House dust mite allergy: from T-cell epitopes to immunotherapy.
CD4+ T-lymphocytes induce and regulate allergic inflammatory responses to common environmental aeroallergens derived from Dermatophagoides spp. (house dust mite, HDM), which cause clinical symptoms in approximately 10% of the population. Definition of the molecular structure of HDM proteins combined with the ability to isolate monoclonal populations of human CD4+ T-cells representative of the 'interleukin-4 (IL-4) dominant' functional phenotype, which support immunoglobulin E (IgE) synthesis, has allowed T-cell recognition of HDM to be examined in detail. The results of these investigations demonstrated extensive heterogeneity in both the antigen and HLA class II restriction specificity of the HDM reactive T-cell repertoire. Furthermore, long-lived clones of T-cells with oligoclonality in T-cell antigen receptor (TcR) usage, driven by chronic stimulation with HDM, have been identified in human peripheral blood. The presentation of specific peptides and superantigens under conditions that induce T-cell non-responsiveness has provided an in vitro model for analysing the mechanisms of CD4+ T-cell targeted immunotherapy. It appears that the mechanisms underlying T-cell anergy are accompanied by a transient downregulation of TcR and CD28 and mediated by a shift in the cytokine profile from that of the 'IL-4 dominant' to the 'interferon-gamma (IFN-gamma) dominant' functional phenotype of CD4+ T-cells. In parallel, using a murine model, it has been demonstrated that administration of an immunodominant peptide via the mucosal surfaces of the respiratory and alimentary tracts may tolerize an established response to intact HDM proteins. The potential application of these models in the development of novel approaches to immunotherapy is discussed.
O'Hehir
R E
RE
Department of Immunology, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London.
Hoyne
G F
GF
Thomas
W R
WR
Lamb
J R
JR
D000485:Allergens / Q000737:chemistry / Q000276:immunology; D000818:Animals; D004391:Dust / Q000009:adverse effects*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000628:therapy*; D007167:Immunotherapy; D008925:Mites / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000485:Allergens; D004391:Dust; D000939:Epitopes; D000949:Histocompatibility Antigens Class II