Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2

Abstract

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with ALS. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis (IMODALS) was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for five days every twenty-eight days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-Treg-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient Treg-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

“…It was also observed that pretreatment expression levels of two genes correlated with the magnitude of drug responsiveness, allowing the development of a two-biomarker-based regression model to predict the T reg cell response to low-dose IL-2. These findings and the application of this embedded experimental medicine approach could be particularly relevant for future application of precision medicine approaches in ALS clinical trial design 198 .…”

“…The trial met its primary end point, with both doses of aldesleukin resulting in a significant, dose-dependent, increase in T reg cell numbers, compared with placebo. This increase was accompanied by enhancement of T reg cell suppressive function, suggesting an improved ability to control the inflammatory mechanisms that contribute to neuronal injury in ALS 198 . There was also a significant, dose-dependent drop in CCL2 (MCP-1) levels, an inflammatory biomarker which is frequently elevated in patients with ALS 197 .…”

“…There was also a significant, dose-dependent drop in CCL2 (MCP-1) levels, an inflammatory biomarker which is frequently elevated in patients with ALS 197 . The peripheral blood mononuclear cell (PBMC) transcriptome was also analysed at different time points 198 . Participants were classified into low, moderate and high responders based on the magnitude of the upregulation in the T reg cell count.…”

“…The value of undertaking transcriptomics analysis of peripheral blood mononuclear cells to detect gene expression biomarkers of good and poor responsiveness to an experimental compound, as well as a panel predicting the level of response, has recently been shown in a phase II trial of low-dose IL-2 as an anti-inflammatory agent for the treatment of ALS 198 .…”

Interleukin-2 expands neuroprotective regulatory T cells in Parkinson’s disease

“…Therapies such as low-dose IL-2 or IL-2/anti-IL-2 antibody complexes have been advanced in the clinic to preferentially expand Treg populations as a treatment for chronic inflammatory autoimmune diseases [ 43 ]. Some neuroprotective effects of low-dose IL-2 treatment have been found in AD mice [ 44 ] and in amyotrophic lateral sclerosis (ALS) patients [ 45 ]. Nevertheless, no study thus far has investigated the effects of low-dose IL-2 in PD or pre-clinical PD models.…”