Influence of Dose and Route of Antigen Injection on the Immunological Induction of T Cells

Abstract

If it were possible to promote or suspend the formation of specifically sensitized lymphocytes (activated T cells), the problems of achieving a sustained attack on tumor cells and microbial parasites, or of preventing graft rejection, might be largely overcome. Methods for manipulating the immune response for such purposes have been proposed from time to time (1-3), but progress has been slow because so little is known of how cell-mediated immunity is normally regulated. Although much has been learned about the allied problem cf what controls the formation of antibodies (4), almost nothing is known about the mechanism that regulates the production and function of the cells which mediate delayed-type hypersensitivity (DTH).I While studying the tumor-suppressive activity of Mycobacterium boris BCG it was observed that lymphoid tissues which were under the stimtflatory influence of a BCG infection were capable of a much more vigorous response to a second antigen (5). Both cellular and humoral immunity to sheep red blood cells (SRBC) were augmented, as evidenced by higher and more sustained levels (DTH) and increased numbers of plaque-forming cells (PFC) in responding lymph nodes. Since D T H does not usually appear unless special conditions of immunization are used, these findings suggested that the formation of activated T cells is normally restricted by an inhibitory mechanism that does not operate properly in lymphoid tissues infected with BCG.Miller et al. (5) have shown that mice given a subcutaneous injection of SRBC in saline develop a poorly sustained state of hypersensitivity which conforms to all of the established criteria by which D T H is recognized, including its mediation by 0-bearing lymphocytes. It was therefore possible to study the mechanism which regulates T-cell activity in the absence of any influence from adjuvants such as were used by Nelson and Mildenhall (6) when they, too, showed that mice develop classical D T H in response to SRBC.

Potentiation of T-Cell-Mediated Immunity by Selective Suppression of Antibody Formation With Cyclophosphamide

“…Witness, for example, the contrasting responses of normal and splenectomized mice to a massive intravenous injection of SRBC: The former produce antibody but no DTH, while the latter develop DTH but make little or no antibody (1). This demonstrates, among other things, that antigen alone cannot interfere with the function or formation of activated T cells.…”

“…less responsive to SRBC (1,2). It was nonetheless apparent that DTH was potentiated because CY suppresses the inhibitory mechanism that is activated by a large dose of antigen.…”

“…reaches its peak and begins to decay on day 4 in mice immunized in one footpad with 108 SRBC, the optimum dose for sensitization by this route (1). The effect of CY on DTH was therefore measured at two time points, days 4 and 8.…”

Augmentation of mitogen‐induced thymocyte proliferation by bacterial products is mediated by an Mr 36 000 monokine

“…While Macdonald et al (22) did not detect any abnormality in the delayed hypersensitivity response in germfree mice following sensitization in Freund's complete adjuvant, there was a reduced skin test response to intravenously administered sheep red blood cells. This could be explained by the transient nature of this form of cell-mediated response (23) and therefore the requirement for a substantial population of responding cells. Overall, the findings in germ-free animals are compatible with a limited seeding ofthe peripheral tissues with immunocompetent T cells.…”

Delayed‐Type Hypersensitivity (DTH) Response to Dengue Virus in Mice: Effect of Route of Sensitization and Splenectomy

“…Since the route of sensitization has been shown to be an important factor influencing sensitization of mice for DTH (4), it is of interest to study the various routes of sensitization in the development of DTH to dengue virus in mice. In addition, the spleen is an important organ in the immune responses of a host.…”