Protein/DNA vaccine‐induced antigen‐specific Treg confer protection against asthma

Abstract

Asthma is a chronic inflammatory disorder caused by T-cell-mediated inflammation within airways. No antigen-specific treatment has been available. Using an OVA-induced murine asthma model, we find that co-immunization of an OVA epitope peptide with a DNA vaccine encoding the same epitope is able to prevent this experimental asthma as evidenced in the marked reduction of infiltrations of eosinophils and lymphocytes into the site of the allergen challenge. We demonstrate that the prevention of experimental asthma was directly related to the induction of a population of OVA-specific T-regulatory cells (Treg) exhibiting a CD4 1 CD25 À FoxP3 1 phenotype and expressing IL-10, TGF-b and IFN-c following the co-immunization. Blockade of IL-10 and TGF-b of the Treg by anti-IL-10 and TGF-b antibodies is partially able to reverse the suppression in vitro and in vivo, which caused the recurrence of the inflammation. Furthermore, adoptive transfer of the induced Treg is also able to suppress the OVA-induced asthma. To our knowledge, the combination of peptide with its cognate DNA vaccine protect experimental asthma via the induced epitope-specific Treg has not been previously reported and such strategy may lead to a novel immunotherapy against asthma in humans.Key words: Asthma Á Immune regulation Á Tolerance Á Treg cell Á Vaccination IntroductionAsthma is a chronic inflammatory disorder of the airways characterized by airway obstruction, increased airway responsiveness to a variety of stimuli as well as the infiltration by many inflammatory cells, including eosinophils, macrophages, lymphocytes and mast cells into lung tissue. CD4 1 T cells and Th2-biased cytokines (i.e. IL-4, IL-5 and IL-13) are believed to play a central role in the initiation and maintenance of the asthmatic response by regulating the production of IgE and the differentiation, recruitment and activation of mast cells and eosinophils [1][2][3].It has been proposed that Th1 cells, which secrete interferon-g (IFN-g), could protect against allergic disease by inhibiting the proliferation and development of Th2 cells [4] and IgE production [5]. Approaches of redirecting immunity from a Th2 type to Th1 type have also been demonstrated to result in temporary reduction of allergic reactions [6]. However, both autoimmune disease [7] and pathogen infection [8] induced Th1-biased immune responses were found to reduce the likelihood of allergy disease. Hansen et al. demonstrated that antigen-specific Th1 cells were ineffective in reducing the airway hyper-reactivity induced by Th2 cells but caused serious airway inflammation [9]. Thus, immunotherapeutic approaches using Th1 cell responses against asthma are rather complicated.Besides redirecting immunity-based approaches, several other strategies have also been considered to reduce allergic responses, including non-specific immunosuppressive drugs or monoclonal [21,22]. In this report, we further demonstrated that co-immunization of DNA and peptide vaccines against the same epitope-sequence of ovalbumin (OVA, aa 323...

Caveolin-1–Mediated Negative Signaling Plays a Critical Role in the Induction of Regulatory Dendritic Cells by DNA and Protein Coimmunization

“…Inflammatory bronchitis was induced in BALB/c mice as described previously (12,15). Autoimmune ovarian disease (AOD) was induced in C57BL/6 mice as described previously (11).…”

“…These DCregs could convert naive T cells into Agspecific regulatory T cells (iTregs) of a CD4 + CD25 2 Foxp3 + IL-10 + phenotype in vitro and in vivo (8), which in turn mediated Ag-specific tolerance (8)(9)(10)(11)(12). Given the role of these DCregs in initiating the tolerogenic process, we wish to understand how they are generated during coimmunization.…”

Induced Regulatory T Cells Superimpose Their Suppressive Capacity with Effector T Cells in Lymph Nodes via Antigen-Specific S1p1-Dependent Egress Blockage

“…The immunization induced antigen-specific CD4 + CD25 − asTregs and prevented the host from OVA sensitization-induced asthma (33). To evaluate the therapeutic value of this protocol in established asthma, we induced airway inflammation in BALB/c mice by multi-step sensitization/challenging of intranasal injection of OVA (Figure 1A).…”

“…On day 14, asthma of recipients was evaluated. Plethysmography was analyzed as reported (33). Briefly, mice were anesthetized and ventilated.…”

Manipulation of TH17 responses in pulmonary immunity and disease through vaccination

“…However, it is difficult to determine whether or not the therapies are directly and colleagues has demonstrated that co-administration of a protein with DNA coding for that protein can confer protection to allergic and autoimmune diseases through the induction of regulatory T-cells. [116][117][118] This group additionally demonstrated the converse that regulatory T-cells could be inhibited and the immunogenicity of vaccination increased through use of an inhibitor of regulatory T-cells as an adjuvant. 119 Thereby demonstrating the vast range of combinatorial possibilities with DNA-based vaccination approaches to either increase or suppress immune responses.…”