The Allogeneic Effect in Inbred Mice

Abstract

In recent studies (1-3) it has been demonstrated that the passive transfer of imrnunocompetent allogeneic lymphoid cells to guinea pigs previously primed with 2,4-dinitrophenyl-ovalbumin (DNP-OVA) 1 results in the increased synthesis of anti-DNP and anti-OVA antibodies in the absence of further antigenic challenge, and markedly enhances anti-DNP responses to an appropriately timed challenge with DNP coupled to an unrelated carrier, bovine gamma globulin (BGG). This phenomenon has been termed the "allogeneic effect" and has several salient features. First, the phenomenon reflects and requires the development of a transient graftversus-host (GVtt) reaction in the lymphoid organs of the primed host (1). The existence of a concomitant host rejection reaction is not only not required, but appears to play little if any role (3). Secondly, the lymphoid cells of the host must be primed before the administration of allogeneic cells. Numerous attempts to demonstrate an enhanced primary response by the prior administration of allogeneic cells have failed, and, indeed, the primary response is usually suppressed under these circumstances (1-3a). Finally, the allogeneic effect has been shown to replace the requirement for carrier-specific helper T cells in the development of hapten-specific anamnestic antibody responses manifested by the primed lymphoid cells of the host (2).The studies presented in this and the accompanying paper (4) were undertaken in inbred mice to elucidate further the phenomenon of the allogeneic effect, in that, as a model, the mouse provides greater flexibility in manipulating cell populations and histocompatibility differences. In the experiments described here, we show that: (a) the general features of the allogeneic effect

Cell Interactions Between Histoincompatible T and B Lymphocytes

“…We have referred to this possible mechanism as a bystander effect because the pertinent B cell is not an integral participant in the relevant cell interaction (5,18,19). In fact, in these as well as in many previous attempts to elicit an allogeneic effect in vivo in this manner, we have been unable to do so (5,(17)(18)(19).…”

“…The more obvious manner is that the T cells of the DNP-KLH-primed donor inoculum react against foreign histocompatibility antigens of the irradiated host and, in turn, exert a facilitating effect on their isologous DNP-primed B lymphocytes. This type of "bystander" allogeneic effect was found not to occur in vivo in earlier published experiments from this laboratory (5,(17)(18)(19). The alternative explanation, which in fact seemed at first more improbable, is that sufficient radioresistant T lymphocytes remain in a (600 R) irradiated host to exert a considerable allogeneic effect directly on the primed B cells in the transferred donor inoculum.…”

Activation of T and B Lymphocytes in Vitro

“…This compound has been demonstrated to be highly tolerogenic for DNP-specific B cells both in vivo and in vitro under normal circumstances (29,(42)(43)(44). However, when administered to appropriately primed animals during a critical time period after induction of an allogeneic effect, DNP-D-GL can provide a definite inductive stimulus for primary or secondary anti-DNP antibody responses (29,41,45,46). Since no demonstrable T-cell function specific for the D-GL carrier has been demonstrated, these observations provided the strongest indirect proof that the allogeneic effect is mediated by a direct interaction on the responding B cells.…”

Immunological Tolerance in Bone Marrow-Derived Lymphocytes

“…It has been amply documented, however, that timing of optimal allogeneic cell interaction to antigen encounter by B cells is critical for development of enhancing effects in this system (7,8,14,17). It is possible that the preceding experiments did not allow sufficient time for generation of effective allogeneic cell interactions prior to the tolerogenic signal from DNP-D-GL.…”

“…The intriguing paradox with this molecule is that it induces tolerance extremely rapidly following exposure of B cells to it under normal conditions, and yet in the presence of a strong appropriately timed T-cell influence, such as that provided by the allogeneic effect, the molecule can transmit a positive immunogenic signal (1,4,(7)(8)(9). This provides, therefore, another method by which to test the relative permanence of B-cell inactivation by DNP-D-GL.…”