SUMMARYPreviously, we have reported on a liposomal adjuvant system for stimulation of both systemic IgG and mucosal s-IgA responses against viral antigens (influenza virus subunit antigen or whole inactivated measles virus) administered intranasally to mice. Immune stimulation is observed with negatively charged, but not with zwitterionic, liposomes and is independent of a physical association of the antigen with the liposomes. Furthermore, liposome-mediated immune stimulation requires deposition of the liposomes and the antigen in the lower respiratory tract. In the present study, it is shown that alveolar macrophages (AM) are the main target cells for negatively charged liposomes administered to the lungs of mice. AM isolated from animals, to which negatively charged liposomes were administered beforehand, showed large intracellular vacuoles, suggestive of massive liposome uptake. Under ex vivo conditions, both AM and RAW 264 cells exhibited a high capacity to take up negatively charged liposomes. The deposition of negatively charged liposomes, but not zwitterionic, liposomes in the lung reduced the phagocytic and migratory behaviour of AM, as assessed on the basis of transport of carbon particles to the draining lymph nodes of the lungs. Depletion of AM in vivo with dichloromethylene diphosphonate, facilitated an enhanced systemic and local antibody response against influenza subunit antigen deposited subsequently to the lower respiratory tract. In conclusion, these data provide support for the hypothesis that uptake of negatively charged liposomes blocks the immunosuppressive activity of AM, thereby facilitating local and systemic antibody responses.
It is unknown whether dendritic cells are able to migrate normally from the recipient into the allogeneic lung graft. Using monoclonal antibodies to major histocompatibility complex class II antigens (OX6 for both donor and recipient types; HIS19 for recipient type), we studied the replacement of donor dendritic cells by recipient type cells in rat lung allografts that are indefinitely accepted with a short course of cyclosporine early after transplantation. The recipient dendritic cells started to migrate into lung allografts early (by 1 wk) after transplantation. Donor dendritic cells in the grafts were replaced by recipient cells during the first 2 months after transplantation. Dendritic cells in the perivascular tissue were replaced quickly, most of them within 1 wk, whereas those in the alveolar septa were replaced slowly. In the lung allograft surviving 2 or more months, the normal phenotypic heterogeneity of dendritic cells was preserved. Recipient dendritic cells accumulated in dense peribronchial aggregates that remained 6 months. The dendritic aggregates were associated with late airway changes in allografted lungs. The abnormal accumulation of dendritic cells peribronchially might be related to an abnormal mucosal immune response or a chronic rejection process.
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