Cartilage proteoglycan (PG) aggrecan-induced arthritis (PGIA) is an autoimmune murine model that shows similarities to rheumatoid arthritis (RA) as indicated by clinical and histopathological assessments. PGIA is the only known autoimmune arthritis model which exhibits recessive inheritance via both MHC and non-MHC genetic components. In this model, joint inflammation is induced by systemic immunization of susceptible mice (e.g., BALB/c) heterologous (human) cartilage PG, where a Th1-dominated cross-reactive immune response to mouse (self) cartilage PG drives the emigration of cells into the joints. The studies proposed herein are the continuation of our current project. We identified a new PGIA-susceptible murine strain (C3H), replaced complete Freund's adjuvant by a less noxious adjuvant, and introduced novel methods for the induction and transfer of the disease from wild-type BALB/c to genetically manipulated BALB/c and/or severe immunodeficient (BALB/c[SCID] or Rag2-/-.BALB/c) mice. In addition, we mapped all potential T cell epitopes of human cartilage PG in PGIA-susceptible strains of mice. We also found that T cell responses to human PG in the """"""""original"""""""" HLA-DR4.Ab(0) and HLA-DQ8.Ab(0) transgenic mice (lacking the mouse own class II alleles) were identical with those backcrossed into BALB/c, but transgenic animals developed arthritis only when the RA-predisposing HLA alleles were expressed in arthritis-susceptible BALB/c background. We selected two dominant/""""""""arthritogenic"""""""" T cell epitopes of PG that elicited positive responses in both BALB/c and HLA* transgenic mice, and in a number of RA patients tested. We then generated transgenic mice expressing a T cell receptor (TCR) that recognizes an arthritogenic PG-specific peptide. We propose to use these TCR transgenic mice to study the (i) arthritogenicity of the wild-type PG peptide and (ii) the tolerizing effect of altered peptide ligand (APL) sequences; and (iii) the ability of this peptide-specific transgenic TCR+/CD4+ T cells (with or without wild-type peptides, or altered peptide sequences) to transfer the disease into immunodeficient BALB/c mice that carry either their own (H-2d) or RA-predisposing HLA-DR4.Ab(0) or HLA-DQ8.Ab(0) MHC class II alleles in an arthritis-susceptible genetic background. These studies should generate fundamental information for the development of an in vivo system where PG-specific human TCRs will be expressed and tested in HLA+.Ab(0) transgenic BALB/c(SCID) or Rag2-deficient BALB/c mice.
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