FROM EPITOPES TO PEPTIDES TO IMMUNOTHERAPY

Allergic inflammatory responses are regulated by cytokines [interleuki n (IL)-4, IL-5, IL-10, and IL-13] produced by CD4+ helper (Th-0 and Th -2) cells. The activation of these T cells follows engagement of T-cel l antigen receptors (TCR) by antigenic peptides complexed with major h istocompatibility complex (MHC) class II molecules. Under defined cond itions presentation of T-cell epitopes as peptides can downregulate im mune responses, and here we discuss the potential of peptide-mediated immunotherapy in the regulation of responses to the house dust mite (H DM). 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 molecu les, and that multiple T-cell epitopes are recognized. There is, howev er, evidence for a bias in TCR gene usage, which has prompted the anal ysis of peptide-mediated densitization of human T cells in vitro. CD4 T cells exposed to high concentrations of HDM peptides become refract ory to restimulation and fail to provide B-cell help. This is accompan ied by complex changes in the surface phenotype, including the downreg ulation of TCR and CD28. During the induction of anergy cytokine-speci fic mRNA levels are enhanced, but when the anergic T cells are restimu lated they fail to secrete IL-4 and IL-5, although interferon (LFN)-ga mma production may remain unaltered. The ability of peptides to modula te the function of HDM-specific T cells in vivo has been investigated in mice. Following inhalation of peptide containing a major T-cell epi tope of Der p 1 (residues 111-139) transient T-cell activation was obs erved prior to the inhibition of responses in naive and sensitized mic e. T cells from the tolerant mice restimulated in vitro produced low l evels of cytokines and failed to provide help for B cells. (C) 1996 Ac ademic Press, Inc.