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1.
Brain Behav Immun ; 111: 395-411, 2023 07.
Article in English | MEDLINE | ID: mdl-37169133

ABSTRACT

Aging coincides with major changes in brain immunity that aid in a decline in neuronal function. Here, we postulate that systemic, pro-aging factors contribute to immunological changes that occur within the brain during aging. To investigate this hypothesis, we comprehensively characterized the central and peripheral immune landscape of 20-month-old male mice using cytometry by time-of-flight (CyTOF) and investigated the role of age-associated circulating factors. We found that CD8+ T cells expressing programmed cell death protein 1 (PD1) and tissue-resident memory CD8+ T cells accumulated in the aged brain while levels of memory T cells rose in the periphery. Injections of plasma derived from 20-month-old mice into 5-month-old receiving mice decreased the frequency of splenic and circulating naïve T cells, increased memory CD8+ T cells, and non-classical, patrolling monocytes in the spleen, and elevated levels of regulatory T cells and non-classical monocytes in the blood. Notably, CD8+ T cells accumulated within white matter areas of plasma-treated mice, which coincided with the expression of vascular cell adhesion molecule 1 (VCAM-1), a mediator of immune cell trafficking, on the brain vasculature. Taken together, we here describe age-related immune cell changes in the mouse brain and circulation and show that age-associated systemic factors induce the expansion of CD8+ T cells in the aged brain.


Subject(s)
CD8-Positive T-Lymphocytes , T-Lymphocytes, Regulatory , Mice , Male , Animals , Age Factors , Aging , Brain
2.
Neurobiol Dis ; 31(3): 413-21, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18586096

ABSTRACT

Leukocyte infiltration is a key step in the development of demyelinating lesions in multiple sclerosis (MS), and molecules mediating leukocyte-endothelial interactions represent prime candidates for the development of therapeutic strategies. Here we studied the effects of blocking the integrin-associated tetraspanin CD81 in in vitro and in vivo models for MS. In an in vitro setting mAb against CD81 significantly reduced monocyte transmigration across brain endothelial cell monolayers, both in rodent and human models. Interestingly, leukocyte as well as endothelial CD81 was involved in this inhibitory effect. To assess their therapeutic potential, CD81 mAb were administered to mice suffering from experimental autoimmune encephalomyelitis (EAE). We found that Eat2, but not 2F7 mAb directed against mouse CD81 significantly reduced the development of neurological symptoms of EAE when using a preventive approach. Concomitantly, Eat2 treated animals showed reduced inflammation in the spinal cord. We conclude that CD81 represents a potential therapeutic target to interfere with leukocyte infiltration and ameliorate inflammatory neurological damage in MS.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antigens, CD/drug effects , Chemotaxis, Leukocyte/drug effects , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Immunosuppressive Agents/pharmacology , Monocytes/drug effects , Animals , Antibodies, Monoclonal/therapeutic use , Antigens, CD/immunology , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/immunology , Cell Line, Transformed , Cerebral Arteries/cytology , Cerebral Arteries/drug effects , Cerebral Arteries/immunology , Chemotaxis, Leukocyte/immunology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/immunology , Female , Humans , Immunosuppression Therapy/methods , Immunosuppressive Agents/therapeutic use , Mice , Monocytes/immunology , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Multiple Sclerosis/physiopathology , Rats , Tetraspanin 28 , Treatment Outcome
3.
Brain ; 127(Pt 3): 616-27, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14691063

ABSTRACT

Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive cellular infiltration in the development of acute experimental allergic encephalomyelitis (EAE), the animal correlate of multiple sclerosis. Cerebrovascular leakage and monocytes infiltrates were separately monitored by quantitative in vivo MRI during the course of the disease. Magnetic resonance enhancement of the contrast agent gadolinium diethylenetriaminepentaacetate (Gd-DTPA), reflecting vascular leakage, occurred concomitantly with the onset of neurological signs and was already at a maximal level at this stage of the disease. Immunohistochemical analysis also confirmed the presence of the serum-derived proteins such as fibrinogen around the brain vessels early in the disease, whereas no cellular infiltrates could be detected. MRI further demonstrated that Gd-DTPA leakage clearly preceded monocyte infiltration as imaged by the contrast agent based on ultra small particles of iron oxide (USPIO), which was maximal only during full-blown EAE. Ultrastructural and immunohistochemical investigation revealed that USPIOs were present in newly infiltrated macrophages within the inflammatory lesions. To validate the use of USPIOs as a non-invasive tool to evaluate therapeutic strategies, EAE animals were treated with the immunomodulator 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, lovastatin, which ameliorated clinical scores. MRI showed that the USPIO load in the brain was significantly diminished in lovastatin-treated animals. Data indicate that cerebrovascular leakage and monocytic trafficking into the brain are two distinct processes in the development of inflammatory lesions during multiple sclerosis, which can be monitored on-line with MRI using USPIOs and Gd-DTPA as contrast agents. These studies also implicate that USPIOs are a valuable tool to visualize monocyte infiltration in vivo and quantitatively assess the efficacy of new therapeutics like lovastatin.


Subject(s)
Blood-Brain Barrier , Brain/pathology , Encephalomyelitis, Autoimmune, Experimental/immunology , Magnetic Resonance Imaging , Monocytes/pathology , Animals , Capillary Permeability , Cell Movement/drug effects , Contrast Media , Dextrans , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/pathology , Ferrosoferric Oxide , Gadolinium DTPA , Image Processing, Computer-Assisted , Immunohistochemistry , Iron , Lovastatin/therapeutic use , Magnetite Nanoparticles , Male , Microscopy, Electron , Oxides , Rats , Rats, Inbred Lew , Spinal Cord/pathology
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