myelin-proteolipid-protein-(178-191) and myelin-oligodendrocyte-glycoprotein-(35-55)

This study introduces a flexible format for tolerogenic vaccination that incorporates IFN-β and neuroantigen (NAg) in the Alum adjuvant. Tolerogenic vaccination required all three components, IFN-β, NAg, and Alum, for inhibition of experimental autoimmune encephalomyelitis (EAE) and induction of tolerance. Vaccination with IFN-β + NAg in Alum ameliorated NAg-specific sensitization and inhibited EAE in C57BL/6 mice in pretreatment and therapeutic regimens. Tolerance induction was specific for the tolerogenic vaccine Ag PLP178-191 or myelin oligodendrocyte glycoprotein (MOG)35-55 in proteolipid protein- and MOG-induced models of EAE, respectively, and was abrogated by pretreatment with a depleting anti-CD25 mAb. IFN-β/Alum-based vaccination exhibited hallmarks of infectious tolerance, because IFN-β + OVA in Alum-specific vaccination inhibited EAE elicited by OVA + MOG in CFA but not EAE elicited by MOG in CFA. IFN-β + NAg in Alum vaccination elicited elevated numbers and percentages of FOXP3

Topics: Adjuvants, Immunologic; Alum Compounds; Animals; Bystander Effect; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental; Forkhead Transcription Factors; Humans; Immune Tolerance; Interferon-beta; Interleukin-2 Receptor alpha Subunit; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Sclerosis; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; T-Lymphocytes, Regulatory; Vaccines

Studies of MS histopathology are largely dependent on suitable animal models. While light microscopic analysis gives an overview of tissue pathology, it falls short in evaluating detailed changes in nerve fiber morphology. The ultrastructural data presented here and obtained from studies of myelin oligodendrocyte glycoprotein (MOG):35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice delineate that axonal damage and myelin pathology follow different kinetics in the disease course. While myelin pathology accumulated with disease progression, axonal damage coincided with the initial clinical disease symptoms and remained stable over time. This pattern applied both to irreversible axolysis and early axonal pathology. Notably, these histopathological patterns were reflected by the normal-appearing white matter (NAWM), suggesting that the NAWM is also in an active neurodegenerative state. The data underline the need for neuroprotection in MS and suggest the MOG model as a highly valuable tool for the assessment of different therapeutic strategies.

Topics: Animals; Axons; Encephalomyelitis, Autoimmune, Experimental; Female; Kinetics; Lumbar Vertebrae; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Recombinant Fusion Proteins; Spinal Cord

B7 costimulatory molecules play an important role in inducing autoimmunity, tumor immunity, and transplant rejection, and therapeutic manipulation of B7 is being investigated in human diseases. To determine whether B7 costimulation is essential for inducing autoimmunity on different genetic backgrounds, we backcrossed B7.1/B7.2 deficient ((-/-)) mice on to the C57BL/6 (B6) and SJL backgrounds and induced experimental autoimmune encephalomyelitis (EAE) in these mice. B7.1/B7.2(-/-) mice on the B6 background were resistant to EAE induced with MOG 35-55, whereas the SJL B7.1/B7.2(-/-) mice were susceptible to PLP 139-151 or PLP 178-191-induced EAE. The SJL B7.1/B7.2(-/-) mice had a qualitatively different lesion pattern in that they showed increased white matter vacuolation compared to wild-type SJL mice when immunized with either PLP 139-151 or PLP 178-191. (B6xSJL)F1 B7.1/B7.2(+/+) mice were susceptible to EAE whereas (B6xSJL)F1 B7.1/B7.2(-/-) mice were resistant to EAE induced with either encephalitogenic peptide. Thus, genetic background determines the B7 requirement for inducing autoimmunity. These data have important implications for developing B7-based immunotherapies for human diseases.

Topics: Abatacept; Amino Acid Sequence; Animals; Antigens, CD; Antigens, Differentiation; Autoimmunity; B7-1 Antigen; B7-2 Antigen; Crosses, Genetic; CTLA-4 Antigen; Encephalomyelitis, Autoimmune, Experimental; Female; Genetic Predisposition to Disease; Glycoproteins; Immunization; Immunoconjugates; Lymph Nodes; Lymphocyte Activation; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments

We demonstrate the absolute requirement for a functioning class II-restricted Ag processing pathway in the CNS for the initiation of experimental autoimmune encephalomyelitis (EAE). C57BL/6 (B6) mice deficient for the class II transactivator, which have defects in MHC class II, invariant chain (Ii), and H-2M (DM) expression, are resistant to initiation of myelin oligodendrocyte protein (MOG) peptide, MOG(35-55)-specific EAE by both priming and adoptive transfer of encephalitogenic T cells. However, class II transactivator-deficient mice can prime a suboptimal myelin-specific CD4(+) Th1 response. Further, B6 mice individually deficient for Ii and DM are also resistant to initiation of both active and adoptive EAE. Although both Ii-deficient and DM-deficient APCs can present MOG peptide to CD4(+) T cells, neither is capable of processing and presenting the encephalitogenic peptide of intact MOG protein. This phenotype is not Ag-specific, as DM- and Ii-deficient mice are also resistant to initiation of EAE by proteolipid protein peptide PLP(178-191). Remarkably, DM-deficient mice can prime a potent peripheral Th1 response to MOG(35-55), comparable to the response seen in wild-type mice, yet maintain resistance to EAE initiation. Most striking is the demonstration that T cells from MOG(35-55)-primed DM knockout mice can adoptively transfer EAE to wild-type, but not DM-deficient, mice. Together, these data demonstrate that the inability to process antigenic peptide from intact myelin protein results in resistance to EAE and that de novo processing and presentation of myelin Ags in the CNS is absolutely required for the initiation of autoimmune demyelinating disease.

Topics: Adoptive Transfer; Amino Acid Sequence; Animals; Antigen Presentation; Antigens, Differentiation, B-Lymphocyte; Cell Movement; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Epitopes, T-Lymphocyte; Female; Glycoproteins; Histocompatibility Antigens Class II; Immunity, Innate; Injections, Subcutaneous; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Nuclear Proteins; Peptide Fragments; Th1 Cells; Trans-Activators