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Thursday, June 5, 2014

theory: Deficiency in CD8 T cells in MS...

Wednesday, 4 June 2014

Deficiency in CD8 T cells in MS....a reason why EBV is a problem?

Can the Pender Hypothesis explain the mode of action of the emerging DMTs? #MSResearch #MSBlog

"The following paper from Professor Pender's group supports his theory that MS is due to a deficiency of CD8+ effector cells; these are the cells that kill virally infected cells and are responsible for tumour surveillance. His hypothesis is that a deficiency of these cells against EBV-infected B cells within the brain lets the EBV cells survive long-term and drive autoimmunity. If we can boost these cells to kill EBV infected cells then we can down regulate one arm of the autoimmune loop and switch off inflammation in the CNS."

"Against the Pender theory is the recent observation that MSers have a lower incidence of cancer than the  general population; if MSers had a long-standing deficiency of these CD8+ effector cells we would expect more tumours, not less. Another observation that goes against this theory would be the effectiveness of some of the newer DMTs that target the immune system; in particular natalizumab, fingolimod, alemtuzumab, anti-CD20 and daclizumab (anti-CD25) therapies. How do these treatments improve the deficiency of CD8+ effector cells in MSers? Natalizumab blocks their entry of CD8+ cells into the brain; we know this because of PML. CD8+ effector cells are needed to fight the JC-virus. Fingolimod, drastically reduces circulating numbers of lymphocytes; although has a greater effect on naive rather than memory cells. According the Pender theory would expect fingolimod to make MS worse. However, it may depend on  the balance between CD8+ and CD4+ cells entering the brain and spinal cord. Alemtuzumab depletes all cells and they reconstitute slowly over the next 12 months; T cells, which include the CD8+ population, take the longest to reconstitute and they never come back to normal. Anti-CD20 ablates peripheral B-cells and does not target CD8+ cells. In rheumatoid arthritis patients rituximab treatment does not alter CD4+, CD8+ or T-regulatory cells numbers. Some would argue that the response of MS to anti-CD20 would support the Pender hypothesis as it is working via EBV infected B-cells. This is a possibility, but we have no clear evidence that rituximab works on B cells within the central nervous system. Daclizumab increases natural killer cells (NK cells) and reduce T-regulatory and CD8+ cells; the effectiveness of daclizumab in MS would argue against the Pender hypothesis unless the NK cells are substituting for the CD8+ effector cells and killing the EBV-infected B cells within the central nervous system."

"As you can see immunology is very complex and can be very confusing; it is not helped by the difficult reproducing results across labs. What is evident that if you do come up with a causation hypothesis it needs to explain everything and I mean everything, the epidemiology, the clinical phenotypes, pathology and responses to treatment to mention a few. There can be no facts, little of big, left untouched. To quote Thomas Huxley 'the great tragedy of Science: the slaying of a beautiful hypothesis by an ugly fact.'"








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