A Role for Regulatory T Cells?

With the aim of further understanding neuroinflammation in an experimental model of PD, Laurie et al., immunized mice with glatiramer and observed neuroprotection following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication [78]. Adoptive transfer of lymphoid cells from glatiramer-immunized mice led to CD4+CD25+ T cell accumulation, increased IL-10, TGFp and decreased TNFa, iNOS production in microglia, upregulation of glial cell derived neurotrophic factor, and significant rescue of Nissl+TH+ neurons in the SN [79 ] . Other studies have shown similar effects after immunization using Complete Freund’s Adjuvant and, surprisingly, after infection with BCG [80]; the cell type responsible for the neuroprotective effect were identified as CD4+CD25+FoxP3+ T cells [81]. In addition, GM-CSF treatment reduces microgliosis, mediated by IL-27 production and promotion of natural Treg development, whilst increasing apoptosis of effector memory T cells, similar as reported for Rapamycin [82]. In the same MPTP model, adoptive transfer of natural regulatory T cells (Treg) specific for a-synuclein, are neuroprotective, while N-a-syn-specific helper T cells (Th1 and Th17) exacerbated neuronal degeneration [83] . Collectively these studies led to the conclusion that brain-specific Treg cell responses can home to damaged areas in the CNS and ameliorate neurodegenerative disease, but it should be noted that most studies used adult healthy mice treated with the neurotoxin MPTP. The use of aged mice has not yet been reported in the literature, but other models of neurodegeneration have. Synuclein vaccination of rats at early stages of PD (i.e., prior to neuronal dysfunction) induces a neuroprotective infiltration of CD4+/FoxP3+ Treg cell into the SN with sustained microglial activation, characterised by MHCII expression [84]. Neuroprotection was achieved by deleting a-synuclein specific effector T cells during thymic development in the mice; therefore, vaccination most likely induced a regulatory or tolerant immune response toward a-synuclein that conveys protection by preventing or stopping a detrimental immune response. To further confirm a protective effect of the adaptive immune system, Treg depletion in APP/PS1 mice, results in enhanced effector CD4+ T cell responses in AD compared with wild-type animals [85].

 
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