Rhinitis, sinusitis, and ocular diseases
Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA

https://doi.org/10.1016/j.jaci.2004.03.003Get rights and content

Background

In animal models administration of immunostimulatory DNA sequences preferentially elicits TH1-dominated (type 1-dominated) immunity and can inhibit developing or ongoing TH2 (type 2) responses.

Objective

Our objective was to investigate this phenomenon in humans.

Methods

In a randomized, third party-blinded, placebo-controlled, proof-of-concept study conducted entirely in the winter in 19 adults with ragweed allergy, we administered 6 subcutaneous injections of purified Amb a 1 linked to the 22-base-long immunostimulatory phosphorothioate oligodeoxyribonucleotide 1018 (Amb a 1–immunostimulatory DNA sequence conjugate [AIC]). Before the course of AIC or placebo injections and 2 and 16 weeks afterward, we measured recall responses to ragweed, streptokinase, and PHA in short-term primary culture of fresh PBMCs after restimulation with antigen. We quantified regulatory cytokine and chemokine responses characteristic of TH2 immunity (IL-5, IL-13, CCL17 [TARC], and CCL22 [MDC]), and TH1 immunity (IFN-γ, CXCL9 [Mig], and CXCL10 [IP-10]), as well as IL-10, a cytokine sometimes linked to regulatory T-cell populations.

Results

We demonstrated for the first time that human systemic in vivo ragweed-specific TH2 responses were selectively redirected toward TH1 responses, with significant increases in IFN-γ, CXCL9, and CXCL10 and significant decreases in IL-5, CCL17, and CCL22 found at 2 and 16 weeks after the sixth injection. Cytokine and chemokine responses to the unrelated bacterial antigen streptokinase and the global capacity to mount immune responses on polyclonal activation with PHA did not change. No clinically significant systemic or local allergic reactions were associated with AIC or placebo injections.

Conclusions

AIC, injected in concentrations that were approximately 40-fold lower than those used in most murine studies published to date, led to a prolonged shift from TH2 immunity toward TH1 immunity and appeared to be safe. This novel approach has the potential for immune redirection in human immediate hypersensitivity diseases.

Section snippets

Methods

This randomized, third party–blinded, placebo-controlled Phase I investigation was approved by the University of Manitoba Research Ethics Board, and written informed consent was obtained from all participants. The study was conducted entirely in midwinter, when there was no exposure to ragweed or other pollens. Individuals received 6 injections of investigational vaccine or placebo administered at weekly intervals (Fig 1).

Results

The AIC and placebo groups were demographically and clinically similar (AIC [n = 9]: 4 men, 41 ± 13 y, 76 ± 20 kg; placebo [n = 10]: 6 men, 41 ± 13 y, 79 ± 18 kg). They did not differ significantly in the intensity of cytokine and chemokine production or in the balance between their TH1 and TH2 immunity at preinjection baseline (P > .05); however, when ragweed-specific responses were evaluated 2 and 16 weeks after the sixth and last injection, the individuals in the AIC group exhibited striking

Discussion

In this proof-of-concept study of a novel approach to immune modulation in humans, we determined the effect of AIC on ongoing immunoregulatory responses and investigated its safety. We demonstrated for the first time that human systemic in vivo TH2 cytokine and chemokine ragweed-specific recall responses and IL-5, CCL17, and CCL22 levels readily detectable 6 months after the end of the ragweed season were markedly reduced after AIC, but not placebo, injections. In some individuals, reductions

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    Supported by Dynavax Technologies Corp, the Canadian Institutes of Health Research, and the Canada Research Chairs Program. F. E. R. Simons, Y. Shikishima, and K. T. HayGlass have no competing financial interests. G. van Nest and J. J. Eiden are associated with Dynavax Technologies Corp.

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