Alemtuzumab in Multiple Sclerosis: Short- and Long-Term Effects of Immunodepletion on the Peripheral Treg Compartment. Haas J, Würthwein C, Korporal-Kuhnke M, Viehoever A, Jarius S, Ruck T, Pfeuffer S, Meuth SG, Wildemann B. Front Immunol. 2019 Jun 4;10:1204
Treatment with alemtuzumab is followed by an early increase in Treg frequencies. Whether naïve and memory subsets are differentially affected and how depletion influences dysfunctional MS-Treg is unclear. In this study, we analyzed the effect of alemtuzumab on regulatory T-cells (Treg) in patients with multiple sclerosis (MS)….(SO Nothing NEW then) For this purpose 182 blood samples from 25 MS patients were taken shortly before treatment and serially for up to 24 months after two alemtuzumab cycles. We studied Treg by flow cytometry (quantitation, phenotypical characterization), real-time polymerase chain reaction (T-cell receptor (TCR) excision circles [TREC] content), CDR3-spectratyping (clonal distribution), and proliferation assays (suppressive function). CD52-mediated cytolysis of Treg and conventional T-cells was determined by a complement-dependent cytolysis assay. Our studies revealed that 1 week post-alemtuzumab, Treg were depicted at constant frequencies among CD4+ T-cells. In contrast, Treg frequencies were massively increased at month 1 . Post-depletional Treg exhibited a CD45RO+memory phenotype, a skewed TCR repertoire, and contained minimum TREC numbers. Naïve Treg, thymic markers, and TCR-variability commenced to rise after 6 months but did not attain baseline levels In vitro, Treg exhibited higher susceptibility to lysis than Tcon. Treg suppressive function constantly increased within 1 year when co-cultured with syngeneic T-cells, but remained stable against allogeneic T-cells from normal donors.
Our findings suggest that (1) Treg are not spared from alemtuzumab-mediated depletion (AGREE) and thymopoiesis does not considerably contribute to long-term recovery, (2) either homeostatic proliferation and/or conversion from residual Tcon contributes to Treg expansion during the early post-treatment phase (3) the enhanced inhibitory effect of Treg following alemtuzumab is due to altered composition and reactivity of post-depletional Tcon. (Yep so what’s new?)
They say “Treatment with alemtuzumab is followed by an early increase in Treg frequencies”…..NOT TRUE I say….There is a decrease in absolute numbers. They EMA label is wrong because they say there is a T reg increase but that is based on the percentages not the abolute numbers that go down. At least based on the information I had.
So what.. I hear you say. Why is it important?
Well the increase is suppposed to make you think this why alemtuzumab stops MS because it increases T regulation…but it they go down you think this is why is causes autoimmune problems.
Therefore, there are a number of corporate abstracts trying to imply that the effects on T regs is unrelated to autoimmune problems.
However, we have this new post and they look at T regs and they look at 1 week after treatment as well as one month and one would conclude that T reg numbers go up…
They say “Shortly after immune cell depletion by alemtuzumab (week 1) a concomitant reduction in numbers of circulating CD4+ T cells and Treg (2 ± 2/μl [Treg cell count]), was observable resulting in constant relative proportions of Treg (3.5 ± 2.4% [of CD4+ T cells]) among circulating CD4+ T-cells compared with baseline (19 ± 6/μl, 2.7 ± 1.5%; p = 0.008 and 0.285). In contrast, Treg numbers had recovered to 11 ± 5/μl at 1 months, translating into a massive increase in percentages among CD4+ T cells (18.1 ± 9.3%; p = 0.022 and < 0.0001)”……So there is an increase after the decrease. Should I apologise?
However….there still about a 50% depletion from baseline so there is not an increase but a relative decrease
“Treg expansion then decreased, but proportions remained consistently higher at baseline throughout year 1 and year 2” ….So there you go the reason why MS is stopped