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Istvan Pirko,
Yi Chen,
Anne K Lohrey, Jeremiah McDole,
Jeffrey D Gamez,
Kathleen S Allen,
Kevin D Pavelko,
Diana M Lindquist,
R Scott Dunn,
Slobodan I Macura,
Aaron J Johnson
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ABSTRACT: MRI is sensitive to tissue pathology in multiple sclerosis (MS); however, most lesional MRI findings have limited correlation with disability. Chronic T1 hypointense lesions or "T1 black holes" (T1BH), observed in a subset of MS patients and thought to represent axonal damage, show moderate to strong correlation with disability. The pathogenesis of T1BH remains unclear. We previously reported the first and as of yet only model of T1BH formation in the Theiler's murine encephalitis virus induced model of acute CNS neuroinflammation induced injury, where CD8 T-cells are critical mediators of axonal damage and related T1BH formation. The purpose of this study was to further analyze the role of CD8 and CD4 T-cells through adoptive transfer experiments and to determine if the relevant CD8 T-cells are classic epitope specific lymphocytes or different subsets. C57BL/6 mice were used as donors and RAG-1 deficient mice as hosts in our adoptive transfer experiments. In vivo 3-dimensional MRI images were acquired using a 7 Tesla small animal MRI system. For image analysis, we used semi-automated methods in Analyze 9.1; transfer efficiency was monitored using FACS of brain infiltrating lymphocytes. Using a peptide depletion method, we demonstrated that the majority of CD8 T-cells are classic epitope specific cytotoxic cells. CD8 T-cell transfer successfully restored the immune system's capability to mediate T1BH formation in animals that lack adaptive immune system, whereas CD4 T-cell transfer results in an attenuated phenotype with significantly less T1BH formation. These findings demonstrate contrasting roles for these cell types, with additional evidence for a direct pathogenic role of CD8 T-cells in our model of T1 black hole formation.
PLoS ONE 01/2012; 7(2):e31459. · 4.09 Impact Factor
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ABSTRACT: Intracerebral hemorrhage (ICH) is a stroke subtype with high rates of mortality and morbidity. The immune system, particularly complement and cytokine signaling, has been implicated in brain injury after ICH. However, the cellular immunology associated with ICH has been understudied. In this report, we use flow cytometry to quantitatively profile immune cell populations that infiltrate the brain 1 and 4 days post-ICH. At 1 day CD45(hi) GR-1(+) cells were increased 2.0-fold compared with saline controls (P<or=0.05); however, we did not observe changes in any other cell populations analyzed. At 4 days ICH mice presented with a 2.4-fold increase in CD45(hi) cells, a 1.9-fold increase in CD45(hi) GR-1(-) cells, a 3.4-fold increase in CD45(hi) GR-1(+) cells, and most notably, a 1.7-fold increase in CD4(+) cells (P<or=0.05 for all groups), compared with control mice. We did not observe changes in the numbers of CD8(+) cells or CD45(lo) GR-1(-) cells (P=0.43 and 0.49, respectively). Thus, we have shown the first use of flow cytometry to analyze leukocyte infiltration in response to ICH. Our finding of a CD4 T-cell infiltrate is novel and suggests a role for the adaptive immune system in the response to ICH.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 11/2008; 29(1):137-43. · 5.46 Impact Factor
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ABSTRACT: Defining the epitope specificity of CD8+ T cells is an important goal in autoimmune and immune-mediated disease research. We have developed a translational molecular approach to determine the epitope specificity of CD8+ T cells using the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis (MS). TMEV-specific CD8+ T cells were isolated from brains and spleens of 7-day TMEV-infected C57BL/6J mice and stimulated by Cos-7 cells that were co-transfected with expression vectors encoding the D(b) class I molecule along with overlapping segments of the TMEV genome. Both brain-infiltrating and spleen-derived CD8+ T cells expressed IFN-gamma when Cos-7 cells were co-transfected with D(b) class I molecule and the TMEV genomic segment that encoded the immunodominant TMEV epitope. This demonstrated that peripheral and brain-infiltrating CD8+ T-cell responses were focused on peptide epitope(s) encoded by the same region of the TMEV genome. We propose that a similar molecular approach could also be used to determine the antigen specificity of suppressor CD8 T cells by the measurement of transforming growth factor-beta (TGF-beta) production. In addition, with a randomly generated library and peripheral blood or isolated CSF CD8+ T cells, this would be an effective method of predicting the epitope specificity of CD8+ T cells in human inflammatory CNS diseases, in animal models of MS or other organ-specific inflammatory diseases with a protective or pathogenic role of CD8 T cells.
Human Immunology 10/2008; 69(11):805-10. · 2.84 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system. It is universally accepted that the immune system plays a major role in the pathogenesis of MS. For decades, CD4 T cells have been considered the predominant mediator of neuropathology in MS. This perception was largely due to the similarity between MS and CD4 T-cell-driven experimental allergic encephalomyelitis, the most commonly studied murine model of MS. Over the last decade, several new observations in MS research imply an emerging role for CD8 T cells in neuropathogenesis. In certain experimental autoimmune encephalomyelitis (EAE) models, CD8 T cells are considered suppressors of pathology, whereas in other EAE models, neuropathology can be exacerbated by adoptive transfer of CD8 T cells. Studies using the Theiler's murine encephalomyelitis virus (TMEV) model have demonstrated preservation of motor function and axonal integrity in animals deficient in CD8 T cells or their effector molecules. CD8 T cells have also been demonstrated to be important regulators of blood-brain barrier permeability. There is also an emerging role for CD8 T cells in human MS. Human genetic studies reveal an important role for HLA class I molecules in MS susceptibility. In addition, neuropathologic studies demonstrate that CD8 T cells are the most numerous inflammatory infiltrate in MS lesions at all stages of lesion development. CD8 T cells are also capable of damaging neurons and axons in vitro. In this chapter, we discuss the neuropathologic, genetic, and experimental evidence for a critical role of CD8 T cells in the pathogenesis of MS and its most frequently studied animal models. We also highlight important new avenues for future research.
International Review of Neurobiology 02/2007; 79:73-97. · 2.35 Impact Factor
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ABSTRACT: The etiology of multiple sclerosis (MS) remains unknown. However, both genetic and environmental factors play important roles in its pathogenesis. While demyelination of axons is a hallmark histological feature of MS, axonal and neuronal dysfunction may correlate better with clinical disability. All major immune cell types have been implicated in the pathogenesis of MS, with the CD4+ T-cells being the most commonly studied. In this review, we discuss the involvement of CD8+ T-cells in MS. In addition, we review the contribution of CD8+ T-cells to the pathogenesis of experimental autoimmune encephalitis (EAE) and Theiler's murine encephalomyelitis virus (TMEV) mouse models of MS, including the concept of CD8+ T-cell mediated axonal damage.
Neurological Research 05/2006; 28(3):256-61. · 1.52 Impact Factor
