Immunological Adjuvants and the Mechanism of Cell Cooperation

Abstract

Immunological adjuvants are defined as agents which act nonspecifically to enhance immune responsiveness to a specific antigen. While many substances are known to have adjuvanticity, remarkably little is understood about the mechanism by which they enhance either the antibody response or cellular immunity. It is now clear, for at least some antigens, that interaction of three cell types is required for antibody formation: thymus-derived lymphocytes (T cells), bone marrow-derived lymphocytes (B cells), and probably macrophages. In studies on the specificity of response to haptenprotein conjugates, it has emerged that the specificity of the antibody-producing cell (hapten specific) is generally not the same as that of the T cell which bears immunological memory (carrier specific) (1-3). In addition, the characteristics of the helper cell involved in antibody formation, i.e. thymus derived, nonantibody secreting, carrier specific, and nondividing, appear at present indistinguishable from those of the thymus-derived lymphocyte responsible for cell-mediated immunity (4).We chose to pursue this analogy by exploring the effects of the two most effective immunological adjuvants in mice, pertussis vaccine and tubercle bacilli, the latter at least, known also to engender delayed-type hypersensitivity. The in vitro immunization system developed by Mishell and Dutton (5) permitted us to study the effect of adjuvant on a primary in vitro response to sheep erythrocytes (SRBC).We Materials and MethodsThe adjuvants used in this study were Bordetdla pertussis vaccine, fluid, USP (E. Lilly & Co., Indianapolis, Ind.) containing 8 antigenic units (AU/ml (equivalent to no fewer than 6.4 X 101° standard pertussis organisms/ml). For use in vitro, the organisms were dialyzed * Present address:

Immunodeviation by Passive Antibody, an Expression of Selective Immunodepression

“…In order to be activated, the B cell apparently needs more than one signal: two or more molecules of antigen cross-linked by anticarrier antibody (25) or by anticarrier T cells, these being then linked to the B cell through the antigen (26). In some instances, however, the second signal does not originate in the antigen under study; T cells might act on B cells either directly as in the allogeneic effect (22,23) or through the liberation of a mediator induced by their interaction with any antigen to which they are sensitized (21,24). These interpretations must be accepted with caution, inasmuch as they are inferred from complex systems in which cross-reactivity between antigens might furthermore exist.…”

“…Carrier and hapten determinants are unrelated, separate determinants (14, 17); this conclusion is strongly favored by experiments where tolerance to the carrier reduces the response to the hapten (13,18,19). Carrier and hapten determinants must be on the same molecule (14,17,20), although recent reports challenge this conclusion (21)(22)(23)(24).…”

Adjuvant Activity of Mycobacterial Fractions

“…Maillard and Bloom reported that tubercle bacilli affect T cells which produce the soluble factor(s) which mediates the adjuvant effect [34]. More recently, Mitchell et al have shown that BCG cells nonspecifically enhanced cell-mediated cytotoxicity in which T cells are effector cells [38].…”

“…Maillard and Bloom suggested that pertussis and tubercle bacilli act on T cells, resulting in soluble factor(s) being released from T cells and capable of exerting an adjuvant effect [34]. In this report, we have tried to elucidate whether the cell wall of BCG stimulates the humoral responses against SRBC and hapten-protein conjugate and have also tried to identify the type of cell responsible for the adjuvant effect using the in vitro culture system.…”

Enhancement of Humoral Immune Responses

“…Many experiments have been performed to show that DTH reactions can result in nonspecific enhancement of in vitro humo ral immune responses [11,15]. This phe nomenon is thought to be related in some way to the mechanisms of action of adju vants and may provide possible explana tions for some functions of adjuvants.…”