Biomedical subjects
Publications and source records attributed to C Süsal.
Anti-IgG autoantibodies are reported to possess immunoregulatory properties. In the present study, we investigated the effect of pretransplant serum IgG-anti-F(ab')2gamma autoantibody activity on kidney graft outcome in recipients from two transplant centers.
Immunization of LEW rats with strongly histoincompatible BN blood cells induces, in addition to anti-donor antibody, a broadly reactive IgG autoantibody which binds to IgG and IgM molecules (IgG anti-Ig). Minute amounts of affinity purified IgG anti-Ig (0.2 pg/10(6) cells) suppress the antibody production in vitro of antigen receptor (AgR)-stimulated B cells derived from rats of the same strain. The suppressive antibody is also active in the whole serum IgG fraction. Importantly, anti-Ig-induced suppression is governed by restriction mechanisms: only AgR-occupied B cells are affected, the suppression is cell cycle dependent, and maximum suppression is obtained at an optimum IgG concentration. Treatment of rats in vivo with 0.8 mg Ig-anti-Ig (whole IgG fraction) along with allogeneic cells resulted in nearly complete suppression of the anti-donor antibody response. Possible mechanisms of B cell suppression by IgG anti-Ig are crosslinking of AgR with FcR, or cocapping of the two receptors with sterical interaction as a consequence of their separate occupation. Both alternatives lead to the release of an inactivating signal.
Heterologous antiimmunoglobulin antibodies are efficient regulators of the B cell response. We have shown that during the immune response against allogeneic cells the immune system develops autologous IgG-antiimmunoglobulin. A few molecules of this "physiological" autoantibody suppress the IgM production of one B cell in vitro. In the current series of experiments we further define the regulation of antigen receptor-activated B cells by this autoantibody. To mimic the in vivo situation, where IgG-anti-Ig appears a few days after alloimmunization, the antibody's effect on an already ongoing B cell response was studied. Interestingly, we found that the IgG-anti-Ig loses its suppressive effect when added to the cell culture 1 or 2 days after B cell activation, but that suppression can be completely restored when the cells are restimulated via their antigen receptor. Thus, the IgG-anti-Ig antibody suppresses B cells only when their antigen receptor is occupied. Even restimulated B cells become refractory 8 hr after activation, and later (24 hr) regain their susceptibility to IgG-anti-Ig-induced suppression. The Fc receptor is involved in mediating suppression since the antibody's suppressive capacity is abolished after removal of its Fc region. Possible mechanisms of B cell suppression by IgG-anti-Ig are crosslinking of antigen receptor with Fc receptor, or cocapping and functional interaction of the two receptors as a result of their separate occupancy. Our experiments demonstrate that B cell regulation by IgG-anti-Ig produced during an immune response to allogeneic cells is governed by 3 restriction mechanisms: antigen receptor occupancy, activation stage dependency, and optimal antibody concentration.
Pretransplant sera of 474 kidney graft recipients were tested for IgG-anti-F(ab')2 gamma activity. The patients had significantly higher IgG-anti-F(ab')2 gamma activity than healthy controls (P = 0.0004). Serum lymphocytotoxic antibodies were correlated with IgG-anti-F(ab')2 gamma (P = 0.004), whereas CMV infection and blood transfusions were not. We found a significant association between pretransplant IgG-anti-F(ab')2 gamma activity and early and 1-year kidney graft outcome. This association was pronounced in recipients with no lymphocytotoxic antibodies. Recipients with immediately functioning grafts and a creatinine < 130 mumol/L at 1 year had strikingly higher pretransplant IgG-anti-F(ab')2 gamma activity than patients with graft failure (P < 0.0001).
Sera of 76 HIV-negative hemophilia patients, 103 HIV-positive (HIV+) hemophilia patients free of AIDS or AIDS related complex (ARC), and 32 HIV+ hemophilia patients with AIDS/ARC were tested for four different anti-IgG activities. IgG-anti-F(ab')2 gamma, IgM-anti-F(ab')2 gamma, and IgG-anti-Fc gamma serum activities were significantly associated with the clinical stage of HIV infection, whereas IgM-anti-Fc gamma was not. IgG-anti-F(ab')2 gamma activity was found to be caused by cross-reaction of anti-HIV antibody with an epitope within the constant CH1 domain of human IgG. HIV+ hemophilia patients with severe thrombocytopenia (less than 50,000/microliters platelet counts) had significantly higher IgM-anti-IgG activity than patients with greater than 50,000/microliters platelets. Because anti-IgG antibodies possess immunoregulatory properties, our results may serve as a possible explanation for the frequent B cell disorders encountered in HIV-infected patients.
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To demonstrate whether anti-IgG autoantibodies of different isotypes and specificities play a role in kidney transplantation, pretransplant sera of recipients (a) with well-functioning grafts (n = 40); (b) with reversible rejection episodes that were treated successfully (n = 63); and (c) with irreversible graft rejection (n = 40) were tested for four different anti-IgG autoantibody activities. A protective effect of IgG-anti-F(ab)2 gamma antibodies on graft survival was observed (p less than 0.01). High pretransplant IgG-anti-Fc gamma activity was found to be associated with a low kidney graft survival rate (p less than 0.02). Pretransplant IgM-anti-F(ab)2 gamma and IgM-anti-Fc gamma activities showed no effect on kidney graft outcome.
Treatment of LEW rats before transplantation with BN blood cells preincubated with LEW-anti-BN serum resulted in prolonged BN kidney graft survival (untreated, 8 +/- 0.4 days; pretreated, 124 +/- 36). The serum of pretreated animals contains a factor which suppresses T cell proliferation against donor antigens. This effect was not mediated by antiidiotypic antibodies because it was reproduced in a donor-unrelated system. The serum and IgG of pretreated animals also suppressed the humoral immune response. As for T cells, the antibody-suppressive effect was not donor-restricted. A broadly reactive anti-immunoglobulin (anti-B cell) autoantibody was found in the IgG fraction of immunized animals. The mediation of immunosuppression by broadly reactive anti-B and T cell autoantibodies induced by the immunization with antibody-coated blood cells is discussed.
This study is an extension of our previous report that alloimmunization produces a serum factor that suppresses the lymphocytotoxic antibody response. The experiments presented herein show that: (1) serum and IgG of pretreated rats contain an antibody directed against the constant region of IgG; (2) the anti-IgG has strong anti-Fc-gamma and weak anti-Fab activity; (3) the antibody also reacts with IgM; (4) the antiimmunoglobulin is an autoantibody; and (5) the antiimmunoglobulin suppresses the primary B cell response in vitro.
The pretreatment of LEW (RT-1l) rat recipients with antibody-coated BN (RT-1n) blood cells resulted in the suppression of the LEW antibody response against subsequent BN platelet and leukocyte transfusions. Both coating with homologous LEW-anti-BN serum or heterologous rabbit-anti-rat lymphocyte serum was effective. Repeated boosting with uncoated platelets or leukocytes did not abrogate the suppression. The degree of suppression was dependent on the amount of antibody used for cell coating. The induced suppression was also extended to uncoated antigens and unrelated third-party cells. The serum-IgG fraction of pretreated rats was strongly immunosuppressive, suggesting that the mechanism of suppression was related to the induction of a broadly reactive regulatory IgG.
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Transfusion with antibody-coated allogeneic blood cells suppresses the cytotoxic antidonor antibody response in a strongly incompatible rat combination (BN----LEW). Cell coating with homologous recipient antidonor antiserum, rat monoclonal antibodies against MHC class I donor antigens, or rabbit antirat lymphocyte serum all were effective. The suppression was not abrogated by repeated booster transfusions with untreated donor blood. Moreover, the suppression extended to antibody-uncoated antigens present on the same donor cell. Not only the antibody response but also the Graft-versus-host reaction against donor antigens was suppressed. The serum of pretreated animals contained suppressive activity. It suppressed the cytotoxic antibody response as well as the cellular immune response (GVH) when transferred into syngeneic recipients. A weaker suppression of antibody response was obtained by transferring spleen cells of pretreated animals into syngeneic recipients. The transfer data suggest that broadly reactive serum factor(s) were mainly responsible for the suppressive effect. Transfusion with LEW-anti-BN-coated donor cells before transplantation induced markedly prolonged kidney graft survival in the BN----LEW combination without additional immunosuppression (untreated controls: 8.4 +/- 0.4, pretreated recipients: 124 +/- 36 days, P less than 10(-4)).
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