Modulation of immunogenicity and allergenicity by controlling the number of immunostimulatory oligonucleotides linked to Amb a 1 - 16/08/11
, Roberto Rodriguez, BS a, Robert Milley, BA a, Jason Marshall, PhD a, Christi Abbate, BS a, Tracy dela Cruz, BA a, Kathryn Patton, BS a, Fiona Walker, BS a, Kristin Chichester, MS b, Joseph Eiden, MD, PhD a, Stephen Tuck, PhD a, Gary Van Nest, PhD a
Reprint requests: Deborah Higgins, BA, Dynavax Technologies, 2929 Seventh St, Suite 100, Berkeley, CA 94710.Berkeley, Calif, and Baltimore, Md
Abstract |
Background |
Immunostimulatory DNA sequences (ISS) are potent immunomodulators that can drive TH1 responses to antigens or allergens. This effect can be dramatically enhanced by direct linkage of ISS to the protein.
Objective |
Evaluate the effects of the number of ISS bound to the major ragweed allergen Amb a 1 on immunogenicity and allergenicity.
Methods |
Immunogenicity in mice and allergenicity using PBMC or sera from subjects with ragweed allergy were assayed.
Results |
Both antibody induction in vivo and antibody recognition in vitro were highly sensitive to the number of ISSs linked. IgE recognition of Amb a 1 in competitive ELISA or histamine release assays was inhibited by ISS linkage and showed an inverse relationship to the number of ISSs bound. Type and magnitude of antibody induction in mice was also highly dependent on the number of ISS bound. At the highest ISS to protein ratios, antibody induction was very low. Moderate ISS to protein ratios induced high antibody responses in which IgG2a generally predominated. Low ISS to protein ratios produced the highest overall antibody responses in which IgG1 predominated. In contrast, varied ISS to protein ratios did not affect T-cell responses. In both in vivo mouse studies and in vitro human PBMC studies, all ISS to protein ratios evaluated induced similar responses represented by high levels of IFN-γ and low levels of TH2 cytokines.
Conclusion |
Controlling the number of ISS bound to a protein allows manipulation of antibody recognition and induction while retaining the potent TH1 properties of an ISS-linked protein.
Clinical implications |
Immunostimulatory DNA sequence–linked Amb a 1 conjugate represents a safe, novel therapeutic approach for treating ragweed allergy.
Le texte complet de cet article est disponible en PDF.Key words : Allergy, immunostimulatory oligonucleotide, linked, immunogenicity, ragweed, Amb a 1, allergy vaccine
Abbreviations used : AIC, AIC-H, AIC-L, AIC-M, ISS, MW, OVA, SAv-HRP, TMB
Plan
| Supported by Dynavax Technologies. Disclosure of potential conflict of interest: D. Higgins, R. Milley, J. Marshall, T. dela Cruz, K. Patton, S. Tuck and G. Van Nest are employed by and own stock in Dynavax Technologies. R. Rodriguez, C. Abbate, F. Walker, and J. Eiden own stock in Dynavax Technologies. K. Chichester has declared that she has no conflict of interest. |
Vol 118 - N° 2
P. 504-510 - août 2006 Retour au numéro
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