A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor

Abstract

Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected autoimmune pathogenesis. Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined, except for major histocompatibility (MHC) genes. Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development less compared with their contribution to disorders such as insulin-dependent diabetes mellitus. Due to the strong linkage disequilibrium in the MHC class II region, it has not been possible to determine which gene(s) is responsible for the genetic predisposition. In transgenic mice, we have expressed three human components involved in T-cell recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II candidate MS susceptibility genes found in individuals of European descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone specific for the HLA-DR2 bound immunodominant myelin basic protein (MBP) 4102 peptide; and the human CD4 coreceptor. The amino acid sequence of the MBP 84-102 peptide is the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease. Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells.

Transgenic models of autoimmune disease

“…These experiments of course also require that the restricting human HLA molecule is also expressed transgenically in the model (see below). One group have described induction of an EAE-like disease in hu-TCR transgenic mice expressing a TCR directed against an immunodominant epitope of MBP [17]. We have also generated hu-TCR transgenic mice and find spontaneous autoimmunity associated with an overtly Th1 response to MBP peptide (manuscript in preparation).…”

Blockade of Ca2+‐activated K+ channels in T cells: an option for the treatment of multiple sclerosis?

“…It would be challenging to address the efficacy in preventing antigen-induced EAE development using different native proteins and engineered peptides fragments as well as showing efficacy in genetically modified animals exhibiting spontaneous EAE [11,12]. Also, it would be interesting to see the effects in animal models of other autoimmune diseases, such as rheumatoid arthritis, diabetes and psoriasis.…”

Activation of myelin reactive T cells in multiple sclerosis: A possible role for T cell degeneracy?

“…Some functional differences were reported when comparing T cell responses to myelin antigens in MS as compared to controls. For example, differences were reported with respect to cytotoxic properties [7]. Probably the best evidence for a direct pathogenic role of MBP reactive T cells comes from a clinical trial where it was demonstrated that MS patients treated with an altered peptide ligand based on the MBP(83-99) epitope developed clinical worsening, increased brain inflammation and increased anti-MBP T cell responses [8].…”