SKIN DELIVERY OF A HYBRID LIPOSOME ISCOM VACCINE IMPLICATES A ROLE FOR ADJUVANTS IN RAPID MODULATION OF INFLAMMATORY CELLS INVOLVED IN INNATE IMMUNITY BEFORE THE ENHANCEMENT OF ADAPTIVE IMMUNE-RESPONSES/

There is now compelling evidence that intradermal vaccination with an efficacious adjuvanted antigen triggers a series of coordinated respon ses characterized initially by the rapid mobilization and recruitment of granulocytes to the lung. Activation of effector cells of the innat e immune system is intended to provide surveillance and temporary prot ective cover at vulnerable mucosal sites while both T and B cell precu rsors, as well as haematopoietic progenitor cells, are undergoing dram atic reductions in numbers during the first 2-4 days post-vaccination. Some of these events recapitulate those seen after infection with a p athogen. Initial decreases in cell numbers in the thymus and bone marr ow (BM) are followed by rapid increases in cellular proliferation in t hese organs, probably in response to peripheral signals. Vaccine-induc ed cell death (by apoptosis) in the thymus may provide one of many sti muli needed to up-regulate BM production of progenitor cells, and cell s of the B, myeloid and monocytic lineages so that depleted peripheral compartments are replenished. Reconstitution of the latter cell popul ation is critical in ensuring sufficient numbers of APC are generated to deal with extraneous antigen resulting from either vaccination or p roliferation of a pathogen. Ultimately, these APC, as effector cells o f the innate immune system, must provide pattern recognition of danger ous pathogens and serve to activate appropriate T cell responses. Vacc ination not only educates both the innate and adaptive arms of the imm une response but also more interestingly, appears to regulate subseque nt innate immune responses following exposure to a lethal challenge do se of bacteria. Under these conditions, the rate of loss of RM precurs ors is greatly attenuated in mice previously vaccinated with adjuvante d antigen compared to unvaccinated controls or mice that had received only antigen. Mice intradermally vaccinated with adjuvanted antigen al so displayed increased rates of granulocyte and monocyte recruitment i n the lung;Ind spleen. These events occurred very rapidly within 12-36 h of challenge and may be crucial in providing complete protection in vaccinated mice against a challenge dose that was otherwise lethal fo r unvaccinated controls. Therefore, an important characteristic of an efficacious intradermal vaccine may be the ability to deplete T and B precursors in the thymus and BM lymphoid compartments followed by incr eased rates of haematopoiesis to re-supply peripheral requirements for granulocytes/monocytes, and T and B cells. Adaptive immunity elicited by intradermal vaccination is, therefore, dependent upon prior activa tion of the innate immune system.