Low-dose interleukin-2 in patients with mild to moderate Alzheimer’s disease: a randomized clinical trial
Abstract Background We previously documented that regulatory T cells (Tregs) immunomodulatory mechanisms are compromised in Alzheimer’s disease (AD), shifting the immune system toward a pro-inflammatory response. However, Tregs are a potentially restorable therapeutic target in AD. In this study, we...
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BMC
2025-07-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01791-x |
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| author | Alireza Faridar Nazaret Gamez Daling Li Yanling Wang Reena Boradia Aaron D. Thome Weihua Zhao David R. Beers Jason R. Thonhoff Mohammad O. Nakawah Gustavo C. Román John J. Volpi Jon B. Toledo Michael George Charles S. Davis Belen Pascual Michael Grundman Joseph C. Masdeu Stanley H. Appel |
| author_facet | Alireza Faridar Nazaret Gamez Daling Li Yanling Wang Reena Boradia Aaron D. Thome Weihua Zhao David R. Beers Jason R. Thonhoff Mohammad O. Nakawah Gustavo C. Román John J. Volpi Jon B. Toledo Michael George Charles S. Davis Belen Pascual Michael Grundman Joseph C. Masdeu Stanley H. Appel |
| author_sort | Alireza Faridar |
| collection | DOAJ |
| description | Abstract Background We previously documented that regulatory T cells (Tregs) immunomodulatory mechanisms are compromised in Alzheimer’s disease (AD), shifting the immune system toward a pro-inflammatory response. However, Tregs are a potentially restorable therapeutic target in AD. In this study, we evaluated the safety and efficacy of two dosing frequencies of low-dose Interleukin-2 (IL-2) in expanding Tregs to modify disease progression in AD individuals. Methods In this phase 2a, randomized, double-blind, placebo-controlled study, 38 participants were assigned to receive subcutaneous IL-2 (10^6 IU/day) for five days, administered either every 4 weeks (IL-2 q4wks) or every 2 weeks (IL-2 q2wks), versus placebo, for 21 weeks, followed by 9 weeks of observation. The primary endpoints were the incidence and severity of adverse events. For the secondary endpoints, changes in Treg numbers and suppressive functions were evaluated. Exploratory endpoints included changes in plasma inflammatory mediators, CSF AD-related biomarkers, and clinical scales. Results Of the 38 participants, 9 received IL-2 q4wks, 10 received IL-2 q2wks, and 19 received placebo. All participants completed the trial with no serious adverse events or deaths. Both IL-2 dosing regimens increased Treg numbers and suppressive function, but IL-2 q4wks treatment exhibited superiority in enhancing Treg percentage and Foxp3 mean fluorescent intensity. In longitudinal analysis of 45 inflammatory mediators, IL-2 q4wks administration demonstrated greater efficacy in alleviating the plasma inflammatory mediators CCL2, CCL11, and IL-15, while enhancing IL-4 and CCL13 levels. A significant improvement in CSF Aβ42 levels (p = 0.045 vs. placebo) on Day 148 was observed following IL-2 q4wks administration, compared to placebo. While CSF NfL increased by 217 pg/ml in placebo recipients, it remained stable in the IL-2 q4wks group (p = 0.060, IL-2 q4wks vs. placebo). The adjusted mean change from baseline in the ADAS-cog score at week 22 indicated a trend toward slower clinical progression in IL-2 q4wks recipients compared to placebo (p = 0.061). Conclusions The IL-2 immunotherapeutic strategy was safe and well-tolerated. IL-2 q4wks effectively expanded Treg populations, leading to modification in inflammatory mediators and CSF Aβ42 levels, while also showing promising trends on clinical scales. These findings provide a foundation for further investigation of low-dose IL-2 as a potential treatment for Alzheimer’s Disease. Trial registration ClinicalTrials.gov Identifier: NCT06096090, Registration Date: 10-17-2023. |
| format | Article |
| id | doaj-art-2c3d13922d3d4925b5fd96b57fc5aece |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-2c3d13922d3d4925b5fd96b57fc5aece2025-08-20T03:45:27ZengBMCAlzheimer’s Research & Therapy1758-91932025-07-0117111410.1186/s13195-025-01791-xLow-dose interleukin-2 in patients with mild to moderate Alzheimer’s disease: a randomized clinical trialAlireza Faridar0Nazaret Gamez1Daling Li2Yanling Wang3Reena Boradia4Aaron D. Thome5Weihua Zhao6David R. Beers7Jason R. Thonhoff8Mohammad O. Nakawah9Gustavo C. Román10John J. Volpi11Jon B. Toledo12Michael George13Charles S. Davis14Belen Pascual15Michael Grundman16Joseph C. Masdeu17Stanley H. Appel18Stanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteDepartment of Pharmacy, Houston Methodist HospitalCSD Biostatistics, Inc.Stanley H. Appel Department of Neurology, Houston Methodist Research InstituteGlobal R&D Partners, LLCStanley H. Appel Department of Neurology, Houston Methodist Research InstituteStanley H. Appel Department of Neurology, Houston Methodist Research InstituteAbstract Background We previously documented that regulatory T cells (Tregs) immunomodulatory mechanisms are compromised in Alzheimer’s disease (AD), shifting the immune system toward a pro-inflammatory response. However, Tregs are a potentially restorable therapeutic target in AD. In this study, we evaluated the safety and efficacy of two dosing frequencies of low-dose Interleukin-2 (IL-2) in expanding Tregs to modify disease progression in AD individuals. Methods In this phase 2a, randomized, double-blind, placebo-controlled study, 38 participants were assigned to receive subcutaneous IL-2 (10^6 IU/day) for five days, administered either every 4 weeks (IL-2 q4wks) or every 2 weeks (IL-2 q2wks), versus placebo, for 21 weeks, followed by 9 weeks of observation. The primary endpoints were the incidence and severity of adverse events. For the secondary endpoints, changes in Treg numbers and suppressive functions were evaluated. Exploratory endpoints included changes in plasma inflammatory mediators, CSF AD-related biomarkers, and clinical scales. Results Of the 38 participants, 9 received IL-2 q4wks, 10 received IL-2 q2wks, and 19 received placebo. All participants completed the trial with no serious adverse events or deaths. Both IL-2 dosing regimens increased Treg numbers and suppressive function, but IL-2 q4wks treatment exhibited superiority in enhancing Treg percentage and Foxp3 mean fluorescent intensity. In longitudinal analysis of 45 inflammatory mediators, IL-2 q4wks administration demonstrated greater efficacy in alleviating the plasma inflammatory mediators CCL2, CCL11, and IL-15, while enhancing IL-4 and CCL13 levels. A significant improvement in CSF Aβ42 levels (p = 0.045 vs. placebo) on Day 148 was observed following IL-2 q4wks administration, compared to placebo. While CSF NfL increased by 217 pg/ml in placebo recipients, it remained stable in the IL-2 q4wks group (p = 0.060, IL-2 q4wks vs. placebo). The adjusted mean change from baseline in the ADAS-cog score at week 22 indicated a trend toward slower clinical progression in IL-2 q4wks recipients compared to placebo (p = 0.061). Conclusions The IL-2 immunotherapeutic strategy was safe and well-tolerated. IL-2 q4wks effectively expanded Treg populations, leading to modification in inflammatory mediators and CSF Aβ42 levels, while also showing promising trends on clinical scales. These findings provide a foundation for further investigation of low-dose IL-2 as a potential treatment for Alzheimer’s Disease. Trial registration ClinicalTrials.gov Identifier: NCT06096090, Registration Date: 10-17-2023.https://doi.org/10.1186/s13195-025-01791-xAlzheimer’s DiseaseInflammationImmunotherapyClinical trialTregImmune system |
| spellingShingle | Alireza Faridar Nazaret Gamez Daling Li Yanling Wang Reena Boradia Aaron D. Thome Weihua Zhao David R. Beers Jason R. Thonhoff Mohammad O. Nakawah Gustavo C. Román John J. Volpi Jon B. Toledo Michael George Charles S. Davis Belen Pascual Michael Grundman Joseph C. Masdeu Stanley H. Appel Low-dose interleukin-2 in patients with mild to moderate Alzheimer’s disease: a randomized clinical trial Alzheimer’s Research & Therapy Alzheimer’s Disease Inflammation Immunotherapy Clinical trial Treg Immune system |
| title | Low-dose interleukin-2 in patients with mild to moderate Alzheimer’s disease: a randomized clinical trial |
| title_full | Low-dose interleukin-2 in patients with mild to moderate Alzheimer’s disease: a randomized clinical trial |
| title_fullStr | Low-dose interleukin-2 in patients with mild to moderate Alzheimer’s disease: a randomized clinical trial |
| title_full_unstemmed | Low-dose interleukin-2 in patients with mild to moderate Alzheimer’s disease: a randomized clinical trial |
| title_short | Low-dose interleukin-2 in patients with mild to moderate Alzheimer’s disease: a randomized clinical trial |
| title_sort | low dose interleukin 2 in patients with mild to moderate alzheimer s disease a randomized clinical trial |
| topic | Alzheimer’s Disease Inflammation Immunotherapy Clinical trial Treg Immune system |
| url | https://doi.org/10.1186/s13195-025-01791-x |
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