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Freshly isolated murine PP B cells were cultured with 10 different cytokines, including IL-1 alpha, IL-2, IL-4, IL-5, IL-6, IL-7, IFN-gamma, TNF-alpha, and TGF-beta, to investigate a possible role for these cytokines in induction of Ig synthesis. Of interest was the finding that only IL-5 and both mouse recombinant (mr) and human recombinant (hr) IL-6 enhanced IgA synthesis. The effect was greater with either mrIL-6 or hrIL-6 than with mrIL-5. IL-6 induced cycling mIgA+ PP B cells to secrete high levels of IgA (approximately 7-fold increase over control). Of importance was the finding that mrIL-6 had little effect on secretion of IgM or IgG by PP B cell cultures. hrIL-6 also increased IgA secretion by PP B cells and this enhancement was abolished by a goat anti-hrIL-6 antiserum. mrIL-6 did not cause B cell proliferation but induced a sharp increase in numbers of B cells secreting IgA. Isotype-switching was not a mechanism for this marked increase in IgA synthesis since mIgA- PP B cells were not induced to secrete IgA by mrIL-6. From these studies we conclude that IL-6 plays an important role in promoting the terminal differentiation of PP B cells to IgA-secreting plasma cells.

Use of electroporation after PV administration provided superior immunogenicity than delivery without electroporation. This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans.

The highly sensitive gamma interferon (IFN-␥) enzyme-linked immunosorbent spot (ELISPOT) assay permits the investigation of the role of cell-mediated immunity (CMI) in the protection of young children against influenza. Preliminary studies of young children confirmed that the IFN-␥ ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to <36 months, an intranasal dose of 10 7 fluorescent focus units (FFU) of a live attenuated influenza virus vaccine (CAIV-T) elicited substantial CMI responses. A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination. The role of CMI in actual protection against community-acquired, culture-confirmed clinical influenza by CAIV-T was investigated in a large randomized, double-blind, placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to <36 months in the Philippines and Thailand. The estimated protection curve indicated that the majority of infants and young children with >100 spot-forming cells/10 6 peripheral blood mononuclear cells were protected against clinical influenza, establishing a possible target level of CMI for future influenza vaccine development. The ELISPOT assay for IFN-␥ is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza, especially those used for children.