Specific Immunotherapy of Multiple Sclerosis by Altered Peptide Ligands — Risk or Benefit?

Abstract

Multiple sclerosis (MS) is a chronic inflammatory/demyelinating disease of the central nervous system (CNS) with various degrees of axonal loss [1, 2] in which autoreactive CD4+ T cells are considered to play a crucial role [3–5]. In different forms of experimental autoimmune encephalomyelitis (EAE), which serves as an animal model of MS, a number of myelin, glial components, and even heat-shock antigens can serve as targets for the encephalitogenic process [6–8]. In order to identify similar target antigens in humans, human myelin-specific T cells have been studied in great detail during the last decade. Many parallels have been found that are shared by encephalitogenic cells in EAE and T cells isolated from MS patients, i.e., they are CD4+ T-helper cells that frequently express a T-helper 1 (Th1)-proinflammatory phenotype with high secretion of interferon (IFN)-γ and tumor necrosis factor (TNF)-α/β [9–11]. Furthermore, they often recognize epitopes similar to those identified as encephalitogenic in animals and frequently are restricted by MS-associated HLA-DR molecules such as HLA-DRB 1*1501 or -DRB5*0101 [12–15]. However, such autoreactive T cells have also been isolated from healthy donors [12, 16–19], which seemed to contradict their pathophysiological relevance in MS.