Time-dose-response studies on cellular immunity

The time-dose responses to several murine histocompatibility antigens were studied using lymphocytes as an antigen source for immunization and the speed of rejection of skin grafts as an assay of the level of immune responsiveness. It was observed that the weaker the first set response to an antigen the higher the minimal immunizing dose and the lower the tolerizing dose; thus, there was a small "immunizing window." The speed of onset of immune responsiveness and the magnitude of change in it following first antigen contact depended on the "strength" of the antigen. When the antigen was "strong" the level of response increased rapidly following first antigen contact. When the antigen was "weak" a period of tolerance appeared following first antigen contact, which then gave way to a state of immunity; the "weaker" the antigen the longer the interval and the greater the magnitude of tolerance. Increasing the antigen dose tended to magnify and prolong the tolerance. The "weaker" the antigen the longer the interval between first antigen contact and the appearance of immunity. Once established, the level of immunity was not constant. Undulations in the levels of all responses were noted; the "weaker" the antigen the larger the undulations. Possible explanations for the undulations and implications of the time-dose-response curves in immunotherapy are discussed.