Antigen-nonspecific CD8+ cytotoxic T cells induced with anti-CD3 monoclonal antibody (mAb) are able to kill tumor cells in a major histocompatibility complex (MHC)-unrestricted fashion. However, the role of CD8 in the MHC-independent tumoricidal activity of anti-CD3-activated killer T (AK-T) cells has not been investigated. Here we show that anti-CD8 alpha mAb inhibits, in a dose-dependent fashion, lysis of P815 and YAC-1 tumor cells by mouse AK-T cells. The inhibition of MHC-unrestricted cytotoxicity by anti-CD8 alpha mAb cannot be attributed to interference with an adhesion-like function of CD8 towards class I MHC molecules on the target cells because anti-CD8 alpha mAb (i) had equal inhibitory effects on the cytolysis of tumor target cells regardless of their relative level of class I MHC molecule expression and (ii) did not interfere with the formation of conjugates between AK-T cells and class I MHC-bearing P815 tumor cells. However, anti-CD8 alpha mAb abrogated AK-T cell granule exocytosis in the presence of P815 tumor cells, indicating a regulatory role for CD8 in the signal transduction events which result in lysis of the tumor target cells. Immunoblot analysis of the post-nuclear fraction of lysates from AK-T cells exposed to P815 tumor cells in the presence of anti-CD8 alpha mAb revealed reduced phosphorylation of tyrosine residues on a protein with an Mr of approximately 62 kDa. Taken together, these data suggest that CD8 is able to affect the tumoricidal activity of MHC-unrestricted AK-T cells independent of class I MHC molecules on the target cell.
infusion in our rat model, using powerful anti-inflammatory but non-toxic drugs is to begin soon. ABSTRACT A15Proteoglycans as a double-edged sword in multiple sclerosis: Implications for future approaches to immunomodulatory therapy J Warford, AC Lamport, DW Hoskin, AS Easton Department of Pathology, Dalhousie University, Halifax, NS doi:10.1017/cjn.2017 Proteoglycans are components of the extracellular matrix that have been identified as barriers to endogenous remyelination. Surfen (bis 2-methyl, 4-amino, 6-quinolyl amide) is a small molecule proteoglycan antagonist. We have previously reported that surfen reduces T cell proliferation in vivo and in vitro while also decreasing the production of chemotactic and pro-inflammatory factors produced by macrophages. Here we extend these studies to clinically relevant mouse models of chronic neuroinflammation (experimental autoimmune encephalomyelitis; EAE) and focal demyelination (lysolecithin). In the EAE model, surfen treated mice displayed a reduced disease severity that was associated with decreased percentages of CD4+CD45+ T cells and CD11b/F480 myeloid populations in the spinal cord. The chemokines RANTES, CCL2, and CCL3 were reduced in the spinal cords of surfen treated mice, resembling previous in vitro macrophage results and implicating a chemotactic mechanism that reduces cell infiltration. By contrast, when surfen was administered into a developing brain lesion using the lysolecithin model of demyelination it produced significantly larger lesions. The opposing effects of surfen observed in EAE and the lysolecithin model suggests that distinct proteoglycan families influence inflammation and remyelination differently depending on the stage of repair. ABSTRACT A16Biopsy pathology in a large cohort of juvenile dermatomyositis is heterogeneous and, for the most part, independent of autoantibody phenotype
may be associated with a variety of neuropsychiatric and motor syndromes. In addition, loss-of-function mutations in TAHP1 are known to cause a variety of dystonia syndromes. Therefore, it is believed that brain calcinosis in this family is related to the deletion of SLC20A2, while the TAHP1 deletion likely contributes to the early onset dystonia phenotype. CONFLICTS OF INTEREST:None. Utilizing the National Alzheimer's Coordinating Center database we analyzed 728 patients with Alzheimer's disease (AD), neuropathologically confirmed based on the CERAD criteria, comparing those (n = 271) that at any moment in their evolution suffered delusions or hallucinations (P + ) versus those (n = 457) that did not (P-). There was no difference in AD lesion load. P + subjects had a higher prevalence of subcortical arteriosclerotic leukoencephalopathy (SAL) and, as expected, higher Lewy body stage. Hypertension was more common in P + patients and diabetes in subjects with both delusions and hallucinations. P + patients tended to quit smoking later in life. The functional associations diverged: patients with delusions only had better CDR, MMSE and FAQ than P-patients, whereas the opposite was true for patients with hallucinations, whether isolated or associated with delusions. In contrast, an overlapping sample of 890 subjects from the same database with a clinical diagnosis of AD and available neuropathological exam showed greater AD load in the P + group, a result we interpret as due to clinical misdiagnosis, since the P-group was enriched in subjects with a Braak stage I and II. We conclude that SAL is, along with Lewy bodies, a substrate for psychotic symptoms in AD, and that vascular risk factors are likely to contribute to the development of this condition. ABSTRACT CONFLICTS OF INTEREST:None. ABSTRACT A5Compared to normals, the cerebral expression of multiple inflammatory markers is reduced in Alzheimer's disease and Diffuse Lewy body disease AC Lamport, J Warford, AS Easton
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