Treatment of autoimmune diseases through manipulation of antigen presentation.
In rheumatoid arthritis, HLA-DR alleles associated with elevated relative risk share a common sequence in the third hypervariable domain of the major histocompatibility complex class II molecule (MHC II). Immunization of mice with a peptide vaccine comprised of the appropriate MHC II sequence in adjuvant blocked the onset and reduced the relapse rate of experimental autoimmune encephalomyelitis (EAE). A phase I clinical trial testing a single injection of a third hypervariable domain peptide from the HLA-DRB1*0401 sequence in alum adjuvant showed that the vaccine is well tolerated and generates an anti-HLA-DR antibody response in approximately 25% of the treated patients. A phase II trial testing multiple boosts is in progress. In a more antigen-specific approach, solubilized MHC II molecules loaded with an autoantigenic peptide are injected intravenously to induce unresponsiveness by the binding of the T-cell receptor (TCR) in the absence of costimulation. Appropriate soluble MHC II:autoantigenic peptide complexes inhibit the recall antigen proliferative response of T clones or draining lymph node cells, and reduce the progression of EAE and experimental autoimmune myasthenia gravis (EAMG). A test of a soluble HLA-DR2:myelin basic protein (MBP) complex in multiple sclerosis is progressing in phase I.
Spack
E G
EG
Department of Immunology, Anergen, Inc., Redwood City, CA 94063, USA.
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D009103:Multiple Sclerosis / Q000276:immunology; D010455:Peptides / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology
D000949:Histocompatibility Antigens Class II; D010455:Peptides; D014614:Vaccines, Synthetic