Induction of experimental autoimmune encephalomyelitis in transgenic mice expressing ovalbumin in oligodendrocytes

Abstract

We have used the 5 0 flanking sequence of the myelin basic protein gene known to include the core promoter and a strong oligodendrocyte (ODC)-specific enhancer to target expression of the well-studied model antigen ovalbumin (OVA) to ODC in transgenic mice. OVA protein was detected in a tissue-and cell-specific manner in these "ODC-OVA" mice. Without immunization, CD4 T cells and B cells remained ignorant of the neo-self antigen expressed in the central nervous system (CNS), as indicated by unimpaired development and lack of activation of OVA/IA b -specific TCR transgenic T cells in these mice, and the ability to mount normal OVA-specific recall and antibody responses. Upon immunization with OVA in complete Freund's adjuvant, about half of the transgenic mice developed neurological symptoms characteristic of experimental autoimmune encephalomyelitis (EAE). Mononuclear infiltrates in the brain and spinal cord contained both macrophages and T cells, similar to classical models of EAE induced by immunization with CNS antigens in adjuvant. The wealth of immunological reagents available to study and manipulate the OVA-specific response should make this new model useful for the investigation of components and mechanisms involved in CNSspecific autoimmunity.

T cell mediated pathogenesis in EAE: Molecular mechanisms

“…Na et al expressed ovalbumin (OVA) cytosolically in ODCs and found a very early fulminant demyelinating CNS inflammation in double-transgenic animals co-expressing the OT-1 transgenic TCR. [133,134] Also, this group did not investigate inasmuch the perforin-granzyme pathway was implicated in disease. Like in the C3H MBP system by Goverman's group, they found that IFN-g played an important role in pathogenicity, probably via activation of ODCs through upregulation of MHC class I and co-stimulatory molecules.…”

Cutting Edge: Multiple Sclerosis-Like Lesions Induced by Effector CD8 T Cells Recognizing a Sequestered Antigen on Oligodendrocytes

“…An analogous transgenic model has been recently used to investigate CD4 T cell reactivity to OVA expressed specifically in oligodendrocytes (16). We focused on oligodendrocyte-specific CD8 T cells because little in vivo information is currently available regarding the pathogenicity of this subset and because both CD8 T cell infiltration and loss of oligodendrocytes are essential features of MS lesions.…”

Glatiramer Acetate Attenuates Pro-Inflammatory T Cell Responses but Does Not Directly Protect Neurons from Inflammatory Cell Death

“…Wilde type (WT) C57BL/6, ß2-microglobulin Ϫ/Ϫ16 , transgenic mice expressing ovalbumin (OVA) in oligodendrocytes (ODCs) (ODC-OVA), 17 and mice transgenic for a T cell receptor recognizing the ovalbumine 257-264 (OVA) peptide in the context of H2K b MHC-I molecules (OT-I) 18 and Dark Agouti (DA) rats were kept under pathogen-free conditions and had access to food and water ad libitum. All experiments were conducted according to the German law of animal protection and were approved by local authorities.…”

“…17,19 After 6 hours of incubation in the absence and presence of different GA concentrations (10 to 200 g/ ml) we stained for the density of activated caspase-3 ϩ , NeuN ϩ apoptotic neuronal cell bodies in two gray matter areas (hippocampus and cortex; Figure 3, A and C). Incubation of GA for 6 hours in ODC-OVA slices in the absence of OT-I T cells tended to increase the density of activated caspase-3 ϩ neuronal cell bodies in both gray matter areas, although this tendency did not reach statistical significance [ Figure 3, A and C, left panels; density of apoptotic neuronal cell bodies after 6 hours of incubation without OT-I T cells: Hippocampus: GA (0 g/ml): 10 Ϯ 2/mm 2 vs. GA (200 g/ml): 15 Ϯ 3/mm 2 ; P ϭ 0.209; n ϭ 6; Cortex: GA (0 g/ml): 11 Ϯ 1/mm 2 vs. GA (200 g/ml): 15 Ϯ 1/mm 2 ; P ϭ 0.131; n ϭ 6].…”