Immune reactivity of allogeneically pregnant mice to paternal MHC antigens on fetal and placental cells assessed by second set rejection of ascites tumor cells

In vivo immunogenicity of fetus- and placenta-derived cells as well as the immune reactivity of pregnant mice to fetal cells were examined for graft rejecting response (GRR). Systemic administration of small numbers of fetal cells but not placental cells from allogeneically pregnant mice (10(6) cells per mouse) or adult allogeneic spleen cells (10(4) cells) sensitized mice for second-set rejection of an ascitic tumor bearing paternal major histocompatibility complex (MHC) antigens. Despite this fact and the known positive humoral response, pregnant and parous mice are not even minimally sensitized with fetal MHC antigens for GRR transplacentally. Nevertheless, any pregnancy-related systemically active control, which would selectively prevent the mother from being sensitized for GRR by limiting numbers of semi-allogeneic fetal cells, was not demonstrable in either allogeneically or syngeneically pregnant mice. Irrespective of pregnancy, mice did not, however, respond to repeated administration of very small numbers of allogeneic spleen cells (5 X 10(2) cells per mouse) for graft rejection. These findings support the notion that deviation of maternal immunity to fetal antigens away from harmful GRR is mediated principally by local mechanisms which inhibit fetal cells from gaining access to the mother for GRR, and additionally by the innate inability of mice to respond to very small numbers of allogeneic cells that might escape past the local maternal-fetal barrier.     

Impairment of the thymus-dependent humoral immune response by syngeneic or allogeneic pregnancy

Pregnancy results in a diminished capacity of the gravid mouse to respond to thymus-dependent antigens. The IgM response to thymus dependent and independent antigens is relatively unaltered whereas the IgG response to thymus-dependent antigens is markedly suppressed in both syngeneic and allogeneic pregnancy. The impairment of the humoral immune response is not due to loss of antibody-forming precursor lymphocytes (AFPL) from the spleen since their number remains unaltered. During pregnancy the spleen becomes enlarged and the precursor frequency is diluted somewhat but the AFPLs retain their normal activity in vitro. This implies an alteration in their amplification by accessory cells (T cells or macrophages) is responsible for the impaired IgG responses.     

Humoral immune responses in murine pregnancy. I. Anti-paternal alloantibody levels in maternal serum

The kinetics and properties of anti-paternal alloantibody produced by female C57BL(H-2^b) mice in response to mating with CBA(H-2^k) males have been investigated using an immunobead adsorption assay. No alloantibody was ever detected in the first pregnancy or post-partum period. 72% of females exhibited a humoral response in their second pregnancy, detectable from day 16 or 17 post-coitum, and almost all females responded in their third pregnancy. Column chromatographic and immunoelectrophoretic analysis showed that the alloantibody was IgG. Although passive transfer experiments suggested similar stability characteristics to those of cytotoxic antibody induced by experimental hyperimmunization, the pregnancy-induced alloantibody did not exhibit complement-dependent cytotoxicity. The findings are discussed in relation to the nature of the immunogenic stimulus from the conceptus and the regulation and possible function of the humoral immune response in allogeneic pregnancy.     

Immunology of pregnancy: towards a unifying hypothesis.

The variable findings of hormonal-immunoregulation and the variable cellular and humoral immune responses in pregnancy have been considered in relationship to the physiological response. From such considerations it appears that the peripheral blood lymphocyte/leukocyte response in pregnancy is not important, but rather the local uterine immune response at implantation and throughout pregnancy. It is proposed, and evidence is presented, that a normal allogeneic immune response is initiated at the time of implantation of the blastocyst. This immune response regulates the invasive nature of the trophoblast and initiates the first stage of parturition. The initiation and maintenance of this immune response is based on an interplay between maternal and paternal HLA and trophoblast antigens. In the case of HLA-incompatible donor-recipient blastocyst transplants, a more pivotal role for immunoregulation by trophoblast antigens is proposed. This is because it is considered that the local uterine immune response suppresses the expression of allogeneic HLA. This concept is further developed in terms of haploid HLA suppression on maternal and fetal lymphocytes that cross the placenta. This is considered to allow the interaction of these lymphocytes with each other and explains maternal transfer of cell-mediated immunity.     

Maternal growth restriction and stress exposure in rats differentially alters expression of components of the placental glucocorticoid barrier and nutrient transporters

The placenta plays a major role in the development of fetal growth restriction, which affects 10% of pregnancies and contributes to chronic adult disease risk. We have reported that female rats born small develop cardiometabolic dysfunction only during pregnancy. The physiological tests performed during pregnancy induced a maternal stress response as indicated by increased maternal corticosterone concentrations. This stress effected placental growth compared to females who were unhandled during pregnancy. Maternal stress and growth restriction independently program F2 offspring metabolic dysfunction. This study investigated the effects of maternal stress and growth restriction on placental and fetal metabolic parameters that may contribute to F2 offspring metabolic disease. Maternal growth restriction reduced F2 fetal weight whilst maternal stress reduced placental weight. Stressed mothers had reduced insulin and increased glucose concentrations, changes that were reflected in the fetus. Fetal β-cell number was reduced by maternal growth restriction, but was increased by stress exposure. Maternal growth restriction reduced placental Slc2a1, Igf2, Slc38a2 and Nr3c1 gene expression. Maternal stress decreased the expression of Slc2a1, Igf2, Slc38a2, Nr3c1, Slc2a3, Slc2a4, Nr3c2, Hsd11b2, Crhr1 and Ogt. Maternal birth weight effects on fetal weight were likely due to changes in placental nutrient transporter and Igf2 expression. On the contrary, maternal stress induced a systemic effect by altering maternal metabolic parameters, placental gene expression and fetal glucose and insulin concentrations. This study highlights the importance of informing pregnant women on effective ways to cope with stress during pregnancy to prevent adverse long-term disease outcomes in their children.     

Altered humoral immunity during pregnancy in the guinea pig

A guinea pig model was developed to determine whether humoral immune responsiveness is altered during pregnancy. Pregnant animals were immunised at mid-gestation with haptenated protein. The humoral response to antigen was measured as numbers of antibody-producing cells in the spleen, the affinity of the antibody produced by spleen cells and the levels of IgG in the serum. The values obtained were compared with those from an age matched non-pregnant control group.

Early in the primary response, there was a significant decrease in the number of IgM antibody-producing cells with an associated decrease in serum IgM levels in pregnant animals. Late in the primary response, pregnant and control animals had similar levels of IgM antibody-producing cells. During the later stages of the response, many of the pregnant animals did not respond with IgG antibody-producing cells or IgG in the serum. When IgG-producing cells were detected, the antibody was of lower affinity than that observed with the control group.

A selective lack of responsiveness was detected in the primary response of pregnant guinea pigs. The reduced number of IgG antibody-producing cells in gravid animals suggests that an immune switch from IgM to IgG is impaired in pregnancy. The low affinity of antibody produced indicates the immunoglobulin produced in pregnancy may also be functionally limited.     

Maternal immune responses to oncofetal antigens

The maternal host responds immunologically to antigens of the fetus. While the immune responses to paternally derived alloantigens and to placental antigens have been intensively studied, the immune responses to oncofetal antigens have been relatively unexplored. Oncofetal antigens are present on fetal and malignant tissues but absent from normal adult somatic tissues. These antigens elicit both cell-mediated and humoral immune responses in the parous female. Limited data suggest that these immune responses may influence reproductive processes. More investigation in this area is desirable.     

Fetal DNA does not induce preeclampsia-like symptoms when delivered in late pregnancy in the mouse

IntroductionThe etiology of preeclampsia is unclear. Fetal DNA is present in higher concentrations in the plasma of pregnant women suffering from preeclampsia than in the plasma of healthy pregnant women. A previously published study has shown that human fetal DNA injected into pregnant mice induces preeclampsia-like symptoms when administered between gestation days 10–14. The aim of our experiment was to determine whether or not similar effects would be induced by administration of human and mouse fetal DNA, as well as mouse adult DNA and lipopolysaccharide during late pregnancy in the mouse.MethodsExperimental animals were injected daily intraperitoneally during gestation days 14–18 with either saline – negative control, lipopolysaccharide – positive control, or various types of DNA. On gestation day 19, blood pressure and proteinuria were measured, and placental and fetal weights were recorded.ResultsFetal and placental hypotrophy were induced only by lipopolysaccharide (p < 0.001). Neither fetal nor adult DNA induced changes in fetal/placental weight. None of the experimental groups had higher blood pressure or urinary protein in comparison to saline treated animals.DiscussionIn our experiment, we found that there was no effect from intraperitoneally injected human fetal DNA, mouse fetal DNA, or mouse adult DNA on pregnant mice. Additionally, relatively high doses of various types of DNA did not induce preeclampsia-like symptoms in mice when administered in late pregnancy. Our negative results support the hypothesis that the increase of fetal DNA circulating in maternal circulation during the third trimester is rather a consequence than a cause of preeclampsia.     

Antigen presenting capacity of human decidua: no evidence for human decidual antigen presenting cell mediated immunoregulation.

Decidual antigen presenting cell (APC) mediated maternal immunoregulation has been reported. In the present study the ability of villous chorion as well as fetal cell pulsed early human pregnancy decidual APC to generate selectively antigen non-specific and MHC class II unrestricted CD8 positive T suppressor cells was reassessed in view of the fact that placental trophoblast, unlike the fetus, constitutes the fetal tissue of major contact at the maternal-fetal interface. Neither fetal cell nor villous chorion pulsed decidual APC generated maternal T cells with the ability to immunosuppress PHA-, Con A- and PWM-induced autologous or allogeneic lymphoproliferation. In only 2 out of 45 assays with villous chorion pulsed decidual APC was significant inhibition of mitogen induced lymphoproliferation detected and on no occasion with fetal cell pulsed decidual APC. No change in CD4/CD8 ratio of the maternal putative regulatory cells was detected by FACS analysis compared with control cultures. These findings suggest that decidual APC mediated immunoregulation plays no role in directing the maternal immune response.     

An investigation of allogeneic pregnancy in multiparous mice subjected to in vivo depletion of CD8 (Ly2)-positive lymphocytes by monoclonal antibody treatment

Adult thymectomized C57/Bl (H-2b) and DBA/1 (H-2q) female mice were subjected to treatment with rat anti-mouse CD8 and mouse anti-rat Ig (kappa) prior to entering their third pregnancy with CBA/Ca (H-2k) males. The treatment protocol drastically reduced the number of CD8 (Ly2)-carrying lymphocytes (T-cytotoxic/suppressor phenotype) in the spleen and para-aortic lymph nodes, as assessed by immuno-staining. All mice were investigated on day 18 of their third gestation. The following data were collected from experimental and control groups: (1) resorption frequency, (2) weight of the placenta, fetuses, spleen and para-aortic lymph nodes, (3) immunohistochemical analysis of maternal lymphoid tissues, (4) level of anti-paternal IgG serum antibodies, (5) content of "background" IgM and IgG-secreting cells in spleen and para-aortic lymph nodes. Neither the resorption frequency nor placental/fetal weight was affected by anti-CD8 treatment. However, the formation of anti-paternal antibodies was enhanced in anti-CD8 treated C57/Bl mice.     

17 beta-hydroxysteroid oxidoreductases of human fetal and adult tissues: immunological cross-reactivity with an anti-human placental cytosolic 17 beta-hydroxysteroid oxidoreductase antibody

To determine whether the immunological determinants of human placental 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR) were present in 17 beta-HSORs of tissues of the human fetus and adult and of various non-human cells maintained in culture, western immunoblot analysis was conducted by use of a polyclonal antibody directed against determinants of the placental cytosolic enzyme. Tissues and cells were evaluated for the presence of immunocross-reactive proteins with a relative molecular mass (Mr) similar to that of placental 17 beta-HSOR (approximately 34,000). By use of homogenates of human fetal tissues, immunostaining of 17 beta-HSORs of Mr approximately 34 kDa was detected in trophoblast, fetal adrenal neocortex, fetal zone of the adrenal gland, liver, intestine, kidney, brain, lung, skin, heart, spleen, pancreas, chorion laeve, and, occasionally, amnion. Immunostaining at Mr approximately 34 kDa also was demonstrated by use of cytosolic preparations of fetal tissues and, in some cases, by use of unwashed microsomal fractions; this protein was either absent or present in almost undetectable amounts in washed microsomes, except for placenta and fetal brain. Immunostaining at approximately 34 kDa was demonstrated occasionally in decidua of pregnant women by use of homogenates, but was not detected in endometrium or myometrium of non-pregnant women, testis of an adult man, mouse and rat Leydig tumour cells, mouse and rat adrenal tumour cells, and normal bovine adrenocortical cells.     

Humoral immune responses in murine pregnancy. III. Relationship between anti-paternal alloantibody levels in maternal serum, placenta and fetus

Studies have been carried out on allogeneically mated pregnant female mice to examine the relationship between the levels of anti-paternal alloantibody occurring free or as soluble immune complexes in the maternal peripheral circulation and that existing in a bound form in the placenta and free in the fetal circulation. In a 'non-responder' strain of mouse, as defined by the inability to detect anti-paternal alloantibody in the peripheral serum of multiparous allogeneically mated females, no alloantibody could be detected as soluble immune complexes, bound to the placenta or in the fetal circulation. A similar situation existed in females of a 'responder' strain during their first pregnancy and in some individuals during their second. However, in 'responder' strain females possessing alloantibody in their peripheral serum, alloantibody could be eluted from the semi-allogeneic placenta when peripheral titres exceeded 1:16, and was found in the fetal serum when they exceeded 1:128. When such females were subsequently mated syngeneically, alloantibody was detected in placental eluates only when peripheral titres exceeded 1:128-256 and in the fetal serum when they exceeded 1:16. The alloantibody eluted from placentae and that found in neonatal serum exhibited similar isotype distribution to that in the peripheral serum. These results are discussed with reference to the relative importance of the yolk sac and the immunoabsorbent semi-allogeneic placenta in the restricted transfer of pregnancy-induced anti-paternal alloantibody to the fetus.     

The alloantibody response of pregnant women and its suppression by soluble HLA antigens and anti-idiotypic antibodies.

The aim of this study was to investigate the time course of maternal allosensitization to fetal HLA antigens during normal human pregnancy and to explore mechanisms of suppression of anti-HLA alloantibodies. We found that the mother produces antibodies against some but not all of the mismatched HLA antigens of the fetus as early as the 8th week of pregnancy. These antibodies (Ab1), however, are often complexed with soluble HLA alloantigens and become detectable when immune complexes are dissociated. Soluble HLA antigens of fetal origin are present in the maternal circulation throughout the entire pregnancy beginning at 8 weeks. In some women the production of anti-anti-HLA antibodies (Ab2) became evident as early as the first trimester, while in others Ab2 was documented during the second or third trimester. Analysis of antibody specificity showed that some healthy primipara develop antibodies reactive with self HLA antigens. Although the allo- and autoantibody responses appear to be modulated by soluble HLA antigens, cyclic variations in the level of alloantibodies, as well as the mother's selective response to some, but not all, paternal HLA antigens, are best explained by the development of anti-idiotypic antibodies.     

Deviation of humoral and cellular alloimmune reactions by placental extracts

Modifications of the alloimmune response at both the humoral and the cellular levels by placental extracts (PE) syngeneic to the recipient were studied in the mouse using two different H-2 strain combinations. CBA (H-2k) or C57BL/Ks (H-2d), immunized with A/J (H-2a) spleen cells. The tests included in vivo tumor allograft evolution (accelerated rejection or enhancement reactions), and in vitro analysis of the involved immune agents, both cellular and humoral, using mixed lymphocyte reactions (MLR) and biological activity studies of serum samples. Animals from the recipient strains exhibited a delayed rejection of A/J tumor Sa 1 allografts if preimmunization was carried out with 10(6) A/J spleen cells combined with PE syngeneic to the recipients, as compared to controls immunized with A/J cells only or supplemented with isogeneic liver extracts (LE). The serological analysis revealed that PE treatment did not modify the overall hemagglutinating antibody production but resulted simultaneously in both a decreased production of cytotoxic complement fixing antibodies and an increase of specific anaphylactic mast cell degranulating antibodies, as compared to controls. The sera from PE-treated donors also demonstrated enhancing activity following passive transfer to isogeneic recipients. MLR regulatory activity was exhibited by spleen cells from PE- and immunogen-treated mice although the same or stronger activity was obtained from mice immunized without the addition of PE. However, in vivo transfer of these cells to syngeneic recipients showed that PE treatment erased the accelerated rejection caused by allogeneic immunization in the absence of PE and could even cause some degree of allografted tumor enhancement. The cells responsible for this inhibitory effect were mainly IJ+ lymphocytes, since their elimination with a relevant anti-IJ serum and complement restored a secondary type rejection pattern. These results show that PE present during the onset of immunization can promote the activation of regulatory agents such as enhancing antibodies and suppressor cells favoring allograft survival.     

Reduction in popliteal lymph node graft-versus-host reactivity by homologous and heterologous pregnancy serum

The popliteal lymph node assay was used to investigate the effect of pregnancy on graft-versus-host reactivity (GvHR) of mouse spleen cells. After local injection of splenocytes from primiparous syngeneically pregnant (by BALB/cJ males) or allogeneically pregnant (by CBA/Ca males) mice no differences in lymph node weight gain were observed in F1 recipients (CBA/Ca x BALB/cJ) when compared to injections of cells from age-matched non-pregnant BALB/cJ mice. However, lymphocytes of pregnant BALB/cJ females which had previously been pregnant between 4 and 6 times by CBA/Ca males induced a significantly lower GvHR compared to cells of matched non-pregnant multiparous mice. These results suggested an inhibitory effect of gestation on cells possibly primed towards paternal antigens by multiple pregnancies. To test this hypothesis, virgin BALB/cJ mice were actively immunized with lymphocytes of male CBA/Ca mice. Before injection into F1 recipients, spleen cells of immunized animals were incubated for 1 h at 37 degrees C in heat-inactivated serum of primiparous pregnant or virgin non-pregnant mice. Pre-incubation in pregnancy serum had no effect on unprimed cells, but GvHR of cells derived from immunized donors was significantly depressed in female recipients. In male animals this effect was only irregularly observed. Inhibition of GvHR was also observed with serum from pregnant but not non-pregnant pigs. Depression of cellular immune response was observed as early as days 4-9 post-coitum (p.c.) with mouse serum and days 16-19 p.c. with pig serum. These results indicate that pregnancy serum contains factor(s) which modulates the GvHR of primed lymphocytes in both a species- and an antigen-non-specific manner while reactivity of naive spleen cells is not changed.     

妊娠期风疹病毒感染对孕妇及胎儿的影响

目的 探讨妊娠期妇女风疹病毒的感染状况及对胎儿的影响。方法 应用酶联免疫吸附方法对1471例孕妇进行风疹病毒IgG,IgM抗体检测;对其中3例引产和死产的胎儿组织及胎盘行组织切片和电子显微镜检查,并用逆逆录-聚合酶链反应（RT-PCR）技术检测风疹病毒核酸。结果 76.1%(1119/1471)的孕妇风疹病毒IgG阳性;7.4%(109/1471)的孕妇风疹病毒IgM阳性,14.1%(208/1471)的孕妇风疹病毒IgG,IgM阴性;2.4%(35/1471)的孕妇风疹病毒IgG,IgM阳性。7例跟踪随访孕妇中,2例出现死胎,1例要求引产;1例引产胎儿的心肌组织细胞和2例死胎的心肌,肝,脑组织细胞及胎盘中均发现风疹病毒颗粒,并经RT-PCR检测到风疹病毒核酸。结论 妊娠期7.4%的孕妇可感染风疹病毒,并导致胎儿宫内感染,造成胎儿不同程度的损伤或严重的先天性风疹综合征。     

A fraction of murine placental extract enhances IgA production in cultured splenocytes.

During the second half of murine pregnancy there is a characteristic increase in the number of spontaneous immunoglobulin-secreting cells in the maternal spleen (IgM, IgG and IgA), the uterus-draining lymph nodes (IgG) and Peyer's patches (IgA). There are indications that signals originating from the feto-placental unit are of importance for the generation of at least some of these changes. To evaluate further the role of placental factors as regulators of maternal Ig-secretion, placental extract (PE) was separated into eight fractions by gel-chromatography and each fraction was screened for its effect on splenic (1) background DNA-synthesis, (2) background Ig-secretion and (3) Ig-secretion in lipopolysaccharide (LPS) activated B-cells (anti-Thy1.2 + complement-treated splenocytes). Similarly prepared extracts of fetuses, maternal spleen and maternal liver served as controls. All tissue extracts and splenocytes were syngeneic to avoid reaction to allogeneic determinants. Placental extract fractions did not differ significantly from the other tissue extracts in affecting background lymphocyte activity. However, fraction number 3 from placental extract (PE3, corresponding to an approximate molecular weight of 18-70 kDa) was found strongly to increase the number of IgA-secreting cells (P less than or equal to 0.001) in LPS-activated B-cells. This effect was absent or much less pronounced in the corresponding controls. Blocking of PE3-activity by antibodies against rat prolactin indicated that the enhancing activity may be attributed to proteins of the prolactin/placental lactogen/growth hormone family. This assumption was further strengthened by experiments demonstrating that prolactin exerted preferential enhancement of IgA secretion when added to LPS-activated B-cell cultures in vitro. The possible role of placental prolactin-like molecules as regulators of maternal IgA secretion is discussed.     

Inhibition of in vitro lymphocyte proliferation by ovine placenta-conditioned culture medium

Conditioned culture media of ovine placental tissues or fetal skeletal muscle collected at Days 60, 100 and 140 of pregnancy were tested for their ability to inhibit in vitro lymphocyte proliferation. All conditioned cultures contained low-molecular-weight factors which suppressed [3H]Tdr uptake by PHA-stimulated sheep lymphocytes. Non-dialyzable, inhibitory molecules were released only by placental tissues, with the greatest activity occurring for fetal cotyledonary placenta at Days 100 and 140 of gestation. Dialyzed conditioned culture medium of Day 100 cotyledonary placenta suppressed lymphocyte proliferation stimulated by PHA, PWM and MLR, but had no effect on ConA-stimulated cultures. Inhibitory actions were effective only during the first 24 h of lymphocyte activation and were abrogated with exogenous IL-2. Size-fractionation by gel filtration chromatography of the conditioned medium resolved the inhibitory activity into a peak of molecular weight greater than 4 X 10(6) Da and another peak with estimated molecular weight range of 46-162 kDa. Inhibitory action of the high molecular weight fraction was destroyed by sodium periodate oxidation whereas the lower molecular weight peak was sensitive to pronase. Presence of these immunosuppressive factors at the maternal-conceptus interface may contribute to down-regulation of local immune functions in the uterus and survival of the allogeneic conceptus.     

Maternal alloimmune reactions towards the murine conceptus and graft-versus-host reaction (GVHR). II. Inhibition of priming by placental extracts

Gestation can induce a priming for a GVHR towards paternal strain antigens, although this priming is significantly lower than the one induced by experimental immunization. A role has been sought for placental substances in decreasing this priming through immunomodulation. BALB/c (H-2d) spleen cells do not usually induce a systemic, lethal GVHR in DBA/2 (H-2d) newborn mice except when the donors are preimmunized with DBA/2 cells. Placental extracts (as well as RPMI medium or liver extracts used as controls) were added to DBA/2 cells injected into BALB/c mice used as cell donors for GVH induction. The latter's spleen cells, harvested on day 6 after immunization, were used for systemic and local GVHR. In the systemic assay (lethal effect on DBA/2 newborn mice injected i.v. with BALB/c spleen cells) a significant protection was observed. In the local assay (popliteal lymph node assay in F1 hybrids injected with BALB/c spleen cells into the foot-pad) a highly significant inhibition of priming was detected in recipients injected with spleen cells from placental extract-treated donors. The stimulation index was even lower than that obtained with unprimed BALB/c spleen cells. The same type of local GVHR in (CBA/Ca X A/J) F1 hybrids injected with CBA cells led to similar results. In both situations (systemic and local GVHR) the observed inhibition was found to be specific to the priming cell strain. These results support the working hypothesis that placental substances are able to modify the systemic response of an organism towards both H-2 and non-H-2 alloantigens.     

Pregnant and pseudopregnant mice produce a low cytotoxic alloantibody response when challenged by fetal but not adult F1 alloantigens

The tertiary cytotoxic alloantibody response of syngeneically pregnant, pseudopregnant and non-pregnant BALB/c mice immunised with semi-allogeneic lymphocytes from fetal and adult (CBA X BALB/c)F1 donors was investigated by the microcytotoxicity method. The pregnant and pseudopregnant animals showed a significantly lower response to fetal alloantigens compared to that towards adult alloantigens (P less than 0.001). In contrast, control non-pregnant recipients showed no diminution of response to fetal alloantigens. These observations suggest that the hormonal status of pregnancy, even in the absence of a conceptus, permits a low cytotoxicity antibody response when challenged specifically by fetal, but not when challenged by adult, F1 alloantigens.