Mice immunized with optimal doses of autologous tumor–derived gp96 resist a challenge with the tumor that was the source of gp96. Immunization with quantities of gp96 5–10 times larger than the optimal dose does not elicit tumor immunity. This lack of effect is shown to be an active, antigen-specific effect, in that immunization with high doses of tumor-derived gp96, but not normal tissue–derived gp96, downregulates the antitumor immune response. Furthermore, immunization with fractionated doses of gp96 elicits the same kind and level of response as elicited by a single dose equivalent to the total of the fractionated doses. This is true of the tumor-protective doses as well as the high downregulatory doses of gp96. The downregulatory activity can be adoptively transferred by CD4+ but not CD8+ T lymphocytes from mice immunized with high doses of gp96. These observations indicate that immunization with gp96 induces a highly regulated immune response that, depending upon the conditions of immunization, results in tumor immunity or downregulation.
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