Long-lasting unresponsiveness to polyclonal T cell-binding immunoglobulins.
We have shown that mice after a single injection of anti-T cell antibody followed by multiple injections of a second xeno-, allo- or syngeneic anti-T cell antibody differing from the former in species origin developed specific, long-lasting tolerance to the second antibody. To characterize 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 multiple 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 injected RbATG. Non-depleting mAb were less effective, and antibody-induced CD4 modulation or blockade were inconsequential. (ii) The prevention 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 conjugates. (iii) Suppression of anti-antibody responses involves T cell unresponsiveness rather marginally, as demonstrated by in vitro spleen cell restimulation with RbATG and in vivo antibody response to RbATG-fluorescein 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 survival 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. Mice 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 humoral unresponsiveness to foreign, polyclonal, T cell-binding immunoglobulins.
Mysliwietz
J
J
GSF-National Research Center for Environment and Health, Institute of Immunology, Munich, Germany.
Thierfelder
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000961:Antilymphocyte Serum / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D017635:Clonal Anergy; D007108:Immune Tolerance; D007132:Immunoglobulin Isotypes / Q000276:immunology; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011817:Rabbits; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D007132:Immunoglobulin Isotypes