As stated above, in the current model for the mechanism of gp96-induced tumor-specific immunity gp96-peptide complexes are processed by professional phagocytic APC and gp96-associated peptides are channelled into the MHC-class I restricted antigen presentation pathway. This model was corroborated by cell depletion experiments which showed that for the priming phase of gp96-induced immunity CD8 positive T cells and phagocytic cells are needed  and by representation of gp96-associated peptide antigens by mouse macrophages in vitro . The observation that extremely small quantities of peptides complexed with gp96 are sufficient to induce immunity led to the hypothesis that the uptake of gp96/peptide complexes by APC is receptor-mediated , There is no direct evidence so far that this is the case. We could observe preferential binding of gp96 to monocytes within human PBMC subpopulations and to subpopulations of monocytic dendritic cells (Heike and Bethke, unpublished results). Both APC types could mediate gp96-induced CTL activation in our experiments, although dendritic cells were more effective than monocytes. However, a characterization of a stress protein receptor on APC awaits further characterization. The intracellular processing pathways of gp96/peptide complexes in APC remain also unclear.
Another function of tumor stress protein preparations, which augments the specific immune responses and may be responsible for the extraordinary effec-tivity of tumor-derived HSP vaccines is the activation of innate immunity. NK cells are essential in addition to T cells for the gp96-induced therapeutic immunity against tumors in early phases of tumor growth and metastasis . This corresponds to the observation of Multhoff et. al. [16, 29] that NK cells can recognize HSP 70 directly on the surface of human tumor cells. It is still unclear, as to whether, or not, yS-T cells also contribute to stress protein-induced tumor immunity. The demonstration that yS-T cells or CD4/CD8 negative T cells can recognize HSP 70 on the cell surface of tumor cells, presumably in association with specific tumor antigens [32, 33], points to this possibility. In addition to the activation of cytotoxic effector cells of the innate immune system, preliminary data suggest that gp96 preparations primarily activate pro fessional APC to release proinflammatory cytokines [48, and Heike et al., unpublished results]. If this can be substantiated, gp96 vaccines would be especially suitable for primary activation of T cells, because they would represent danger signals, which are postulated to be essential for a primary immune activation , Gp96 and possibly other stress proteins like HSP 70 and 90 would then have a unique combination of adjuvant effects: binding to APC, channeling of associated antigens into the MHC class I restricted antigen presentation pathway of APC and primary APC activation to release proinflammatory cytokines. An additional effect would be that the stress proteins themselves elicit a T-cell helper response. These mechanisms might also explain the strong adjuvant effects of the stress proteins HSP 60, 70 and gp96 for antigens from infectious agents complexed with the respective stress proteins or bound covalently to them [49, 67-72], These stress protein/antigen complexes were clearly superior to the antigens alone in eliciting antigen-specific helper or cytotoxic T-cell responses, antibody responses and protective immunity against the respective infectious agents.
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