Immunological, oxidative, and structural factors and their responses to regulatory t lymphocyte therapy in amyotrophic lateral sclerosis

Abstract

Aim: Amyotrophic lateral sclerosis (ALS) is a systemic disease in which multiple dysfunctional pathways converge, culminating as this devastating disease. Immunological, oxidative, and structural analytes in cross-sectional and longitudinal patient sera samples were investigated and evaluated for their responses following autologous regulatory T lymphocyte (Treg)/IL-2 therapy. Methods: This retrospective cohort study was conducted at Houston Methodist Hospital and Massachusetts General Hospital in adults with sporadic ALS. Cross-sectional and longitudinal sera levels for each of the immunological (CCL2, IL-18), oxidative (4-HNE, MDA), and structural analytes (Nf-L, pNf-H) were assayed by ELISAs, and correlated with disease progression and clinical outcomes. Results: CCL2 and IL-18 levels were elevated in patients, especially rapidly progressing patients. 4-HNE was elevated in a subset of patients, whereas MDA was elevated in cross-sectional and longitudinally studied subjects. Nf-L was elevated in rapidly progressing patients, whereas pNf-H was decreased in these same patients. In the eleven patients assayed longitudinally, only three patients had increased levels of Nf-L or pNf-H; no patient had increased levels of both neurofilaments. Treg/IL-2 therapy suppressed levels of CCL2, IL-18, and 4-HNE. Conclusions: In these cohorts of patients with sporadic ALS, CCL2, IL-18, and 4-HNE accurately reflected disease progression on and off therapy; MDA was elevated but did not respond to therapy. The cross-sectional and longitudinal data were complementary. Nf-L and pNf-H did not reliably and consistently reflect disease progression. Immunological and oxidative pathological factors accurately reflected therapeutic responses in these pathways and are candidates to target clinical trial endpoints.