LONG-LASTING UNRESPONSIVENESS TO POLYCLONAL T-CELL-BINDING IMMUNOGLOBULINS

We have shown that mice after a single injection of anti-T cell antibo dy followed by multiple injections of a second xeno-, allo-or syngenei c anti-T cell antibody differing from the former in species origin dev eloped specific, long-lasting tolerance to the second antibody. To cha racterize the mechanism of this anti-antibody unresponsiveness and the modalities accompanying the preinjection step, we injected mice with anti-pan T, anti-CD4 or anti-CD8 monoclonal antibodies, followed by mu ltiple injections of polyclonal rabbit anti-mouse thymocyte globulin ( RbATG). Our observations indicate that: (i) Depletion of CD4(+) cells is the most important factor for tolerance induction to subsequently i njected RbATG. Non-depleting mAb were less effective, and antibody-ind uced CD4 modulation or blockade were inconsequential. (ii) The prevent ion of anti-antibody responses involves specific B cell tolerance, as shown by suppression of anti-RbATG but not anti-bovine serum albumin ( BSA) antibodies after challenge of tolerant mice with RbATG-BSA conjug ates. (iii) Suppression of anti-antibody responses involves T cell unr esponsiveness rather marginally, as demonstrated by in vitro spleen ce ll restimulation with RbATG and in vivo antibody response to RbATG-flu orescein isothiocyanate hapten conjugate. (iv) Analysis of isotypes of anti-RbATG antibodies does not suggest alterations in Th1/Th2 tuning as being responsible for this kind of tolerance. (v) Over 150-day surv ival of fully allogeneic skin grafts (CBA-to-C57BL/6) was observed in mice preinjected with anti pan-T or anti-CD4 mAb followed by RbATG. Mi ce treated with anti-CD4 mAb alone rejected allografts within 21 days and induced anti-antibodies. Taken together, our experiments suggest B cell tolerance as main mechanism in this type of acquired long-term h umoral unresponsiveness to foreign, polyclonal, T cell-binding immunog lobulins.