into the market much.

A typical idea would be to have one arm of the antibody bind a T cell surface label protein like CD8 and the there arm would bind an activation marker - some protein only expressed if the cell was angry or excited. The idea would be that you only kill off cells that have got out of hand when really they should be laid back doing nothing.
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Is this doable?
 
Jonathan Edwards said:
It is very doable. The question is why, if it actually works, it has not been translated into treatment. It is harder to see how it work for B cells. But T cells use surface activation proteins a lot when interacting with antigen presenting cells.
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Sounds like a possible target for e.g. MS?
 
Jonathan Edwards said:
Except that MS is a B cell disease - as at last shown with ocrelizumab twenty years late.
Like RA, it has always been promoted as a T cell disease by the Twitterati.
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I did not know that! I was going off papers like this:
https://pmc.ncbi.nlm.nih.gov/articles/PMC5880159/
Multiple sclerosis (MS) has long been considered a CD4 T-cell disease, primarily because of the findings that the strongest genetic risk for MS is the major histocompatibility complex (MHC) class II locus, and that T cells play a central role in directing the immune response. The importance that the T helper (Th)1 cytokine, interferon γ (IFN-γ), and the Th17 cytokine, interleukin (IL)-17, play in MS pathogenesis is indicated by recent clinical trial data by the enhanced presence of Th1/Th17 cells in central nervous system (CNS) tissue, cerebrospinal fluid (CSF), and blood, and by research on animal models of MS, such as experimental autoimmune encephalomyelitis (EAE).
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Multiple sclerosis (MS) has long been considered a CD4 T-cell disease, primarily because of the findings that the strongest genetic risk for MS is the major histocompatibility complex (MHC) class II locus, and that T cells play a central role in directing the immune response. The importance that the T helper (Th)1 cytokine, interferon γ (IFN-γ), and the Th17 cytokine, interleukin (IL)-17, play in MS pathogenesis is indicated by recent clinical trial data by the enhanced presence of Th1/Th17 cells in central nervous system (CNS) tissue, cerebrospinal fluid (CSF), and blood, and by research on animal models of MS, such as experimental autoimmune encephalomyelitis (EAE).

Let's pick that apart.
1. The genetic risk for both RA and MS is MHC Class II, which is the molecule used by B cells to present antigen to T cells largely so that the B cells can make antibody. The obsession with T cells in RA actually arose from my reporting MHC Class II in joint lining in 1980 in a small meeting in Holland. The Class II was on macrophages, which also present antigen to T cells but joints are full of macrophages covered in Class II - so what? The same argument applies to MS. MHC Class II was actually first identified by the monoclonal B1 by Martin Glennie which was initially thought to be a specific marker for B cells. You can't make this stuff up.
2. Who says T cells play a central role in directing the immune response? Avrion Mitchison maybe, but Av proved himself wrong a hundred times over (may he rest in peace). This is the brainless dogma that has ensured that hardly any progress has been made in this field for 25 years now.
3. What clinical trial data please? You are bound to find TH1/TH17 T cells in inflamed tissues of any sort because these, like polymorphs and macrophages are inflammatory policing cells. They turn up whenever there is trouble. In contrast B cells have no local inflammatory function and do not. So the argument is non sequitur. In fact the weird thing about RA and MS is that the lesions are packed full of B and plasma cells when they have no business there!!
4. Animal EAE has nothing to do with MS. It is a monopahsic allergic response to antigens present in both central and peripheral nervous tissue. MS is entirely specific to CNS and almost certainly has nothing to do with antigen localisation.

You are not to know, of course, but this is the very stuff that I made my reputation out of realising was make believe. Even now that CD19 CAR T cells directed at B cells are the hottest thing in therapeutic town people go on about this drivel.

What you are li'ble to read in the Bible
It ain't necessarily so..
 
Jonathan Edwards said:
You are not to know, of course, but this is the very stuff that I made my reputation out of realising was make believe. Even now that CD19 CAR T cells directed at B cells are the hottest thing in therapeutic town people go on about this drivel.

What you are li'ble to read in the Bible
It ain't necessarily so..
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I appreciate the breakdown! I imagine it must be incredibly frustrating to see this happening over and over again..
 
There are a bunch of bispecific mabs

Blinatumomab (Blincyto), Emicizumab (Hemlibra), Amivantamab (Rybrevant), Teclistamab (Tecvayli), Mosunetuzumab (Lunsumio), Epcoritamab (Epkinly), and Glofitamab (Columvi).
 
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