Can the Pender Hypothesis explain the mode of action of the emerging DMTs? #MSResearch #MSBlog
"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.'"
|CD8+ T cells|
Epub: Pender et al. Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis. Mult Scler. 2014 May 19.
BACKGROUND: MSers have a deficiency of circulating CD8+ T cells, which might impair control of Epstein-Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells.
OBJECTIVE: Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course.
METHODS: We used flow cytometry to analyze the memory phenotypes of T cells in the blood of 118 MSers and 112 healthy subjects.
RESULTS: MSers had a decreased frequency of EM (CD45RA-CD62L-) and EMRA (CD45RA+CD62L-) CD8+ T cells, which was present at the onset of disease and persisted throughout the clinical course. The frequencies of CD4+ EM and EMRA T cells were normal.
CONCLUSION: Deficiency of effector memory CD8+ T cells is an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV.