Immune responses can be profoundly altered in mice by treatment with monoclonal antibodies (MAb) to L3T4, the mouse homologue for the CD4 antigen in humans. Treatment of mice with anti-L3T4 blocks both primary and secondary immune responses, delays allograft rejection, and retards autoimmunity. To determine whether anti-L3T4 could also be used to induce tolerance, we investigated the effect of treatment with rat MAb to L3T4 on the immune response to two other rat MAb: MAb to chicken egg ovalbumin (OVA) and MAb to T200, an antigen expressed on all mouse mononuclear blood cells. Treatment with anti-L3T4 prevented the primary humoral response to both of these MAb. Moreover, the anti-L3T4 MAb induced tolerance to itself, and it induced tolerance to the anti-OVA MAb when the two MAb were given concurrently. However, anti-L3T4 did not induce tolerance to the anti-T200 MAb when these MAb were given concurrently. These findings indicate that treatment with MAb to L3T4 may provide a new method for inducing tolerance to some, but not all, antigens. Because L3T4 in mice is homologous to CD4 in humans, our findings suggest that it may be possible to use anti-CD4 to induce tolerance to specific xenogeneic MAb, thereby facilitating their use as therapeutic agents in people.
Treatment of mice with monoclonal antibody (MAb) to L3T4 blocks the humoral immune response to antigens administered when L3T4+ cells are depleted. To determine whether depletion of target cells is required to suppress immunity, we examined the effect of treatment with F(ab')2 fragments of anti-L3T4 on the response of BALB/c mice to immunization with bovine serum albumin (BSA) in complete Freund's adjuvant. Treatment with F(ab')2 fragments of anti-L3T4 every 2 days (1 mg i.p.) beginning at the time of immunization significantly inhibited production of anti-BSA antibodies without depleting target cells. A single injection of anti-L3T4 fragments at the time of immunization also significantly inhibited production of anti-BSA antibodies, but was not as effective as repeated administration of the MAb fragments (75% inhibition compared with 98% inhibition; p less than 0.05). Moreover, one injection of anti-L3T4 fragments stimulated a host immune response to the rat MAb, whereas sustained therapy with the anti-L3T4 fragments blocked this response. Surprisingly, low doses (less than or equal to 10 micrograms/mouse) of intact rat MAb to L3T4 also stimulated a host immune response to the MAb but, as previously reported, higher doses of intact MAb to L3T4 did not. These findings establish that depletion of L3T4+ cells is not required to suppress immunity with MAb to L3T4. They also indicate that the ability of rat MAb to L3T4 to block the immune response to itself is dose dependent. Because the L3T4 antigen in mice is homologous to the CD4 antigen in humans, our findings have implications regarding the potential use of MAb to CD4 in humans.
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