Abstract
Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3–5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets.
Highlights
The ability to induce clinical tolerance in humans carries enormous therapeutic potential
Antigen 5-specific functional T cell responses Having previously documented that high frequencies of wasp venom-specific T cells circulate in allergic individuals and that antigen 5 (Ves v 5) is a dominant target antigen [52], we proceeded to characterize constituent epitopes
Using peripheral blood mononuclear cells (PBMC) derived from 23 wasp allergic individuals, we first investigated the presence of circulating cytokine-producing T cells that were reactive to overlapping peptide pools derived from Ves v 5
Summary
The ability to induce clinical tolerance in humans carries enormous therapeutic potential. Specific IgG blocking antibodies have been implicated in the generation of early clinical non-responsiveness [5,6] and may be induced through local and systemic IL-10 derived from regulatory T cells and other cells [5]. Peptide immunotherapy carries risk of late phase disease exacerbation, possibly due to induction of antigen-specific effector T cell responses [45,46,47,48,49,50]. Such exacerbations may be peptide dose dependent and clearly it will be important to define the optimal parameters for success [51]
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