ovalbumin and Multiple-Sclerosis

Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing, pathogen removal, and autoimmunity. We showed that patients with multiple sclerosis (MS) have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis (EAE). However, unexpectedly, progranulin-deficient mice (Grn

Topics: Adolescent; Adult; Animals; Antigen-Presenting Cells; Antigens; Bone Marrow; Bone Marrow Transplantation; Dendritic Cells; Disease Resistance; Encephalomyelitis, Autoimmune, Experimental; Female; Histocompatibility Antigens Class II; Humans; Lymphocyte Count; Macrophages; Male; Mice, Inbred C57BL; Middle Aged; Multiple Sclerosis; Myeloid Cells; Ovalbumin; Phagocytes; Phagocytosis; Progranulins; Scavenger Receptors, Class B; T-Lymphocytes; Young Adult

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.

Topics: Animals; Antigen-Presenting Cells; Antigens; Astrocytes; Caspase 3; Caspase 7; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Central Nervous System; Cytokines; Demyelinating Diseases; Disease Models, Animal; Gene Expression; Histocompatibility Antigens Class I; Humans; Interferon-gamma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Sclerosis; Myelin Sheath; Oligodendrocyte Precursor Cells; Oligodendroglia; Ovalbumin; Remyelination; T-Lymphocytes

Allergic diseases, including asthma and food allergies, are an increasing health concern. Immunotherapy is an effective therapeutic approach for many allergic diseases but requires long dose escalation periods and has a high risk of adverse reactions, particularly in food allergy. New methods to safely induce Ag-specific tolerance could improve the clinical approach to allergic disease. We hypothesized that Ag-specific tolerance induced by the i.v. injection of Ags attached to the surface of syngeneic splenic leukocytes (Ag-coupled splenocytes [Ag-SPs]) with the chemical cross-linking agent ethylene-carbodiimide, which effectively modulate Th1/Th17 diseases, may also safely and efficiently induce tolerance in Th2-mediated mouse models of allergic asthma and food allergy. Mice were tolerized with Ag-SP before or after initiation of OVA/alum-induced allergic airway inflammation or peanut-induced food allergy. The effects on disease pathology and Th2-directed cytokine and Ab responses were studied. Ag-SP tolerance prevented disease development in both models and safely tolerized T cell responses in an Ag-specific manner in presensitized animals. Prophylactically, Ag-SP efficiently decreased local and systemic Th2 responses, eosinophilia, and Ag-specific IgE. Interestingly, Ag-SP induced Th2 tolerance was found to be partially dependent on the function of CD25(+) regulatory T cells in the food allergy model, but was regulatory T cell independent in the model of allergic airway inflammation. We demonstrate that Ag-SP tolerance can be rapidly, safely, and efficiently induced in murine models of allergic disease, highlighting a potential new Ag-specific tolerance immunotherapy for Th2-associated allergic diseases.

Topics: Allergens; Animals; Arachis; Bronchial Hyperreactivity; Desensitization, Immunologic; Disease Models, Animal; Humans; Immune Tolerance; Inflammation; Leukocytes; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Multiple Sclerosis; Ovalbumin; Peanut Hypersensitivity; Spleen; Th2 Cells

Increasing evidence implies CD8 T cells in tissue-specific autoimmune diseases including multiple sclerosis. mAbs specific for MHC class I molecules presenting a dominant autoantigenic peptide may allow selective immunotherapy in such settings. We demonstrate the prophylactic and therapeutic efficacy of such a mAb in a transgenic mouse model of lethal demyelinating disease in which a neo-self Ag expressed by oligodendrocytes is targeted by CD8 T cells with transgenic Ag receptors. Mechanistic studies performed in vitro and in vivo indicate that it is the low expression of MHC class I on oligodendrocytes, which makes this form of Ag-specific intervention possible.

Topics: Animals; Antibodies, Blocking; Antibodies, Monoclonal; Autoantigens; Autoimmunity; CD8-Positive T-Lymphocytes; Coculture Techniques; Disease Models, Animal; Flow Cytometry; Fluorescent Antibody Technique; Histocompatibility Antigens Class I; Lymphocyte Activation; Mice; Mice, Transgenic; Microscopy, Confocal; Multiple Sclerosis; Oligodendroglia; Ovalbumin; Receptors, Antigen, T-Cell

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) characterized by chronic inflammatory demyelination of the central nervous system (CNS). The pathology of EAE involves autoimmune CD4(+) T(h)1 cells. There is a striking inverse correlation between the occurrence of parasitic and autoimmune diseases. We demonstrate that in mice with Schistosoma mansoni ova immunization, the severity of EAE is reduced as measured by decreased clinical scores and CNS cellular infiltrates. Disease suppression is associated with immune deviation in the periphery and the CNS, demonstrated by decreased IFN-gamma and increased IL-4, transforming growth factor-beta and IL-10 levels in the periphery, and increased frequency of IL-4 producing neuroantigen-specific T cells in the brain. S. mansoni helminth ova treatment influenced the course of EAE in wild-type mice, but not in STAT6-deficient animals. This indicates that STAT6 plays a critical role in regulating the ameliorating effect of S. mansoni ova treatment on the autoimmune response, and provides the direct link between helminth treatment, T(h)2 environment and improved EAE. As some intestinal helminthic infections induce minimal pathology, they might offer a safe and inexpensive therapy to prevent and/or ameliorate MS.

Topics: Animals; Autoimmune Diseases; Encephalomyelitis, Autoimmune, Experimental; Helminths; Immunization; Interleukin-4; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Models, Animal; Multiple Sclerosis; Ovalbumin; STAT6 Transcription Factor; Trans-Activators

Autoreactive T-cells are involved in demyelination, neurodegeneration, and the recruitment of peripheral macrophages and nonspecific activated T-cells in autoimmune diseases such as multiple sclerosis (MS). The ligation of costimulatory B7 molecules on microglia with CD28/CTLA-4 on T-cells is thought to be crucial to the onset and course of MS and its rodent model experimental autoimmune encephalomyelitis (EAE). It is currently unclear as to how far the nature of infiltrating T-cells has an impact on the expression of the B7 molecules on microglia, the resident antigen-presenting cells (APCs) of the brain. We studied the expression of B7-1 and B7-2 on microglia after encounter with preactivated Th1 and Th2 cells from transgenic mice whose T-cells express a receptor (TCR) either specific to myelin basic protein (MBP) or ovalbumin (OVA) using murine organotypic entorhinal-hippocampal slice cultures (OEHSC). Our main finding was that Th1 cells downregulate the constitutive expression of B7-2 and induce B7-1 expression while Th2 cells do not induce this B7-1 upregulation. The main difference between MBP- and OVA-specific cells was seen in experiments were Th1 cells had direct contact to APCs but not to brain tissue. In contrast to MBP-specific Th1 cells, OVA-specific Th1 cells required the addition of antigen to upregulate B7-1 and downregulate B7-2. When the cells were allowed to have contact to brain tissue, no difference was seen in the pattern of B7 regulation between OVA- and MBP-specific T-cells. Our data suggest that T-cells are able to modulate B7 expression on microglial cells in the brain independent of antigen presentation through TCR/MHC-II ligation but presumably by soluble mediators.

Topics: Animals; Antigen Presentation; Antigens; Antigens, CD; B7-1 Antigen; B7-2 Antigen; Brain; Coculture Techniques; Down-Regulation; Epitopes; Gene Expression Regulation; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Microglia; Models, Biological; Multiple Sclerosis; Myelin Basic Protein; Ovalbumin; Th1 Cells; Th2 Cells; Up-Regulation

To detect immunoglobulin G (IgG) oligoclonal bands in unconcentrated cerebrospinal fluid (CSF) we used a recently developed method combining agarose isoelectric focusing (IEF) and double immunofixation peroxidase staining with Avidin-Biotin amplification. We studied 65 CSF and serum paired specimens from normals, multiple sclerosis (MS), other neurological diseases (OND) and benign monoclonal gammopathies (BMG). We found that the oligoclonal IgG pattern can be demonstrated after IEF of 15 microliter of CSF specimens with an IgG concentration of 15 mg/L. In 98% of CSF from patients with clinically definite MS a sharp oligoclonal band pattern was detected. The reliability and the sensitivity of this powerful technique is compared to agarose IEF of concentrated CSF, followed by Coomassie Brilliant Blue staining. This method constitutes a real improvement in the detection of CSF IgG oligoclonal bands because it avoids CSF concentration and allows the detection of IgG bands only.

Topics: Avidin; Biotin; Humans; Immunoenzyme Techniques; Immunoglobulins; Isoelectric Focusing; Monoclonal Gammopathy of Undetermined Significance; Multiple Sclerosis; Nervous System Diseases; Oligoclonal Bands; Ovalbumin; Sepharose; Staining and Labeling

A technique is described for producing large demyelinating lesions of the spinal cord in the guinea pig. Guinea pigs were pretreated by immunization with ovalbumin and water-soluble adjuvant (N-acetyl-muramyl L-alanyl D-isoglutamine, MDP) in water-in-oil emulsion (Freund's incomplete adjuvant). They were given a large dose (10 mg) of ovalbumin i.p. one month later. After a few weeks the animals were sensitized with guinea-pig basic protein in Freund's complete adjuvant. Five out of 11 animals developed large, distinctive, sharply demarcated, symmetrical demyelinating lesions within 30 days. These lesions occurred in the dorsal and anterior columns, root entry zones and subpial region of the spinal cord. Histology showed a considerable amount of free lipids. There were also infiltrative lesions of classical experimental allergic encephalomyelitis (EAE) of normal severity in the same animals. The demyelinating lesions resembled those seen in multiple sclerosis in their location and extent in the spinal cord and in the presence of free lipids. Control experiments indicated that pretreatment with ovalbumin/MDP and the second injection of ovalbumin was necessary for all the demyelination; moreover guinea pigs immunized with basic protein in Freund's complete adjuvant or Freund's incomplete adjuvant plus MDP without pretreatment only developed classical EAE with minimal or no demyelination.

Topics: Adjuvants, Immunologic; Animals; Encephalomyelitis, Autoimmune, Experimental; Female; Guinea Pigs; Lymph Nodes; Male; Multiple Sclerosis; Myelin Sheath; Necrosis; Ovalbumin; Spinal Cord