Restoring regulatory T-cell dysfunction in Alzheimer’s disease through ex vivo expansion

Abstract

Inflammation is a significant component of Alzheimer disease pathology. While neuroprotective microglia are important for containment/clearance of Amyloid plaques and maintaining neuronal survival, Alzheimer inflammatory microglia may play a detrimental role by eliciting tau pathogenesis and accelerating neurotoxicity. Regulatory T cells have been shown to suppress microglia-mediated inflammation. However, the role of regulatory T cells in ameliorating the proinflammatory immune response in Alzheimer disease requires further investigation. Forty-six patients with Alzheimer disease, 42 with mild cognitive impairment and 41 healthy controls were studied. The phenotypes of peripheral regulatory T cells were assessed with multicolor flow cytometry. Regulatory T cells were co-cultured with responder T cells and proliferation was determined by 3H-thymidine incorporation. In separate experiments, regulatory T cells were added to induced pluripotent stem cell-derived pro-inflammatory macrophages and changes in interleukin-6/Tumor necrosis-alpha transcripts and protein levels were measured. Freshly isolated regulatory T cells were expanded ex vivo in the presence of CD3/CD28 expander beads, interleukin-2 and rapamycin to promote their suppressive function. We found that the suppressive function of regulatory T cells on responder T cell proliferation was compromised at the Alzheimer disease stage, compared with mild cognitive impairment and healthy controls. CD25 mean fluorescence intensity in regulatory T cell population was also reduced in Alzheimer dementia patients. Regulatory T cells did not suppress pro-inflammatory macrophages at baseline. Following ex vivo expansion, regulatory T cell suppression of responder T cell proliferation and pro-inflammatory macrophage activation increased in both patients and controls. Expanded regulatory T cells exerted their immunoregulatory function on pro-inflammatory macrophages through a contact-mediated mechanism. In conclusion, regulatory T cell immunophenotype and function are compromised in Alzheimer disease. Following ex vivo expansion, the immunomodulatory function of regulatory T cells is enhanced even at advanced stages of Alzheimer disease. Restoration of regulatory T cell function could be explored as a means to modulate the inflammatory status of Alzheimer disease.

Ex vivo expansion of dysfunctional regulatory T lymphocytes restores suppressive function in Parkinson’s disease

“… 49 , 72 – 74 Tregs are found to be decreased and/or dysfunctional in a number of diseases such as systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. 49 , 50 , 72 , 75 – 82 The current study demonstrates decreased numbers of Tregs in patients with PD. More importantly, this study demonstrates impaired Treg suppressive function starting early in disease and worsening as disease progresses.…”

The Impact of Ageing on the CNS Immune Response in Alzheimer’s Disease

“…Another strategy that might be useful to explore would be the reconstitution of Treg cells in AD patients. It has recently been shown that Treg anti-inflammatory function is impaired in patients with AD, but had increased suppressive activity on effector T cell proliferation and macrophage activation following ex vivo clonal expansion (140). This suggests that Treg function and immunophenotype are impaired in AD, but that administration of ex vivo clonally expanded of Tregs might be a viable therapeutic option (140).…”

Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease

“…Treg deficiency has been associated with increased disease progression in Alzheimer's disease, ALS, stroke, traumatic brain injury, and multiple sclerosis [4] . These reports and our works suggest that controlling neuroinflammation via Treg induction or enhancement may be a promising therapeutic avenue for the clinic [ 13 , 49 , 50 ]. Here, we show that sargramostim treatment induces Tregs and restores Treg function via increased demethylation of FOXP3 TSDR and enhanced expression of biomarkers necessary to maintain a suppressive phenotype.…”