| Autor: |
Faridar, Alireza, Eid, Abdulmunaim M, Thome, Aaron D, Zhao, Weihua, Beers, David, Pascual, Belen, Nakawah, Mohammad O, Roman, Gustavo C, Davis, Charles S., Grundman, Michael, Masdeu, Joseph C., Appel, Stanley H |
| Zdroj: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2023 Supplement 21, Vol. 19 Issue 21, p1-2, 2p |
| Abstrakt: |
Background: Regulatory T cells (Tregs) play a neuroprotective role by suppressing inflammation. We previously documented that Treg immunomodulatory mechanisms are compromised in people with Alzheimer's disease (AD) and are associated with activation of peripheral monocytes and upregulation of inflammatory mediators. In this original study, we investigated the feasibility and potential impact of low‐dose IL‐2 immunotherapy on restoring Tregs and modifying inflammation in an AD clinical setting. Method: Eight patients with mild‐to‐moderate AD dementia (MMSE:12‐25) were enrolled in a phase 1, open‐label, feasibility study of IL‐2 treatment. The presence of elevated brain amyloid, as demonstrated by either CSF or amyloid positron emission tomography (PET) scan, was confirmed in all participants. Enrolled individuals received monthly five‐day‐courses of subcutaneous IL‐2 (1 million units/day) for four months and were followed for an additional two months post‐treatment. Treg immunophenotype and functional analysis were obtained serially at screening, day 1 (before IL‐2 treatment) and day 8 (three days after the fifth dose) of each treatment cycle during therapy, and then at weeks 17 and 24. Two‐sided paired t‐tests were used to assess the statistical significance of changes in each analyte or clinical outcome at each timepoint. Result: Overall, low‐dose IL‐2 immunotherapy was well‐tolerated and all patients received the treatment as planned. The number of CD4+CD25highFoxP3+ Tregs increased two to three‐fold after each IL‐2 treatment cycle (p<0.01) and returned to baseline before the next cycle. Treg suppressive function on responder T cell (Tresp) proliferation also progressively increased through the four‐month IL‐2 treatment phase (p<0.01). IL‐2 treatment down‐regulated IL‐1β, IL‐6 and TNFa transcripts in circulating monocytes and modulated plasma pro‐inflammatory chemokines and cytokines (IL‐15, CCL2, CCL4, CCL11 and FLT3LG; p<0.01). Clinical benefits (mean change ± SE) were observed on the Mini‐Mental State Exam (+2.25 ± 0.59, p = 0.007) and the Clinical Dementia Rating Sum of Boxes (‐0.56 ± 0.24; p = 0.051). Conclusion: IL‐2 immunotherapy restored peripheral Treg function and ameliorated systemic pro‐inflammatory mediators in AD patients. The results of this study warrant conducting a well‐controlled clinical study to further evaluate the safety and efficacy of low‐dose IL‐2 as a potential treatment for AD. [ABSTRACT FROM AUTHOR] |
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