HLA-DR2–restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice

Abstract

IntroductionMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is histologically characterized by focal mononuclear cell infiltration with a varying extent of demyelination (1, 2). It is postulated that autoimmune T cells recognizing myelin autoantigens such as myelin basic protein (MBP) or proteolipid protein (PLP) play a central role in the pathogenesis of MS. This postulate is based on substantial evidence such as increased frequency of activated MBP-or PLP-specific T cells in peripheral blood and cerebrospinal fluid of MS patients (3-6), and significant complementarity-determining region 3 (CDR3) homology between T-cell infiltrates within MS plaques and MBP-or PLP-specific T-cell clones generated from MS patients (7,8). Moreover, previous studies have identified the peptides MBP84-102 and PLP95-116 as immunodominant and possible encephalitogenic epitopes in MS patients with the HLA-DR2 haplotype (9, 10). However, the role of such autoreactive T cells remains unclear. In fact, it is possible that some (but not all) autoreactive T cells may protect against CNS tissue damage by producing neurotrophic factors (11-13).To address the issue regarding the function of autoimmune T cells, we have introduced HLA-DR2 (DRB1*1502) transgenic mice that are able to mount a T-cell response to DR2-related epitopes in the context of HLA-DR2 molecules. To explore the potential pathogenicity of PLP95-116 in HLA-DR2 + MS, we challenged the HLA-DR2 (DRB1*1502) transgenic mice with PLP95-116 and generated 2 peptide-specific T-cell lines (TCLs) from the mice. These TCLs were HLA-DR2-restricted and produced T-helper type 1 (Th1) cytokine in response to the peptide in the presence of mouse or human antigen-presenting cells (APCs) expressing HLA-DR2 (DRB1*1502) molecules. It was remarkable that transfer of 1 of the TCLs induced atypical autoimmune encephalitis involving the deep cere- In multiple sclerosis (MS) patients who carry the Class II major histocompatibility (MHC) type HLA-DR2, T cells specific for amino acids 95-116 in the proteolipid protein (PLP) are activated and clonally expanded. However, it remains unclear whether these autoreactive T cells play a pathogenic role or, rather, protect against the central nervous system (CNS) damage. We have addressed this issue, using mice transgenic for the human MHC class II region carrying the HLA-DR2 (DRB1*1502) haplotype. After stimulating cultured lymph node cells repeatedly with PLP95-116, we generated 2 HLA-DR2-restricted, PLP95-116-specific T-cell lines (TCLs) from the transgenic mice immunized with this portion of PLP. The TCLs were CD4 + and produced T-helper 1 (Th1) cytokines in response to the peptide. These TCLs were adoptively transferred into RAG-2 -/-mice expressing HLA-DR2 (DRB1*1502) molecules. Mice receiving 1 of the TCLs developed a neurological disorder manifested ataxic movement without apparent paresis on day 3, 4, or 5 after cell transfer. Histological examination revealed inflammatory foci primarily restricted to th...

HLA-DQB1*0602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB1*1501;DQB1*0602) Transgenic Mice

“…Many myelin epitopes encephalitogenic for genetically susceptible wild-type mice have been found to be encephalitogenic also in HLA-DR15-Tg mice (46,48,49) and often T cells against these epitopes were also observed in MS patients (53)(54)(55), suggesting that the pathogenic responses modeled here have value for the analysis of events underpinning human disease and the design of therapeutics. In this respect pMOBP15-36, which is encephalitogenic in SJL/J mice (19,20), encompasses an epitope recognized by MS patients' PBL (19), and predicted to contain an HLA-DRB1*1501 epitope (19), was expected to be encephalitogenic in HLA-DRB1*1501-Tg mice.…”

Transgenic models of autoimmune disease

“…Generally, the mere induction of these responses is insufficient to induce disease. However, some groups have achieved disease transfer with HLA-restricted, transgenic mouse T cells [49]. Furthermore, evidence for a role of predisposing alleles comes from experiments where mice expressing HLA-DQ8 (the allele strongly implicated in diabetes susceptibility) do not develop spontaneous disease and nor do mice with transgenic expression of B7-1 targeted to beta cells.…”

Recombinant TCR Ligand Induces Tolerance to Myelin Oligodendrocyte Glycoprotein 35-55 Peptide and Reverses Clinical and Histological Signs of Chronic Experimental Autoimmune Encephalomyelitis in HLA-DR2 Transgenic Mice

“…HLA-DR4-restricted T cell responses, and in some cases clinical signs of autoimmune disease, were demonstrated after immunization with type II collagen (3)(4)(5), human cartilage Ag gp39 (6), glutamic acid decarboxylase 65 (7,8), insulin (9), and myelin oligodendrocyte glycoprotein (MOG)-91-108 peptide (10). HLA-DR2 ϩ mice have also been developed that were susceptible to experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP)-85-99 peptide (11), proteolipid protein-95-116 peptide (12), and MOG-35-55 peptide (A. A. Vandenbark, C. Rich, A.…”