Thursday, 27 August 2015

Killing CD20 T cells

Holley JE, Bremer E, Kendall AC, de Bruyn M, Helfrich W, Tarr JM, Newcombe J, Gutowski NJ, Eggleton P. CD20+inflammatory T-cells are present in blood and brain of multiple sclerosis patients and can be selectively targeted for apoptotic elimination. Mult Scler Relat Disord. 2014;3(5):650-8.

BACKGROUND: A subset of T-cells expresses the B-cell marker CD20 and in rheumatoid arthritis secretes Interleukin (IL)-17. IL-17 secreting T-cells (Th17) have also been implicated in the inflammatory response in the central nervous system in multiple sclerosis (MS) and may be a potential target for elimination by biologic therapeutics. ScFvRit:sFasL comprises of a rituximab-derived antibody fragment scFvRit genetically fused to human soluble FasL that specifically eliminated T-cells.
OBJECTIVE: To determine the presence and phenotype of CD20+T-cells in blood and brain of MS patients. Second, to determine whether scFvRit:sFasL can selectively eliminate CD20+T-cells. After CD20-selective binding, scFvRit:sFasL is designed to trigger FasL-mediated activation-induced cell death of T-cells, but not B-cells.
METHODS: Flow cytometry and immunohistochemistry were used to screen for CD20+inflammatory T-cells in MS blood and brain tissue. ScFvRit:sFasL pro-apoptotic activity was evaluated by Annexin-V/PI staining followed by flow cytometry assessment.
RESULTS:Peripheral blood (n=11) and chronic but not active lesions of MS patient brains (n=5) contained CD20+inflammatory T-cells. Activated CD20+T-cells were predominantly CD4+and secreted both IL-17 and INF-γ. ScFvRit:sFasL triggered CD20-restricted FasL-mediated activation-induced cell death in peripheral blood CD20+T-cells, but not CD20+B-cells.
CONCLUSION: CD20+inflammatory T-cells are present in blood and chronic brain lesions of MS patients. ScFvRit:sFasL selectively eliminated CD20+T-cells and may eliminate pathogenic T-cells without B-cell depletion.


It is clear that anti-CD20 antibodies are very effective at inhibiting relapsing MS. This causes a problem for the dogma of MS in that people say it is a T cell-mediated disease. effective drugs for MS target the B cell.

We know that EAE is a T cell mediated disease but it is claimed that anti-CD20 inhibits EAE also, so EAE is like MS..Problem is it is not. Anti-CD20 B cell depleting antibodies have only a marginal effect on EAE and reduce the severity of disease a little bit and this is believed to workk through affecting antigen presentation to T cells. Rituximab is however very effective in human CD20 expressing transgenic mice. However there it is affecting T cell that must be expressing the transgene.

So if we stick with dogma and MS is caused by T cells and anti-CD20 is very effective then if we only kill the CD20 expressing T cells then it should stop MS, but have fewer side effects because it won't be killing B cells. How can this be done?

Well here they take the anti-CD20 binding part of rituximab formed by the variable region of the heavy and light chains of antibody (click) and make a single chain fragment variable (scFV) construct which is the antigen binding bit of the heavy chain linked to a bit on the light chain. This will bind to the B cells and the CD20-expressing T cells. To this they have attached FAS Ligand, this binds to FAS (CD95) expressed on activated T cells. The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis) so kills the cell. So now they have done this and killed CD20 expressing T cells.

The question is what would happen if this was administered to humans would relapsing MS disappear?  Is it safe?

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