ABSTRACT
Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.
Subject(s)
Arthritis, Experimental/enzymology , Immune System/enzymology , Matrix Metalloproteinases/immunology , Adjuvants, Immunologic/administration & dosage , Adoptive Transfer , Animals , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , Autoantibodies/biosynthesis , Autoantigens/administration & dosage , Autoantigens/immunology , Autoantigens/metabolism , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/transplantation , Cartilage, Articular/enzymology , Cartilage, Articular/immunology , Diamines/administration & dosage , Epitopes, T-Lymphocyte/administration & dosage , Epitopes, T-Lymphocyte/immunology , Epitopes, T-Lymphocyte/metabolism , Histocompatibility Antigens Class II/metabolism , Humans , Lymph Nodes/enzymology , Lymph Nodes/immunology , Matrix Metalloproteinase 3/administration & dosage , Matrix Metalloproteinase 3/immunology , Matrix Metalloproteinases/administration & dosage , Matrix Metalloproteinases/metabolism , Peptide Fragments/administration & dosage , Peptide Fragments/immunology , Peptide Fragments/metabolism , Protein Binding/immunology , Quaternary Ammonium Compounds/administration & dosage , Rats , Rats, Inbred Lew , Spleen/enzymology , Spleen/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathologyABSTRACT
We have recently found that matrix metalloproteinases (MMPs) are targets for T-cell and B-cell reactivity in experimental arthritis. In the present article, we investigate whether modulation of MMP-specific T-cell responses could influence the course of adjuvant arthritis (AA). Lewis rats were treated nasally with MMP peptides prior to or after AA induction. Administration of the MMP-10 or the MMP-16 peptide prior to AA induction reduced the arthritic symptoms. In contrast, administration of the MMP-10 peptide after AA induction aggravated the arthritic symptoms. The present study shows the possible usefulness of MMP peptides for immunotherapy. However, a clear understanding of proper timing of peptide administration is crucial for the development of such therapies.
