American journal of reproductive immunology and microbiology : AJRIM最新文献

Natural killer cell (NKC) cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) represent the ability of human leukocyte effector cells to destroy target cells in the absence and presence of antibody, respectively. Since these immune systems play a pivotal role in the body's primary lines of defense against a variety of pathogens including herpes simplex virus (HSV), a study was undertaken to evaluate the influence of pregnancy on these systems. Eleven uncomplicated gravidas were followed serially through each trimester and compared to 11 nonpregnant female controls. Mononuclear cells were acquired by Ficoll-Hypaque centrifugation of heparinized blood. Chang liver cells infected with HSV-I were utilized as target cells in a 51Cr release assay. Mean NKC values in the pregnant patients were uniformly lower than in the controls. No similar decreases in ADCC activity were observed in a comparison between the two study populations. These data support previous observations suggesting that pregnancy represents a relatively immunocompromised state. Differences apparently exist between NKC and ADCC effector cell populations with regard to the influence of pregnancy. Although these physiologic alterations in immunoregulation may help support the fetoplacental allograph, detrimental conditions may exist regarding susceptibility to various pathogens such as HSV.

This report further characterizes the cytotoxic properties of seminal plasma and provides evidence for a role of spermine oxidation in the generation of seminal plasma cytotoxicity. Addition of spermine to lymphocyte cultures was found to result in a cytotoxic effect similar to that observed upon addition of seminal plasma. Furthermore, although seminal plasma is not cytotoxic in serum-free medium, addition of monoamine oxidase was sufficient to result in the generation of seminal plasma-associated cytotoxicity. Analysis of 73 individual seminal plasma samples indicated that all were cytotoxic, suggesting that this is an intrinsic property of seminal plasma. These results support a mechanism for seminal plasma cytotoxicity in which oxidation of spermine in seminal plasma by the amine oxidase of fetal calf serum results in generation of a cytotoxic product. It is hypothesized that this product plays a significant role in the phenomenon of seminal plasma immunosuppression. The general application of this principle to other fluids and tissues is discussed.

The histopathology of decidua obtained from the placental bed was evaluated by phloxine-tartrazine staining, which allows clear definition of cells with cytoplasmic granules. Mononuclear cells with large granules were seen in biopsy specimens taken from women at 8-31 weeks of normal pregnancy. In contrast, cells with large granules were missing in sections taken from the decidua of five women who were aborting or were destined to abort. Since the presence of suppressor cell activity in murine decidua correlates with the success of pregnancy and since this suppression is associated with small lymphocytes with cytoplasmic granules, the observations made using human placental bed biopsy material suggest that a possible suppressor cell deficiency might occur in the early stages of spontaneous abortion in human females.

Sperm-specific monoclonal antibodies (MS 204, MS 207, HS 11, and HS 63) that had been shown to inhibit fertilization of mouse oocytes in vitro were used to passively immunize male and female mice. In vitro and in vivo fertilization experiments were performed to compare the efficacy of resulting antifertility effects owing to the presence of circulating sperm antibodies. When the sperm from the antibody-treated mice were recovered for insemination, a partial inhibition of fertilization of mouse oocytes in vitro was observed. However, under the same antibody dose that effectively inhibits the in vivo fertilization of treated female mice the fertilization rate of the treated male was not significantly reduced, when they were mated with normal superovulated females followed by in vitro embryo culture. Similarly, on day 9 after mating with the antibody-treated males, the number of fetuses in mated females was not significantly different from that of the control. In contrast, when the antibody-treated females were mated with the proven fertile males, the number of fetuses was significantly reduced in response to the antibody treatment. When I-125-labeled monoclonal sperm antibodies were used to passively immunize male mice, the percentage of antibodies recovered from epididymis (relative to that of blood) was not much different from that of other organs, except for lower percentages detected in brain and testis. In treated females, oviduct and uterus revealed the presence of relatively high percentages of antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

The rosette inhibition titers (RIT) for sera from 94 women at various stages of gestation were detected with a standardized rosette inhibition test. The results showed that an immunosuppressive substance, named early pregnancy factor (EPF), did exist in the pregnancy sera. We confirmed that the EPF activity was very high in the early pregnant stage (the mean RIT = 6.30), gradually decreased with the continuance of gestation, and disappeared at 8 weeks before delivery when the mean RIT for sera (less than 4) had fallen in the RIT nonpregnant range. In addition, observations for the EPF dynamic changes before and at varying stages after the induced abortion in 21 pregnant women showed that the mean RIT was 5.9 +/- 0.25 (SE) before the abortion and dropped below 4 (EPF activity could not be detected) at 3-5 days after the abortion.

We have focused on comparisons of abnormal with normal pregnancies. Humoral and cellular aspects were studied in 50 couples with unexplained consecutive pregnancy failures and compared with 15 fertile couples. The results show that spontaneous aborters generally fall into two groups: Primary spontaneous aborters are those women who, by the same husband, never have carried a pregnancy beyond 20 weeks; secondary spontaneous aborters have had, by the same husband, either a normal pregnancy or a pregnancy failure beyond the 20th week. Primary spontaneous aborting couples tend to share a significantly greater number of HLA antigens than do secondary aborters or normally fertile mates. Secondary spontaneous aborters manifest cytotoxic non-HLA-dependent antibody to husbands' lymphocytes in complement-dependent assays; these are antibodies to trophoblast-lymphocyte cross-reactive (TLX) antigens. Secondary but not primary aborters have complement-independent antibody-dependent cell-mediated cytotoxicity reactions to their husbands' lymphocytes. Both exhibit diminished mixed lymphocyte culture reactions between mating partners if the tests are done in autologous plasma; only primary aborters show poor reactions if the assays are done in control sera. Immunotherapy with nonhusband lymphocytes in more than 20 primary spontaneous aborters has resulted in greater than 90% successful subsequent pregnancies. Leukocyte immunotherapy has not been useful for secondary aborters, but two of three women have had normal pregnancies following daily subcutaneous injections of heparin. The clinical relevance of these findings will be discussed.

The mammalian fetus expresses a variety of paternal histocompatible, oncofetal, and trophoblast antigens against which the mother can mount an immune response. Survival of the "fetal graft" appears to depend upon local immunosuppressive mechanisms in lymph nodes draining the uterus and at the intrauterine implanation site itself. Nonspecific not-T-Fc-receptor-bearing small lymphocytes containing cytoplasmic granules present in successfully allopregnant mice can suppress both the generation of maternal-antipaternal killer T cells and the infiltration of cytotoxic T lymphocytes into sponge-matrix allografts during the effector phase of the immune response. These suppressor cells are deficient at the implantation sites of xenogeneic and allogeneic mouse embryos that are susceptible to maternal immunity and are destined to resorb. A soluble suppressor factor of approximately 100,000 daltons in size can be obtained from the suppressor cells and acts to block the response of T cells to interleukin-2 by interfering with IL-2 receptors. The development of the suppressor cells in the decidua requires certain hormonal signals as well as signals provided by trophoblast cells. Freshly explanted or cultured murine trophoblast cell lines elaborate soluble factor(s) that are active in recruitment or activation of suppressor cells. Since suppressor cells may be isolated from decidua of successfully allopregnant humans, the suppressor cell mechanism and its regulation may represent a key factor in the protection of the "fetal allograft" from rejection by maternal immunity.

Hypotheses concerning reproductive competence focus on immunological and genetic mechanisms. The immunological hypothesis involves arguments that an immune response is necessary for implantation (or at least increased reproductive capacity), the antibody response to the placental antigens is composed of "blocking" antibodies, immunosuppressive factors are produced during pregnancy, and HLA antigen sharing in humans having chronic spontaneous abortions (CSA) causes a decreased immune response. The most potent antigen on the placenta is a class I molecule different from the classical transplantation antigens: Pa in the rat and TLX in the human. The genetic hypothesis states that CSA may be due to the presence of major histocompatibility complex (MHC)-linked, recessive lethal genes in the fetus and that the sharing of HLA antigens is just a marker for this segment of chromosome. Recessive lethal genes linked to the MHC exist in mice and rats and possibly in humans. They could act by themselves to cause fetal loss, or they could act epistatically with nonMHC lethal genes. This type of interaction occurs in the rat between the MHC-linked grc and Tal or Hre. Recent work in our laboratory has shown that the grc also increases susceptibility to the development of cancer following the feeding of a chemical carcinogen. This unique finding presents a new and powerful approach to exploring the relationship between embryogenesis and carcinogenesis.

As a mucosal organ, the uterus is unique in being subject to exposure to three types of antigen: chronically to micro-organisms, episodically to sperm bearing both auto- and alloantigens as well as soluble antigens in seminal plasma, and to conceptuses--nature's allografts--expressing transplantation antigens. That the uterus is effective in handling pathogens is evidenced by the rarity of infections. Local macrophages, immunocytes, and a secretory immune system, most evident in the cervix, probably underlie this attribute. Mammals' reproductive success hints that the uterus is immunologically discriminating toward the nonharmful but biologically important antigens of classes 2 and 3. Why sperm are not normally destroyed immunologically in the female prior to fertilization and why conceptuses are not rejected are central unresolved questions in reproductive immunology. Undoubtedly, important immunoregulatory principles are operating in this remarkable organ and its decidua. Better to understand antigenic exposure in the rat uterus, we have reinvestigated its lymphatic drainage using labeled cell injection and microanatomical procedures. Despite abundant lymphatics in the myometrium, cells placed in the uterine lumen did not readily gain access to the lymphatic system. There was a paucity of lymphatics in the endometrium, but Ia-positive dendritic cells were abundant. Soluble antigen exposure via the uterus failed to evoke a primary antibody response yet did prime the host for a secondary response. This restriction of systemic antigen presentation from the uterus, in conjunction with both cellular and noncellular immunoregulatory principles acting locally, may be important to ensure maternal hyporesponsiveness to paternal alloantigens.