So maybe the CD4 trial was doomed before it started, it would have only taken a few weeks to work out what the level of depletion needed to be in EAE, before embarking on a clinical trial.
Anyway CD4 T cell numbers after alemtuzumab are depleted between 75-90% for 2 year, so does this prove MS is T cell mediated?
To some however, they took a step back and they said this shows us that CD4 T cells doesn't cause MS. If we look in lesions there are more CD8 than CD4 T cells...is that because there is a virus around?....but it has to be autoimmunity, so it must and off we go an make an autoimmune CD8-dependent autoimmune model, which the CD4 evangelists ignore.
Next step lets destroy the CD8 T cell. This is may be planned
Clement M, Pearson JA, Gras S, van den Berg HA, Lissina A, Llewellyn-Lacey S, Willis MD, Dockree T, McLaren JE, Ekeruche-Makinde J, Gostick E, Robertson NP, Rossjohn J, Burrows SR, Price DA, Wong FS, Peakman M, Skowera A, Wooldridge L. Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies. Sci Rep. 2016;6:35332.
So this study says we should not deplete them as this will get rid of the anti-pathogen response but lets block them. This will need a reasonably constant delivery of antibody so a ker-khing approach.
CD8+ T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8+ T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8+ T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8+ T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, "blocking" anti-CD8 antibodies can suppress autoreactive CD8+ T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8+ T-cell compartment.
Potential problem is what is going to be the consequence?, If you deplete a suppressor cell is it going to make the MS worse. If you block the receptor it may still block the function. Alemtuzumab depletes CD8 T cells by about 80% at least for 6-9 months so we can get away with it.
There was only a small but significant increase in the number of viral (Herpes) infections of people treated with alemtuzumab.....
however there is the matter of the autoimmunities and this gets about 50% of people. Will this occur?. Maybe..maybe not as CD8 blockade is not going to cause the B cell hyper-proliferation that is going to cause the autoimmunities.
However, CD20 antibodies have come along and these deplete B cells. So how do we explain this?
Simple it must be T cells...which sounds abit like the dad(s) in my "Big Greek wedding" or the "Kumars" saying that "Greeks" of "Indians" invented everything.
However CD20 antibodies do inhibit T cells number, but is 30% depletion going to be significant?
Schuh E, Berer K, Mulazzani M, Feil K, Meinl I, Lahm H, Krane M, Lange R, Pfannes K, Subklewe M, Gürkov R, Bradl M, Hohlfeld R, Kümpfel T, Meinl E, Krumbholz M.Features of Human CD3+CD20+ T Cells. J Immunol. 2016; 197:1111-7.
However, we all know it is because we are losing B cell antigen presenting activity or is this a stock answer?