The Allogeneic Effect in Inbred Mice

Abstract

The allogeneic effect has been shown to replace the requirement for carrier-specific helper thymus-derived (T) lymphocytes in secondary antihapten antibody responses in guinea pigs or mice. Attempts to enhance primary antibody responses to either 2,4-dinitrophenyl (DNP)-keyhole limpet hemocyanin (KLH) or DNP-ovalbumin (OVA) by the allogeneic effect have failed, and frequently result in suppression. However, the present studies have demonstrated a clear allogeneic effect on primary anti-DNP responses to a DNP-conjugate of the copolymer of D-glutamic acid and D-lysine, DNP-D-GL. This compound, for which no carrier-specific helper T cells exist, normally induces a state of DNP-specific tolerance in the doses employed. However, normal (BALB/c x A/J)F1 recipients developed primary anti-DNP antibody responses, and of the IgG class, when DNP-D-GL was administered shortly after the transfer of allogeneic parental A strain lymphoid cells. To test the possibility that the presence of KLH-specific T lymphocytes might inhibit the expression of the allogeneic effect on the primary response to DNP-KLH, studies were undertaken using T cell-depleted spleen cells. In this model, the allogeneic effect again enhanced the primary response to DNP-D-GL, but still failed to enhance the primary response to DNP-KLH. These studies indicate that the structure of the molecule employed and its specific interaction with the bone marrow-derived (B) cell membrane may be critical in the capacity of primed and unprimed B cells to be influenced by the allogeneic effect.

Immunological Tolerance in Bone Marrow-Derived Lymphocytes

“…This tolerant state is induced extremely rapidly and is not reversible once it has occurred. In marked contrast, however, is the capacity of this very same molecule to serve as a potent stimulus for differentiation of DNP-specific precursor B cells to antibody-producing cells when the initial binding event takes place in a milieu of strong T-cell activity such as that exerted by the allogeneic effect (1,4,(7)(8)(9). In this respect, however, the critical moment of specific binding of DNP-D-GL must occur during or after the generation of this T-cell activity; if the binding event precedes the development of T-cell participation, no stimulation will occur as a result of the very rapid kinetics of the tolerogenic events within the cell population exposed to this molecule.…”

“…Unprimed DNP-specific lymphocytes can also be induced to primary anti-DNP antibody production, and of the IgG class, by DNP-D-GL in the presence of an allogeneic effect (9). Indeed, it is particularly interesting that DNP-D-GL works in an allogeneic effect on unprimed B cells whereas normal immunogenic conjugates such as DNP-KLH fail to behave in the same fashion (9).…”

“…Thus, DNP-primed lymphocytes will develop secondary anti-DNP antibody responses to challenge with DNP-D-GL provided an appropriately timed transient graft-vs.-host reaction (allogeneic effect) has been induced (1,4,7,8). Unprimed DNP-specific lymphocytes can also be induced to primary anti-DNP antibody production, and of the IgG class, by DNP-D-GL in the presence of an allogeneic effect (9). Indeed, it is particularly interesting that DNP-D-GL works in an allogeneic effect on unprimed B cells whereas normal immunogenic conjugates such as DNP-KLH fail to behave in the same fashion (9).…”

“…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.…”

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.…”