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In Vitro Modeling of Natural Killer Cell Cytotoxicity to Inform Personalized ALS Therapeutics
Benjamin J Murdock1, Jihyun Park1, Dae-Gyu Jang1
1Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Objective:
Natural killer (NK) cells might contribute to motor neuron death in amyotrophic lateral sclerosis (ALS) through direct cytotoxicity, a process that could be inhibited with the FDA-approved JAK/STAT pathway inhibitor, tofacitinib. This study aimed to verify that tofacitinib can suppress NK cell cytotoxicity, investigate if immune cell profiles can predict responsiveness to tofacitinib, and assess the role of NK cell cytotoxicity in ALS progression.
Methods:
Primary NK cells were isolated from peripheral blood samples of ALS participants and healthy controls. NK cells were then co-cultured with target cancer cells, with or without tofacitinib, to assess their cytotoxic activity. Flow cytometry was used to generate immune profiles for each participant, based on 154 immune markers, to explore correlations with NK cell cytotoxicity and response to tofacitinib. The potential association between NK cell cytotoxicity and disease severity, as measured by the revised ALS Functional Rating Scale, was also assessed. All analyses were stratified by age and sex.
Results:
Tofacitinib effectively reduced the cytotoxicity of primary NK cells isolated from the blood of ALS participants (n = 80) and healthy controls (n = 71), with immune cell profiles correlating with the response to tofacitinib. However, NK cell cytotoxicity was lower in ALS participants compared to healthy controls and showed no association with ALS progression.
Interpretation:
These findings confirm that tofacitinib suppresses NK cell cytotoxicity, and that immune profiling may help identify treatment responder groups. However, further research is needed to fully understand the role and timing of NK cell activity in ALS pathogenesis.
Insights
Tofacitinib effectively suppresses natural killer (NK) cell cytotoxicity in amyotrophic lateral sclerosis (ALS) patients and controls. Immune profiling may identify patients who will respond to this treatment for ALS.
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Natural killer (NK) cells may cause motor neuron death in amyotrophic lateral sclerosis (ALS).
- Tofacitinib, an FDA-approved JAK/STAT inhibitor, may reduce NK cell cytotoxicity.
- Understanding NK cell involvement in ALS is crucial for developing targeted therapies.
Purpose of the Study:
- To confirm tofacitinib's efficacy in suppressing NK cell cytotoxicity in ALS.
- To determine if immune cell profiles can predict response to tofacitinib.
- To assess the correlation between NK cell cytotoxicity and ALS progression.
Main Methods:
- Primary NK cells were isolated from ALS patients and healthy controls.
- NK cell cytotoxicity was measured via co-culture assays with and without tofacitinib.
- Immune cell profiles were generated using flow cytometry (154 markers) and correlated with NK cell activity and treatment response.
Main Results:
- Tofacitinib significantly reduced NK cell cytotoxicity in both ALS participants and healthy controls.
- Immune cell profiles correlated with tofacitinib response.
- NK cell cytotoxicity was lower in ALS patients than controls and did not correlate with disease progression.
Conclusions:
- Tofacitinib effectively suppresses NK cell cytotoxicity, supporting its potential therapeutic role in ALS.
- Immune profiling shows promise for identifying patient subgroups likely to benefit from tofacitinib.
- Further investigation is required to elucidate the precise role and temporal contribution of NK cells in ALS pathogenesis.
