RESUMO
BACKGROUND: Circulating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS) in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs), representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease. METHODS AND FINDINGS: We tested this working hypothesis in amyotrophic lateral sclerosis (ALS) and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2) cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1) mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS), revealed a two-fold increase in the percentage of circulating MDSCs (LIN(-/Low)HLA-DR(-)CD33(+)) compared to controls. CONCLUSIONS: Taken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might represent a risk factor and a novel target for therapeutic intervention in ALS at least at the early stage.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Animais , Progressão da Doença , Masculino , Camundongos , Superóxido Dismutase/genética , Superóxido Dismutase-1RESUMO
Adaptive and innate immunity, if well controlled, contribute to the maintenance of the CNS, as well as to downregulation of adverse acute and chronic neurological conditions. T cells that recognize CNS antigens are needed to activate resident immune cells and to recruit blood-borne monocytes, which act to restore homeostasis and facilitate repair. However, boosting such a T-cell response in a risk-free way requires a careful choice of the antigen, carrier, and regimen. A single vaccination with CNS-derived peptides or their weak agonists reduces neuronal loss in animal models of acute neurodegeneration. Repeated injections are needed to maintain a long-lasting effect in chronic neurodegenerative conditions, yet the frequency of the injections seems to have a critical effect on the outcome. An example is glatiramer acetate, a compound that is administered in a daily regimen to patients with multiple sclerosis. A single injection of glatiramer acetate, with or without an adjuvant, is neuroprotective in some animal models of acute CNS injuries. However, in an animal model of amyotrophic lateral sclerosis, a single injection of adjuvant-free glatiramer acetate is insufficient, while daily injections are not only ineffective but can carry an increased risk of mortality in female mice.Thus, considering immune-based therapies as a single therapy, rather than as a family of therapies that are regimen dependent, may be misleading. Moreover, the vaccination regimen and administration of a compound, even one shown to be safe in humans for the treatment of a particular neurodegenerative disease, must be studied in preclinical experiments before it is tested in a clinical trial for a novel indication; otherwise, an effective drug in a certain regimen for one disease may be ineffective or even carry risks when used for another disorder.
Assuntos
Esclerose Múltipla/terapia , Doenças Neurodegenerativas/terapia , Peptídeos/imunologia , Vacinação , Animais , Autoimunidade , Encéfalo/imunologia , Acetato de Glatiramer , Humanos , Peptídeos/efeitos adversos , Linfócitos T/imunologiaRESUMO
Microglia are resident cells in the central nervous system (CNS), of hematopoietic origin with a high plasticity. In this study, we examined whether adaptive immune system, involving in CNS maintenance and repair, can induce microglia to express markers of neural cells. We show that long exposure (above 10 days) of microglia to low doses (10 ng/ml) of the 'proinflammatory' T-cell derived cytokine, IFN-gamma, induced them to express neuronal markers including gamma-aminobutyric acid (GABA) and glutamic acid decarboxylase (GAD-67). In contrast, exposure of microglia to low doses (10 ng/ml) of the 'anti-inflammatory' T-cell derived cytokine, IL-4, induced the expression of oligodendrocyte markers and dendritic cell (DC) marker, CD11c. The microglial origin of the neural-like cells was confirmed using microglia from transgenic mice expressing GFP under promoter of the chemokine fractalkine receptor CX(3)CR1, and diphtheria toxin receptor, under CD11c promoter. This study emphasizes that microglial plasticity includes their ability to give rise to neural-like cells and shows that cytokines produced by the adaptive immune system are involved in these processes.