Induction of Adaptive Immunity Leads to Nigrostriatal Disease Progression in MPTP Mouse Model of Parkinson’s Disease

Chandra, Goutam; Roy, Avik; Rangasamy, Suresh B.; Pahan, Kalipada

doi:10.4049/jimmunol.1700149

Cited by 48 publications

(38 citation statements)

References 43 publications

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“…PD patients have also been shown to have increased T cell infiltration of both CD8+ and CD4+ cells [64,65]. A similar profile was been reported in acute neurotoxic models of PD such as 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine (MPTP)-injected mice, where marked T cell infiltration was observed in the substantia nigra at day one after MPTP challenge before progressively decreasing and normalizing by day 30 [66]. Another study identified increased numbers of Th1 and Th17 cells with a concomitant decrease in Th2 and Treg cells in PD patients and animal models [67].…”

Section: Discussionsupporting

confidence: 58%

Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models

Iba

Kim

Sallin

et al. 2020

J Neuroinflammation

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Background: α-Synuclein (α-syn) is a pre-synaptic protein which progressively accumulates in neuronal and nonneuronal cells in neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Recent evidence suggests that aberrant immune activation may be involved in neurodegeneration in PD/DLB. While previous studies have often focused on the microglial responses, less is known about the role of the peripheral immune system in these disorders. Methods: To understand the involvement of the peripheral immune system in PD/DLB, we evaluated T cell populations in the brains of α-syn transgenic (tg) mice (e.g., Thy1 promoter line 61) and DLB patients. Results: Immunohistochemical analysis showed perivascular and parenchymal infiltration by CD3+/CD4+ helper T cells, but not cytotoxic T cells (CD3+/CD8+) or B cells (CD20+), in the neocortex, hippocampus, and striatum of αsyn tg mice. CD3+ cells were found in close proximity to the processes of activated astroglia, particularly in areas of the brain with significant astrogliosis, microgliosis, and expression of pro-inflammatory cytokines. In addition, a subset of CD3+ cells co-expressed interferon γ. Flow cytometric analysis of immune cells in the brains of α-syn tg mice revealed that CD1d-tet+ T cells were also increased in the brains of α-syn tg mice suggestive of natural killer T cells. In post-mortem DLB brains, we similarly detected increased numbers of infiltrating CD3+/CD4+ T cells in close proximity with blood vessels. Conclusion: These results suggest that infiltrating adaptive immune cells play an important role in neuroinflammation and neurodegeneration in synucleinopathies and that modulating peripheral T cells may be a viable therapeutic strategy for PD/DLB.

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Section: Discussionsupporting

confidence: 58%

Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models

Iba

Kim

Sallin

et al. 2020

J Neuroinflammation

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“…Studies have reported these infiltrating lymphocytes as a heterogeneous population of both CD8 + and CD4 + cells [64]. A similar profile was been reported in acute neurotoxic models of PD such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected mice, where marked T cell infiltration was observed in the substantia nigra at day one after MPTP challenge before progressively decreasing and normalizing by day 30 [65]. Another study identified increased numbers of Th1 and Th17 cells with a concomitant decrease in Th2 and Treg cells in PD patients and animals models [66].…”

Section: Discussionsupporting

confidence: 60%

Neuroinflammation is associated with infiltration of T cells in Lewy body disease and ɑ-synuclein transgenic models.

Iba

Kim

Sallin

et al. 2020

Preprint

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Background: ɑ-synuclein (ɑ-syn) is a presynaptic protein which progressively accumulates in neuronal and non-neuronal cells in neurodegenerative diseases such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Recent evidence suggests that aberrant immune activation may be involved in neurodegeneration in PD/DLB. While previous studies have often focused on the microglial responses, less is known about the role of the peripheral immune system in these disorders.Methods: To understand the involvement of the peripheral immune system in PD/DLB, we evaluated T cell populations in the brains of ɑ-syn transgenic (tg) mice (eg: Thy1 promoter line 61) and DLB patients.Results: Immunohistochemical analysis showed perivascular and parenchymal infiltration by CD3+/CD4+ helper T cells, but not cytotoxic T cells (CD3+/CD8+) or B cells (CD20+), in the neocortex, hippocampus, and striatum of ɑ-syn tg mice. CD3+ cells were found in close proximity to the processes of activated astroglia, particularly in areas of the brain with significant astrogliosis, microgliosis, and pro-inflammatory cytokines. In addition, a subset of CD3+ cells co-expressed interferon γ. Flow cytometric analysis of immune cells revealed that CD1d+ T cells were also increased in the brains of ɑ-syn tg mice and matched an expression profile consistent with natural killer T cells. In post-mortem DLB brains, we similarly detected CD3+ T cells that expressed CD4+ or CD1d+ in close proximity with blood vessels.Conclusion: These results suggest that infiltrating adaptive immune cells play an important role in neuroinflammation and neurodegeneration in synucleinopathies and that modulating peripheral T cells may be a viable therapeutic strategy for PD/DLB.

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“…Although the cause of PD is poorly understood, recent studies indicate that PD is regulated by the adaptive arm of the immune system (4)(5)(6)(7)(8)(9)(10)(11). According to Brochard et al (8), both CD8 + and CD4 + T cells significantly invade the SNpc of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice.…”

mentioning

confidence: 99%

Low-Dose Maraviroc, an Antiretroviral Drug, Attenuates the Infiltration of T Cells into the Central Nervous System and Protects the Nigrostriatum in Hemiparkinsonian Monkeys

Mondal

Rangasamy

Roy

et al. 2019

The Journal of Immunology

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Parkinson's disease (PD) is the most common neurodegenerative movement disorder in humans. Despite intense investigation, no effective therapy is available to stop the progression of this disease. It is becoming clear that both innate and adaptive immune responses are active in PD. Accordingly, we have reported a marked increase in RANTES and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra (SN) and the serum of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine-intoxicated hemiparkinsonian monkeys. Because RANTES and eotaxin share a common receptor, CCR5, we examined the efficacy of maraviroc, an inhibitor of CCR5 and a Food and Drug Administration-approved drug against HIV infection, in hemiparkinsonian rhesus monkeys. First, we found glial limitans injury, loss of GFAP immunostaining, and infiltration of T cells across the endothelial monolayer in SN of hemiparkinsonian monkeys. However, oral administration of a low dose of maraviroc protected glia limitans partially, maintained the integrity of endothelial monolayer, reduced the infiltration of T cells, attenuated neuroinflammation, and decreased a-synucleinopathy in the SN. Accordingly, maraviroc treatment also protected both the nigrostriatal axis and neurotransmitters and improved motor functions in hemiparkinsonian monkeys. These results suggest that low-dose maraviroc and other CCR5 antagonists may be helpful for PD patients.

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Induction of Adaptive Immunity Leads to Nigrostriatal Disease Progression in MPTP Mouse Model of Parkinson’s Disease

Cited by 48 publications

References 43 publications

Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models

Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models

Neuroinflammation is associated with infiltration of T cells in Lewy body disease and ɑ-synuclein transgenic models.

Low-Dose Maraviroc, an Antiretroviral Drug, Attenuates the Infiltration of T Cells into the Central Nervous System and Protects the Nigrostriatum in Hemiparkinsonian Monkeys

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