T helper 2 biased de novo immune response to Keyhole Limpet Hemocyanin in humans


Thomas Jung, MD, PhD, Translational Medicine Dermatology, Novartis Exploratory Development, Forum 1, WSJ-27.4.071, CH-4002 Basel, Switzerland. E-mail: thomas.jung@novartis.com


Background Allergen-specific T helper 2 (Th2) cells play an important role in the pathogenesis of atopic disorders. To date, no model system exists in humans that would allow the monitoring of a developing de novo Th2 immune response in vivo.

Objective The aim of the experiment was to establish an immunization protocol inducing a de novo Th2 response in humans using Keyhole Limpet Hemocyanin (KLH) as neo-antigen.

Methods The double-blind placebo-controlled, parallel-group study was conducted in two groups of subjects (16 healthy volunteers and 16 patients with allergic rhinitis). Subjects received three i.m. injections of 100 μg KLH adsorbed to aluminium hydroxide or matching placebo (alum alone) in intervals of 2 weeks. On day 43, KLH alone (10 μg) was given intra-dermally (i.d.) to all subjects to assess immediate and late-phase skin responses.

Results The immunization protocol was well tolerated, highly specific and efficient. Antigen-specific production of Th2-cytokines (mainly IL-5 and IL-13) by PBMCs suggested a Th2 pattern, as did the presence of KLH-specific IgG4 in sera. Intra-dermal KLH challenge induced an immediate-type of response predominantly in atopic subjects followed by a late-phase skin reaction. The latter was accompanied by the presence of IgE+ cells, eosinophils and a strong up-regulation of IL-4 and IL-13 along with the absence of Th1 transcripts in biopsies taken from the site of antigen challenge. IL-17 and IL-22 transcripts were detected only in healthy subjects skin following KLH challenge, while IL-1β and IL-33 expression did not differ between the healthy and the atopics.

Conclusions The immunization protocol resulted in the elicitation of a local and peripheral Th2 immune response in both healthy and atopic individuals. This may permit the investigation and monitoring of novel immunomodulatory strategies aiming to interfere with Th2 responses in man. The relevance of lack of Th17 cells in atopic skin in this model remains to be determined.