From Epitopes to Peptides to Immunotherapy

Abstract

Allergic inflammatory responses are regulated by cytokines [interleukin (IL)-4, IL-5, IL-10, and IL-13] produced by CD4+ helper (Th0and Th2) cells. The activation of these T cells follows engagement of T-cell antigen receptors (TCR) by antigenic peptides complexed with major histocompatibility complex (MHC) class II molecules. Under defined conditions presentation of T-cell epitopes as peptides can downregulate immune responses, and here we discuss the potential of peptide-mediated immunotherapy in the regulation of responses to the house dust mite (HDM). Cloning the major allergens of HDM has allowed detailed analysis of the HDM-reactive T-cell repertoire and has revealed that MHC class II restriction is heterogeneous, involving HLA-DP, -DQ, and -DR molecules, and that multiple T-cell epitopes are recognized. There is, however, evidence for a bias in TCR gene usage, which has prompted the analysis of peptide-mediated densitization of human T cellsin vitro.CD4+ T cells exposed to high concentrations of HDM peptides become refractory to restimulation and fail to provide B-cell help. This is accompanied by complex changes in the surface phenotype, including the downregulation of TCR and CD28. During the induction of anergy cytokine-specific mRNA levels are enhanced, but when the anergic T cells are restimulated they fail to secrete IL-4 and IL-5, although interferon (IFN)-γ production may remain unaltered. The ability of peptides to modulate the function of HDM-specific T cellsin vivohas been investigated in mice. Following inhalation of peptide containing a major T-cell epitope of Der p 1 (residues 111–139) transient T-cell activation was observed prior to the inhibition of responses in naive and sensitized mice. T cells from the tolerant mice restimulatedin vitroproduced low levels of cytokines and failed to provide help for B cells.