Synthetic Double-Stranded RNAs Are Adjuvants for the Induction of T Helper 1 and Humoral Immune Responses to Human Papillomavirus in Rhesus Macaques

PLoS Pathogens

Ralph M. Steinman¹  Klara Tenner-Racz¹  Martin Müller²  Klaus Überla³  Jürgen Kleinschmidt⁴  Karen Nieto⁴  Anna Sacher⁴  Lutz Gissmann⁴  Paul Racz⁴  Tamara Rzehak⁵  Ralf Ignatius⁵  Edith Jasny⁶  Martin Eisenblätter⁶  Mariagrazia Uguccioni⁷  Christine Trumpfheller⁷  Christiane Stahl-Hennig⁸  Reiner Schulte⁸  Andres M. Salazar⁹ 

[1] Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany;Department of Botany and Microbiology, King Saud University, Riyadh, Saudi Arabia;Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany;Infection and Cancer Research Program, German Cancer Research Center (DKFZ), Heidelberg, Germany;Institute for Research in Biomedicine, Bellinzona, Switzerland;Institute of Microbiology and Hygiene, Department of Infection Immunology, Charité–University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm, Berlin, Germany;Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York, United States of America;Laboratory of Infection Models, German Primate Center, Göttingen, Germany;Oncovir Inc., Washington, D.C., United States of America

关键词: Immune response;    Immunologic adjuvants;    T cells;    Enzyme-linked immunoassays;    Lymph nodes;    HPV-16;    Primates;    Monkeys;   

DOI  :  10.1371/journal.ppat.1000373

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Toll-like receptor (TLR) ligands are being considered as adjuvants for the induction of antigen-specific immune responses, as in the design of vaccines. Polyriboinosinic-polyribocytoidylic acid (poly I:C), a synthetic double-stranded RNA (dsRNA), is recognized by TLR3 and other intracellular receptors. Poly ICLC is a poly I:C analogue, which has been stabilized against the serum nucleases that are present in the plasma of primates. Poly I:C12U, another analogue, is less toxic but also less stable in vivo than poly I:C, and TLR3 is essential for its recognition. To study the effects of these compounds on the induction of protein-specific immune responses in an animal model relevant to humans, rhesus macaques were immunized subcutaneously (s.c.) with keyhole limpet hemocyanin (KLH) or human papillomavirus (HPV)16 capsomeres with or without dsRNA or a control adjuvant, the TLR9 ligand CpG-C. All dsRNA compounds served as adjuvants for KLH-specific cellular immune responses, with the highest proliferative responses being observed with 2 mg/animal poly ICLC (p = 0.002) or 6 mg/animal poly I:C12U (p = 0.001) when compared with immunization with KLH alone. Notably, poly ICLC—but not CpG-C given at the same dose—also helped to induce HPV16-specific Th1 immune responses while both adjuvants supported the induction of strong anti-HPV16 L1 antibody responses as determined by ELISA and neutralization assay. In contrast, control animals injected with HPV16 capsomeres alone did not develop substantial HPV16-specific immune responses. Injection of dsRNA led to increased numbers of cells producing the T cell–activating chemokines CXCL9 and CXCL10 as detected by in situ hybridization in draining lymph nodes 18 hours after injections, and to increased serum levels of CXCL10 (p = 0.01). This was paralleled by the reduced production of the homeostatic T cell–attracting chemokine CCL21. Thus, synthetic dsRNAs induce an innate chemokine response and act as adjuvants for virus-specific Th1 and humoral immune responses in nonhuman primates.

【 授权许可】

CC BY