SummaryImmune surveillance against tumors usually depends on T cell recognition of tumor antigens presented by major histocompatibility complex (MHC) molecules, whereas MHC class I tumors may be controlled by natural killer (NK) cells. Perforin-dependent cytotoxicity is a major effector function ofCD8 + MHC class I-restricted T cells and of NK cells. Here, we used perforin-deficient C57BL/6 (PKO) mice to study involvement of perforin and Fas ligand in tumor surveillance in vivo.We induced tumors in PKO and normal C57BL/6 mice by (a) injection of different syngeneic tumor cell lines of different tissue origin in naive and primed mice; (b) administration of the chemical carcinogens methylcholanthrene (MCA) or 12-O-tetradecanoylphorbol-13-acetare (TPA) plus 7,12-dimethylbenzanthracene (DMBA), or (c) by injection of acutely oncogenic Moloney sarcoma virus. The first set of models analyzes the defense against a tumor load given at once, whereas the last two sets give information on immune defense against tumors at the very moment of their generation. Most of the tumor cell lines tested were eliminated 10-100-fold better by C57BL/6 mice in an unprimed situation; after priming, the differences were more pronounced. Lymphoma cells transfected with Fas were controlled 10-fold better by PKO and C57BL/6 mice when compared to untransfected control cells, indicating some role for FasL in tumor control. MCA-induced tumors arose more rapidly and with a higher incidence in PKO mice compared to C57BL/6 or CDS-deficient mice. DMBA+TPA-induced skin papillomas arose with similar high incidence and comparable kinetics in both mouse strains. C57BL/6 and PKO mice have a similar incidence ofMoloney murine sarcoma and leukemia virus-induced sarcomas, but tumors are larger and regression is retarded in PKO mice.Thus, perform-dependent cytotoxicity is not only a crucial mechanism of both cytotoxic T lymphocyte-and NK-dependent resistance to injected tumor cell lines, but also operates during viral and chemical carcinogenesis in vivo. Experiments addressing the role of Fasdependent cytotoxlcity by studying resistance to tumor cell lines that were stably transfected with Fas neither provided evidence for a major role of Fas nor excluded a minor contribution of Fas in tumor surveillance.

5Antigen presenting cells are critical for regulating immune responses. We 6 tested mannan-peptide conjugates for targeting myelin peptides to APC to induce T 7 cell tolerance and resistance to experimental autoimmune encephalomyelitis (EAE). 8Myelin peptides conjugated to mannan in oxidized (OM) or reduced (RM) forms 9 protected mice against EAE in prophylactic and therapeutic protocols, with OM-10 conjugated peptides giving best results. Protection was peptide-specific and 11 associated with reduced antigen-specific T cell proliferation, but not alterations in 12 Th1, Th17 or Treg cell differentiation or T cell apoptosis compared to EAE controls.

The brain responds to injury and infection by activating innate defense and tissue repair mechanisms. Working upon the hypothesis that the brain defense response involves common genes and pathways across diverse pathologies, we analysed global gene expression in brain from mouse models representing three major central nervous system disorders, cerebral stroke, multiple sclerosis and Alzheimer’s disease compared to normal brain using DNA microarray expression profiling. A comparison of dysregulated genes across disease models revealed common genes and pathways including key components of estrogen and TGF-β signaling pathways that have been associated with neuroprotection as well as a neurodegeneration mediator, TRPM7. Further, for each disease model, we discovered collections of differentially expressed genes that provide novel insight into the individual pathology and its associated mechanisms. Our data provide a resource for exploring the complex molecular mechanisms that underlie brain neurodegeneration and a new approach for identifying generic and disease-specific targets for therapy.

Experimental autoimmune encephalomyelitis (EAE) is a valuable model for studying immunopathology in multiple sclerosis (MS) and for exploring the interface between autoimmune responses and CNS tissue that ultimately leads to lesion development. In this study, we measured gene expression in mouse spinal cord during myelin oligodendrocyte gp35–55 peptide–induced EAE, using quantitative RT-PCR, to identify gene markers that monitor individual hallmark pathological processes. We defined a small panel of genes whose longitudinal expression patterns provided insight into the timing, interrelationships, and mechanisms of individual disease processes and the efficacy of therapeutics for the treatment of MS. Earliest transcriptional changes were upregulation of Il17a and sharp downregulation of neuronal and oligodendrocyte marker genes preceding clinical disease onset, whereas neuroinflammatory markers progressively increased as symptoms and tissue lesions developed. EAE-induced gene-expression changes were not altered in mice deficient in IKKβ in cells of the myeloid lineage compared with controls, but the administration of a selective inhibitor of soluble TNF to mice from the day of immunization delayed changes in the expression of innate inflammation, myelin, and neuron markers from the presymptomatic phase. Proof of principle that the gene panel shows drug screening potential was obtained using a well-established MS therapeutic, glatiramer acetate. Prophylactic treatment of mice with glatiramer acetate normalized gene marker expression, and this correlated with the level of therapeutic success. These results show that neurons and oligodendrocytes are highly sensitive to CNS-directed autoimmunity before the development of clinical symptoms and immunopathology and reveal a role for soluble TNF in mediating the earliest changes in gene expression.

Some aspects of CNS-directed autoimmunity in multiple sclerosis are modeled in mice by immunization with myelin Ags where tissue damage is driven by myelin-reactive Th1 and Th17 effector lymphocytes. Whether the CNS plays an active role in controlling such autoimmune diseases is unknown. We used mice in which IκB kinase β was deleted from Ca2+/calmodulin-dependent kinase IIα-expressing neurons (nIKKβKO) to investigate the contribution of neuronal NF-κB to the development of myelin oligodendrocyte glycoprotein 35–55-induced experimental autoimmune encephalomyelitis. We show that nIKKβKO mice developed a severe, nonresolving disease with increased axon loss compared with controls and this was associated with significantly reduced CNS production of neuroprotective factors (vascular endothelial growth factor, CSF1-R, and FLIP) and increased production of proinflammatory cytokines (IL-6, TNF, IL-12, IL-17, and CD30L) and chemokines. The isolation of CNS-infiltrating monocytes revealed greater numbers of CD4+ T cells, reduced numbers of NK1.1+ cells, and a selective accumulation of Th1 cells in nIKKβKO CNS from early in the disease. Our results show that neurons play an important role in determining the quality and outcome of CNS immune responses, specifically that neuronal IκB kinase β is required for neuroprotection, suppression of inflammation, limitation of Th1 lymphocyte accumulation, and enhancement of NK cell recruitment in experimental autoimmune encephalomyelitis-affected CNS and stress the importance of neuroprotective strategies for the treatment of multiple sclerosis.

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Data described here suggest that senescent cells may have similar functions in IVD homeostasis, irrespective of the origin of senescence induction.