Monday, 1 February 2016

T reg function increases after alemtuzumab. Is this the reason for efficacy?

De Mercanti S, Rolla S, Cucci A, Bardina V, Cocco E, Vladic A, Soldo-Butkovic S, Habek M, Adamec I, Horakova D, Annovazzi P, Novelli F, Durelli L, Clerico M.Alemtuzumab long-term immunologic effect: Treg suppressor function increases up to 24 months.Neurol Neuroimmunol Neuroinflamm. 2016 Jan 21;3(1):e194.
OBJECTIVE:To analyze changes in T-helper (Th) subsets, T-regulatory (Treg) cell percentages and function, and mRNA levels of immunologically relevant molecules during a 24-month follow-up after alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS:Multicenter follow-up of 29 alemtuzumab-treated patients with RRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II trials. Peripheral blood (PB) samples were obtained at months 0, 6, 12, 18, and 24. We evaluated (1) mRNA levels of 26 immunologic molecules (cytokines, chemokines, chemokine receptors, and transcriptional factors); (2) Th1, Th17, and Treg cell percentages; and (3) myelin basic protein (MBP)-specific Treg suppressor activity.
RESULTS:We observed 12 relapses in 9 patients. mRNA levels of the anti-inflammatory cytokines interleukin (IL)-10, IL-27, and transforming growth factor-β persistently increased whereas those of proinflammatory molecules related to the Th1 or Th17 subsets persistently decreased after alemtuzumab administration throughout the follow-up period. PB CD4+ cell percentage remained significantly lower than baseline while that of Th1 and Th17 cells did not significantly change. A significant increase in Treg cell percentage was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells.
CONCLUSIONS: The long-lasting therapeutic benefit of alemtuzumab in RRMS may involve a shift in the cytokine balance towards inhibition of inflammation associated with a reconstitution of the PB CD4+ T-cell subsets that includes expansion of Treg cells with increased suppressive function.

It is a central question what causes MS to disappear but also what causes the autoimmunities. It is reported that there is an increase in T regs and this has been reported before. However, if you deal  in percentages you can be misguided. 

If you start with 50% of one and 50% of the other but end up with 60% of one and 40% of the other. Is it that the number of one has gone up 10% or the other has gone down 10%. So you have to deal with absolute numbers. 

So it has been said say that there are 4 times the number of T regs to CD4 cells so 20% CD4 and 80% T reg say compared to 95% CD4 and 5% T reg before treatment (I am making hypothetical numbers here). So at 1000 cells per microlitre before treatments there are 50 cells. But if the CD4 goes to 10 per microlitre after then there are 40 T regs so no change. But I think the realitity is their absolute numbers drop by thousands and relative to the absolute B cells whose numbers goes up by 150% the Treg to B cell ratio plummets.

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