Naïve T-cell homeostasis differs between patients with two subtypes of multiple sclerosis
Author(s): ,
D. Haegert
Pathology, McGill University
Y. Lapierre
Neurology, Montreal Neurological Institute, McGill University
J. Antel
Neuroimmunology Unit, Department of Neurology, McGill University, Montreal, QC, Canada
A. Bar-Or
Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
L. Fitz-Gerald
Pathology, McGill University
ECTRIMS Online Library. Haegert D. Oct 12, 2018; 228917; P1076
David Haegert
David Haegert
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Abstract: P1076

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Immunology

Background: T-cell homeostasis balances thymic output, homeostatic proliferation and T-cell loss. Altered T-cell homeostasis may predispose to autoimmune disease. Some report reduced thymic output in patients with multiple sclerosis (MS), but evidence of altered homeostatic proliferation is controversial and no relevant data are available on T-cell loss. Here, we questioned whether patients with relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) show differences in naïve CD4 T-cell homeostasis.
Methods: We used mathematical modeling, based partly on quantitative T-cell receptor excision circle (TREC) data, to compare daily thymic export (σ) and proliferation (p) and the rate of daily T-cell loss (d) in healthy controls (HCs) (n=12), and patients with RRMS (n=22) and PPMS (n=17), with mean ages of 45, 46 and 48. We derived d from one mathematical model of σ: σ=yNC÷Δ(c-C); y is the T-cell fraction expressing Ki-67, N is the number of T-cells/ml of peripheral blood, Δ is the duration of Ki-67 expression, c is the average TREC content of CD4 recent thymic emigrants, C is naïve CD4 TREC content, and d=(σc/C-dN/dt) ÷N. We incorporated estimates of d into a second mathematical model, and then calculated daily σ and p: σ=NdC/c and p=σ(c-C)/C.
Results: Mean naïve CD4 T-cell numbers did not differ between HCs and patients with RRMS and PPMS (4.6, 3.9 and 4.4 X 105 T-cells/ml) and were constant with age (r=-0.26, -0.02 and 0.29). Daily p exceeded daily σ in HCs (medians, 136.1 vs. 9.6 T-cells/ml, P=0.002), and in patients with RRMS (93.2 vs. 2.5 T-cells/ml, P< 0.0001) and PPMS (167.3 vs. 1.65 T-cells/ml,
P=0.008). Median daily p/ml and d did not differ between the groups. Daily σ/ml was lower in patients with PPMS than in HCs (P=0.01). Daily σ/ml (r =-0.48, P=0.044), daily p/ml
(r =-0.487, P=0.047) and d (r =-0.565, P=0.024) decreased with age only in patients with RRMS.
Conclusions: Proliferation was the main contributor to naïve CD4 T-cells in all groups. Patients with PPMS had reduced daily thymic export but the magnitude of daily proliferation was sufficient to maintain normal naïve CD4 T-cell numbers. In patients with RRMS, the findings suggest that reduced T-cell loss with age maintained naïve CD4 T-cell numbers in spite of declining thymic export and proliferation. In summary, the contributions to naïve T-cell homeostasis differ not only between HCs and the patient groups but also between the patient groups.
Disclosure: This work was supported in part by a grant from the Multiple Sclerosis Society of Canada.
Dr. David Haegert has received grants from Novartis and Sanofi-Genzyme.
Dr. Y. Lapierre has received consulting fees and serves on advisory boards from Biogen Idec, Bayer, EMD Serono, Genzyme, Novartis, Teva.
Dr, Jack Antel serves on advisory/safety monitoring boards for Novartis, Sanofi-Genzyme, Biogen Idec, EMD Serono and Medday Pharmaceuticals and is editor of the Americas, Multiple Sclerosis Journal.
Amit Bar-Or participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from: Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, MAPI, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme.
Leslie Fitz-Gerald has no disclosures.

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