transforming-growth-factor-beta and resiquimod

Integrin αvβ6 can convert the transforming growth factor (TGF)-β precursor to the mature form. Resiquimod (R848) can generate TGF-β-producing regulatory T cells (Treg). Thus, to concurrent administration of specific antigen and R848 may generate antigen-specific Tregs, that is expected to restore immune tolerance in subjects with airway allergic diseases (AAD).. A bio-nanoparticle, designated Rexo, containing an antigen/MHC II complex and R848, was naturally assembled in dendritic cells, that was released as an exosome. An AAD mouse model was developed used to test the effects of Rexo on restoring the immune tolerance in the airways.. Exposure to R848 failed to induce Tregs in the β6-deficient mouse airway tissues, that were successfully induced in wild type mice. The results were validated inin vitro experiments. R848 activated the TLR7/MyD88/p38 signal pathway to increase the αvβ6 levels in CD4. Rexos can inhibit experimental AAD via inducing antigen-specific Tregs to restore immune tolerance in the airway tissues, suggesting that Rexos have the translational potential to be used in the treatment of AAD.

Topics: Allergens; Animals; Antigen Presentation; Antigens, Neoplasm; Dendritic Cells; Exosomes; Histocompatibility Antigens Class II; Imidazoles; Immune Tolerance; Integrins; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Knockout; Nanoparticles; Respiratory Hypersensitivity; Signal Transduction; T-Lymphocytes, Regulatory; Toll-Like Receptor 7; Transforming Growth Factor beta

Adjuvant enhancing mucosal immune response is preferred in controlling many pathogens at the portal of entry. Earlier, we reported that a toll-like-receptor 7 (TLR7) agonist, resiquimod (R-848), stimulated the systemic immunity when adjuvanted with the inactivated Newcastle disease virus vaccine in the chicken. Here, we report the effect of R-848 when adjuvanted with live or inactivated avian infectious bronchitis virus (IBV) vaccines with special emphasis on mucosal immunity. Specific pathogen free (SPF) chicks (n = 60) were equally divided into six groups at two weeks of age and immunized with either inactivated or live IBV vaccine adjuvanted with or without R-848. Groups that received either PBS or R-848 served as control. A booster was given on 14 days post-immunization (dpi). R-848 enhanced the antigen specific humoral and cellular immune responses when co-administered with the vaccines as evidenced by an increase in the antibody titre in ELISA and stimulation index in lymphocyte transformation test (LTT) till 35 dpi and increased proportion of CD4

Topics: Adjuvants, Immunologic; Animals; Antibodies, Viral; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chickens; Coronavirus Infections; Disease Models, Animal; Imidazoles; Immunity; Immunity, Cellular; Immunity, Humoral; Immunity, Mucosal; Immunization; Immunoglobulin A; Infectious bronchitis virus; Leukocytes, Mononuclear; Poultry Diseases; Specific Pathogen-Free Organisms; Transforming Growth Factor beta; Vaccination; Vaccines, Attenuated; Vaccines, Inactivated; Viral Vaccines

The evolution of allergic asthma is tightly controlled by effector and regulatory cells, as well as cytokines such as IL-10 and/or TGF-β, and it is widely acknowledged that environmental exposure to allergens and infectious agents can influence these processes. In this context, the recognition of pathogen-associated motifs, which trigger TLR activation pathways, plays a critical role with important consequences for disease progression and outcome. We addressed the question whether the TLR7 ligand resiquimod (R848), which has been shown to be protective in several experimental allergic asthma protocols, can also suppress typical asthma symptoms once the disease is established. To this end, we used an OVA-induced experimental model of murine allergic asthma in which R848 was injected after a series of challenges with aerosolized OVA. We found that the treatment attenuated allergic symptoms through a mechanism that required Tregs, as assessed by the expansion of this population in the lungs of mice having received R848, and the loss of R848-mediated suppression of allergic responses after in vivo Treg depletion. IL-10 provided only a minor contribution to this suppressive effect that was largely mediated through a TGF-β-dependent pathway, a finding that opens new therapeutic opportunities for the pharmacological targeting of Tregs.

Topics: Animals; Asthma; Disease Models, Animal; Imidazoles; Interleukin-10; Lung; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; T-Lymphocytes, Regulatory; Toll-Like Receptor 7; Transforming Growth Factor beta