Peptide modification in T cell immunology - from molecule to animal

Abstract

Chemical knowledge can be applied in the field of immunology. It provides a better understanding of how a peptide interacts with proteins and cells of the immune system. However, it is not possible to predict the outcome of peptide administration in an animal. Peptides are used in experimental treatment of paralyzed rats, an animal model for human multiple sclerosis (MS). In this autoimmune disease, a T cell recognizes a peptide derived from self tissue. As a result, an aggressive reaction towards self tissue is initiated. When this peptide is modified slightly ( altered peptide ligand ) and administered as a drug, the wrong T cell activity can be stopped. Finally, the severity of an autoimmune disease can decrease in this way. For development of such a specific treatment for autoimmune diseases, as well as to better understand the onset of autoimmunity, insight into the consequences of peptide modification is necessary. Besides, knowledge of the effect of peptide modification is important, because in the body itself also spontaneous conversions to proteins occur, some of which are related with the development of autoimmunity. With molecular modeling techniques we investigated the structure of a (modified) peptide and how it interacts with proteins (MHC and T cell receptor). Subsequently, modified peptides were designed and synthesized. Using protein binding assays, T cell proliferation and in vivo experiments, the consequences of the peptide modification were investigated. Importantly, we were able to understand how modifications to the peptide led to changes in protein binding (to MHC) and recognition by the T cell. The step from a cell to a whole animal was too large. We could not predict how a peptide should be modified to create a therapeutic peptide that could decrease the paralysis in rats. More studies combining chemistry and immunology are expected to improve our understanding of autoimmunity as well as therapeutic strategies.