Role of lymph node phagocytes in the regulation of the IgG-mediated suppression of the immune response to influenza vaccine

Although the binding of an antigen to a specific immunoglobulin often enhances the antibody response against this antigen, the presence of inhibitory responses is also a common phenomenon. Amongst the latter, the best characterized is the IgG-mediated humoral suppression against large particulate antigens. This process, referred to as antibody-mediated immune suppression (AMIS), has been successfully utilized in clinical applications, such as the administration of specific IgGs to RhD negative mother, which prevents them from becoming immunized against RhD+ fetal erythrocytes. However, the immunological mechanism behind the IgG-mediated immune suppression remains poorly understood. We have developed a passive immunisation protocol that involves the administration of anti-influenza IgG antibodies prior to vaccination, namely H36-7 and FI6, which bind to two different epitopes of the viral HA molecule. Interestingly, these antibodies result in different degrees of suppression of the primary antibody responses to the UV-inactivated influenza vaccine, which was found to be complete in the case of H36-7, but only partial with FI6. Remarkably, the inhibition of the humoral response coincided with a reduction in the initial inflammatory reaction measured in the draining lymph node (LN) at 12 h p.v. and a lower activation of the LN-resident dendritic cells (LNDC).On the basis of our preliminary findings, we propose to study the role that the major phagocytic populations in the LN (LN resident macrophages and LNDC) have on the AMIS, using state-of-the-art in vivo imaging technology, molecular and cellular techniques and the generation of new transgenic mouse models. In addition, we wish to investigate the specific role of the Fc?R and the complement system in immune suppression, and the mechanism through which the AMIS reaction affects the humoural responses to viral epitopes that are not recognized by the administered IgG. We will also characterize the role of RIG-I in the initiation of the type I IFN response following vaccination, and how the formation of immune complexes affects the activation of this pathway. Antibody-mediated immune suppression may represent a powerful tool to modulate adverse immune responses in conditions in which self-antibody-mediated autoimmune diseases present serious health implications. Understanding the mechanism of AMIS may contribute to the discovery of new therapies for such immunological conditions. In addition, understanding the immune response to different type of antigens, can, in turn, inform better vaccine design strategies to develop long-term protective humoral immunity to influenza virus.