| The embryo expresses paternal antigens foreign to the mother and therefore has been viewed as a natural allograft. Pregnancy constitutes a major challenge to the maternal immune system, as it has to tolerate the persistence of paternal alloantigen. Induction of the maternal immunosuppression to embryo is a main purpose for the maintenance of materno-fetal tolerance. In organ transplantation, it has been shown that the anergic T cells generated in vivo and in vitro can be transferred as suppresser cells to prevent allograft rejection. However, to our knowledge, the ability of the embryo antigen-anergic T cells to suppress maternal immune responses to the allogeneic fetus in vivo has been less known.The antigen-specific T cell activation is a critical step in the rejection of transplanted allografts. T-cell activation depends on ligation of T-cell receptor (TCR) by specific antigen-MHC complex as well as costimulatory signals delivered by certain adhesion molecules expressed on T cells and antigen-presenting cells (APC). The interaction between TCR and antigen-MHC complex in the absence of a costimulatory signal can induce a state of T-cell anergy in vitro as well as in vivo. Among a series of costimulatory pathways examined so far, the interaction of CD28 or CTLA-4 on T cells to CD80 and CD86 molecules on APC is the most critical pathway that determines whether the TCR-stimulated T cells become activated or anergic. This knowledge has been successfully used in animal models to induce the anergic T cells and prevent allograft rejection by blocking CD80 and/or CD86, thereby leading to long-term graft survival.In the present study, we employed a murine abortion-prone model in which CBA/J females impregnated by DBA/2 males have a high incidence of fetal resorptions,whereas a similar (H-2k x H-2d) matings, CBA/J females impregnated by BAL B/c males, have normal and low resorption rates. The abortion-prone CBA/J females mated with DBA/2 males were injected intraperitoneally with rat anti-murine CD80 and CD86 mAbs to generate the embryo antigen-anergic T cells in vivo. Thereafter, the anergic T cells were adoptively transferred into another abortion-prone CBA/J mice so as to investigate effect of adoptive transfer of embryo antigen-tolerant T cells on pregnant outcome of the abortion-prone matings and its possible mechanisms.Part I. Induction of materno-fetal immuno-tolerance by blockade of costimulatory pathway in abortion-prone matingsObjective: To study effect of blockade of CD28/B7 costimulatory pathway on the proliferation of CBA/J splenocytes in response to DBA/2 stimulator and the pregnant outcome of abortion-prone matings.Methods: The experiments were performed in following two groups, using CBA/J BALB/c matings as the normal pregnancy model and CBA/J DBA/2 matings as the abortion-prone model. The pregnant CBA/J mice were injected intraperitioneally with rat isotype IgG or rat anti-mouse CD80/CD86 mAb at day 4 of gestation (windows of murine implantation). The proliferation of CBA/J splenocytes in response to paternal splenocytes as stimulator was analyzed by one way mixed lymphocyte reaction, and IL-2 production in culture supematants was assayed by ELISA at day 9 of gestation. The embryo resorption rate was counted at day 14 of gestation.Results: In CBA/JxBALB/c matings, the combined administration of anti-CD80 and anti-CD86 mAbs did not affect the embryo resorption rate and proliferation of CBA/J splenocytes in response to BALB/c stimulator. In the CBA/J x DBA/2 matings, the combined anti-CD80/CD86 mAb treatment at day 4 of gestation reduced significantly the embryo resorption rate, and showed a very low proliferation response and IL-2 production by CBA/J splenocytes to DBA/2 stimulator compared with ratisotype IgG treatment.Conclusions: The blockade in vivo of costimulatory pathway with anti-CD80/CD86 mAbs at day 4 of gestation can induce the immuno-tolerance of maternal splenocytes to paternal antigen, which effectively prevented maternal rejection to allogeneic fetus, thus leading the...
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