TABLE 1.
Summary of immunomodulatory therapies used to treat chronic neurodegenerative diseases in patients and in animal models
| Immunomodulatory therapies | ||||
|---|---|---|---|---|
| Model/condition | Intervention | Outcome | Study | |
| Chronic diseases | ||||
| ALS | Human with ALS | GA vaccination: 11 patients treated everyday. Ten patients treated every 2 weeks. | ‐Patients treated everyday shift to a Th2 cytokine production pattern. Meanwhile, patients treated every 2 weeks show a Th1 cytokine profile | Mosley (2007)33 |
| Human with ALS | GA vaccination: 184 patients were treated with 40‐mg GA daily for 52 weeks. |
‐GA was well tolerated. ‐No differences between treated and control groups were observed. |
Meininger (2009)34 | |
| AD | APP‐Tg mice (AD model) | Nasal vaccination: GA + IVX‐908 (25‐µg GA plus 1‐µg IVX‐908) was given on Days 1 and 5 the first week, and 25‐µg GA alone was given on Days 2 and 4. Then, mice received weekly boosts for 6 weeks or starting at age 5 months until age 14 months. |
‐Potently decreases Aβ plaques. ‐Activation of microglia. ‐Reduction in TGF‐β expression. |
Frenkel (2005)35 |
| AD double‐transgenic (APP/PS1) mice (Tg‐AD) and Tg‐AD chimeric mice | GA vaccination: five s.c. injection with a total of 100 µg of high‐molecular‐weight GA dissolved in 200 µl of PBS, twice during the first week and once per week thereafter. |
Neuroprotection and neurogenesis: ‐Recruitment of bone marrow‐derived dendritic cells. ‐Decrease in the number of Aβ‐immunoreactive plaques. ‐Induction of neurogenesis (increase). ‐Attenuated cognitive decline. |
Butovsky (2006)36; Butovsky (2007)37 |
|
| Double‐transgenic APPSWE/PS1∆E9 mice (AD‐tg) | GA immunization: s.c. injections twice a week for the first 2 weeks and then once a week for a total of 3 months (100 µg in 1 × PBS). |
EGR1 as a potential mediator for GA‐induced neuroprotection: ‐Nuclear EGR1 protein levels were elevated in the hippocampus. ‐Negative correlation between EGR1 nuclear protein and Aβ plaque burden in the hippocampus. |
Bakalash (2011)38 | |
| Double‐ transgenic APPSWE/PS1∆E9 mice (AD‐tg) |
GA immunization: weekly s.c. injections (100‐μg GA in PBS). Adoptive transfer: monthly i.v. injection CD115+‐MoBM (5–6 × 106 cells/mouse). |
Retention of cognitive function, synaptic preservation, plaque removal, restriction of astrogliosis, and modulation of the immune molecular milieu: ‐Enhancement of the recruitment of MΦBM, at least partially, due to the significant increase in brain levels of MCP1. ‐Improvement in spatial learning and memory. ‐Elevated levels of the IL‐10 and MMP‐9 (both concentrated around amyloid‐b plaques). ‐Increased ability of MΦBM to phagocytize amyloid‐β1–42 fibrils (high co‐expression of the scavenger receptors CD36 and SCARA1). Activated MΦBM can reduce oligomers and fibrils, and protect synaptic integrity and neuronal structure. |
Koronyo (2015)39; Li (2020)40 |
|
| APPSWE/PS1∆E9‐transgenic mice (AD‐tg) |
GA immunization: weekly s.c. injections (100 μg GA in PBS). Adoptive transfer: monthly i.v. injection CD115+‐MoBM (5–6 × 106 cells/mouse). |
GA induces the recruitment of peripheral phagocytic cells to amyloid plaques by OPN: ‐Upregulation of OPN expression in MΦBM ‐OPN promotes a highly phagocytic phenotype (increased uptake of Aβ fibrils and associated sequestering receptors), anti‐inflammatory (altered cell morphology, decreased iNOS, induction of IL‐10 and Aβ degrading enzyme MMP‐9), and pro‐scarring. |
Rentsendrj (2018)41 | |
| Patients with mild to moderate AD |
Aβ immunization: I.M. AN1792 225ug plus the adjuvant QS‐21.5 µg. As a single 0.5‐ml IM injection on day 0 and at Months 1, 3, 6, 9, and 12. |
‐Improved memory ‐CSF tau was decreased ‐Meningoencephalitis. |
Gilman (2005)42 | |
| Patients of mild‐to‐moderate AD |
Aβ immunization: UB‐311 (UBITh®). Three doses intramuscular route (300 mg/dose) at Weeks 0, 4, and 12. |
‐Generation of antibodies able to bind both Aβ1–42 monomers and oligomers. ‐It induced cognitive improvements in patients with early‐stage Alzheimer's dementia. |
Wang (2017)43 | |
| PD | SJK mice. MPTP PD model | Adoptive transfer of Cop‐1 immune cells |
‐Higher numbers of surviving SNpc dopaminergic neurons. ‐Neuroprotection mediated by Th2 cells. |
Benner (2004)44 |
| C57BL/6J mice. MPTP PD model | GA administration, 3.5 mg/kg (7 days/week) |
‐Motor recovery (grip strength and gait parameters). ‐Restoration of the nigrostriatal pathway |
Churchill (2019)45 | |