That’s the logic, but unfortunately data is the bane of a good idea.
We report the results of a randomized, double-blind, placebo-controlled exploratory trial of the chimeric monoclonal anti-CD4 antibody cM-T412 in 71 patients suffering from active relapsing-remitting and secondary progressive multiple sclerosis. Infusion of the antibody produced frequent but usually minor side effects and resulted in a long-lasting reduction of circulating CD4-positive T cells. There was no significant effect on the primary measure of efficacy, the number of active lesions on monthly gadolinium-enhanced MRI over 9 months. Further statistical evaluation provided evidence that the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months (p = 0.04). There was a statistically significant reduction of 41% in the number of clinical relapses (a secondary efficacy parameter) after 9 months (p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. Other secondary efficacy parameters (Expanded Disability Status Scale progression, number of courses of methylprednisolone) were not influenced by anti-CD4 treatment. We conclude that intravenous treatment with the monoclonal antibody cM-T412 in the dosage we used results in a substantial and sustained reduction of the number of circulating CD4-positive cells, but is not able to reduce MS activity as measured by monthly gadolinium-enhanced MRI, and is therefore unlikely to have a beneficial effect on the clinical disease course. We found preliminary evidence suggesting that more aggressive depletion of CD4-positive cells might lead to a more substantial reduction in MRI activity.
So the hypothesis was put to the test and the experiment above is percieved to have failed…It should have put a major spanner in the works…but we still carry on and the T cells are the bees knees when it comes to autoimmunity and MS……The B cell evangelist says yep that’s what you expect, the T cell evangelist often ignores this and carries on regardless.
At the time, HIV had appeared and AIDS developed when CD4 T cells went below 200 cells/mm3. So the dosing of CD4 was limited to limit dropping below this number.
As we have recently reported the 60-65% depletion may not have been enough to control MS, after all it does not control EAE very well and 30% depletion of CD4 T cells is just plain rubbish.
von Kutzleben S, Pryce G, Giovannoni G, Baker D. Depletion of CD52-positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune-tolerance promoting CD8 T-cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis. Immunology. 2016. doi: 10.1111/imm.12696. [Epub ahead of print].
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.
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.
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.
Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol. 2014 ; 193:580-586.