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Review
. 2022 Mar 31:13:854390.
doi: 10.3389/fneur.2022.854390. eCollection 2022.

Efficacy of Disease Modifying Therapies in Progressive MS and How Immune Senescence May Explain Their Failure

Navid Manouchehri  1 , Victor H Salinas  1 , Negar Rabi Yeganeh  2 , David Pitt  3 , Rehana Z Hussain  1 , Olaf Stuve  1   4
Affiliations
Review

Efficacy of Disease Modifying Therapies in Progressive MS and How Immune Senescence May Explain Their Failure

Navid Manouchehri et al. Front Neurol. .

Abstract

The advent of disease modifying therapies (DMT) in the past two decades has been the cornerstone of successful clinical management of multiple sclerosis (MS). Despite the great strides made in reducing the relapse frequency and occurrence of new signal changes on neuroimaging in patients with relapsing remitting MS (RRMS) by approved DMT, it has been challenging to demonstrate their effectiveness in non-active secondary progressive MS (SPMS) and primary progressive MS (PPMS) disease phenotypes. The dichotomy of DMT effectiveness between RRMS and progressive MS informs on distinct pathogeneses of the different MS phenotypes. Conversely, factors that render patients with progressive MS resistant to therapy are not understood. Thus far, age has emerged as the main correlate of the transition from RRMS to SPMS. Whether it is aging and age-related factors or the underlying immune senescence that qualitatively alter immune responses as the disease transitions to SPMS, that diminish DMT effectiveness, or both, is currently not known. Here, we will discuss the role of immune senescence on different arms of the immune system, and how it may explain relative DMT resistance.

Keywords: adaptive immunity; disease modifying therapies; immunosenescence; innate immunity; multiple sclerosis; progressive multiple sclerosis.

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Conflict of interest statement

OS serves on the editorial boards of Therapeutic Advances in Neurological Disorders, has served on data monitoring committees for Genentech-Roche, Pfizer, Novartis, and TG Therapeutics without monetary compensation, has advised EMD Serono, Celgene, Genentech, Genzyme, TG Therapeutics, and VYNE, receives grant support from EMD Serono and Exalys, was a 2021 recipient of a Grant for Multiple Sclerosis Innovation (GMSI), Merck KGaA, and was funded by a Merit Review grant (federal award document number (FAIN) BX005664-01 from the United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Development). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Immune senescence contribution to the lack of effectiveness of disease-modifying therapies (DMT) in progressive multiple sclerosis (MS). Senescent T and B immune cell phenotypes become more predominant as the immune system ages. Age-dependent deterioration of tissues including central nervous system (CNS) glial cells increases. Bone marrow-derived myeloid cells are activated and compound adaptive immune senescence. Dysregulated myeloid cells prospectively accumulate within the CNS milieu. Inflammatory MS, characterized by active relapses, transitions to non-active progressive MS, which is resistant to DMT.
See this image and copyright information in PMC

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