Maternal Cellular Immune Responses Research Articles

Maternal cytotoxic T cell responses to fetal antigens develop during human pregnancy and exhibit functional capacity in vitro

During pregnancy there is the transplacental ‘traffic’ of allogenic fetal cells into the maternal circulation and this could provoke a maternal cellular immune response. Transgenic murine models suggest during pregnancy...

Maternal Immune Responses to Trophoblast: The Contribution of the Horse to Pregnancy Immunology

The horse has proven to be a distinctively informative species in the study of pregnancy immunology for several reasons. First, unique aspects of the anatomy and physiology of the equine conceptus facilitate approaches that are not possible in other model organisms, such as non-surgical recovery of early stage embryos and conceptuses and isolation of pure trophoblast cell populations. Second, pregnant mares make strong cytotoxic antibody responses to paternal major histocompatibility complex class I antigens expressed by the chorionic girdle cells, permitting detailed evaluation of the antigenicity of these invasive trophoblasts and how they affect the maternal immune system. Third, there is abundant evidence for local maternal cellular immune responses to the invading trophoblasts in the pregnant mare. The survival of the equine fetus in the face of strong maternal immune responses highlights the complex immunoregulatory mechanisms that result in materno-fetal tolerance. Finally, the parallels between human and horse trophoblast cell types, their gene expression, and function make the study of equine pregnancy highly relevant to human health. Here, we review the most pertinent aspects of equine reproductive immunology and how studies of the pregnant mare have contributed to our understanding of maternal acceptance of the allogeneic fetus.

Maternal cytotoxic T cell responses to fetal antigens during and after pregnancy

During human pregnancy there is the ‘transplacental traffic’of fetal cells into the maternal circulation. These cells can persist for decades, a phenomenon termed ‘fetal microchimerism’. Exposure to fetal cells may...

Inhibition of lymphocyte proliferation and activation: a mechanism used by equine invasive trophoblast to escape the maternal immune response

At days 36–38 of gestation, the equine invasive trophoblast cells migrate into the endometrium of the pregnant mare to form the endometrial cups. During their migration, they become surrounded by maternal CD4+ and CD8+ T lymphocytes, and stimulate a cytotoxic antibody response to the paternal major histocompatibility complex class I antigens that they express. Nevertheless, endometrial cup cells remain viable at the site of uterine invasion up to days 80–100 of gestation, suggesting the participation of immunomodulatory mechanisms to the maternal cellular immune response. To determine the effects of the invasive trophoblast cells on lymphocyte proliferation, an in vitro co-culture system was developed using isolated equine invasive trophoblast cells and peripheral blood lymphocytes. Fetal fibroblast cells from the same conceptuses were used as controls. The presence of invasive trophoblast cells or their pre-conditioned medium inhibited 50% or more of lymphocyte proliferation, while fetal fibroblasts had no effect. The invasive trophoblast cell inhibitory factor needed to be present constantly to affect lymphocyte proliferation, and it was ineffective if lymphocytes had been previously stimulated to proliferate. The lymphoproliferative inhibitory mechanism affected lymphocyte subpopulations similarly. In addition, lymphocyte expression of cytokine mRNA including IFNγ, IL-2, IL-4, and IL-10 was affected compared to controls. The implication of these observations in vivo may explain, in part, the apparent equine maternal immune acceptance of the presence and development of endometrial cup cells.

Pregnancy can induce long-persisting primed CTLs specific for inherited paternal HLA antigens

Previous studies showed that pregnancy can prime the maternal cellular immune response directed against paternal HLA antigens. Primed CTLs specific for inherited paternal HLA antigens (IPA) were found in women who had formed HLA allo antibodies, whereas naive CTLs were present in women who did not form antibodies against the paternal HLA antigens. As HLA allo antibodies may disappear in time, it is not clear which women on the waiting list for transplantation have been sensitized to paternal HLA antigens and are at risk for graft rejection if paternal HLA antigens are shared by the donor organ. The presence of primed CTLs specific for a particular antigen is considered to be a reflection of sensitization. In the present study we investigated whether these primed CTLs persist in women who had been pregnant and had formed antibodies against the inherited paternal HLA class I antigens. For this purpose 14 women who had their last pregnancy 10 years ago were analyzed with respect to IPA-specific CTLp frequencies and the presence of high avidity CTLs directed against inherited paternal HLA class I antigens. Although primed CTLs specific for IPA’s were found more frequently in women with persisting alloantibodies, they still can be detected when the antibodies have disappeared. The current data show that primed CTLs directed against inherited paternal HLA antigens towards which antibodies have been formed in the past can persist for more than 10 years after pregnancy. The cellular test used in our study can be useful to detect presensitization in women with a history of pregnancy, who enter the waiting list for transplantation.

Lymphocyte Subsets and Autoantibodies in Pregnancies Complicated by Placental Disorders

The survival of the fetoplacental unit might partly depend on down-regulation of rejection reactions. Pathological maternal cellular immune response mechanisms could therefore be of pathogenic importance in pregnancies complicated by placental disorders. A flow-cytometric analysis of T-cell subsets and B-cell, as well as serological tests for anticardiolipin antibodies (aCL), antinuclear antibodies (ANA), and rheumatoid factor (RF) were done on 90 women with complicated pregnancies. The results were compared with that of nonpregnant women (n = 5), and normal pregnant women (n = 5) in the third trimester. Two women, suffering from severe preeclampsia and eclampsia respectively, had aCL on 12 and 13 units, respectively. ANA occurred in 11 patients with moderate and severe preeclampsia and intrauterine growth retardation. All women had negative RF tests. Within the CD4 T-helper subpopulations, the proportion of suppressor/inducer T-cell population (CD4+CD45RA+) significantly increased, while the memory and helper/inducer T-cells (CD4+CD45RO+ and CD4+CD29+) significantly decreased during normal pregnancy compared to nonpregnant controls. This deviation of CD4 subpopulations was not found, or was less pronounced, in complicated pregnancies. The proportion of cytotoxic T cells (CD8+S6F1+) was significantly reduced during normal pregnancy. This reduction was less pronounced in complicated pregnancies. Systemic immunological deviations toward suppression or decreased activity of the immunological response as seen in normal pregnancies, was not observed in preeclampsia, intrauterine growth retardation, intrauterine fetal death, and abruptio placentae. This lack of suppression or increased T-cell activity may have a primary pathogenic role in some women with a complicated pregnancy, or it may be secondary to the placental disorders.

Purified human early pregnancy factor from preimplantation embryo possesses immunosuppressive properties

This study was undertaken to determine whether early pregnancy factor secreted by preimplantation embryos has immunosuppressive properties. Human early pregnancy factor was purified from embryo growth media of in vitro fertilized ova with ion-exchange and gel filtration chromatography. During each step of purification the fractions were tested for (1) early pregnancy factor activity with the rosette inhibition assay, (2) immunosuppressive properties with a concanavalin A-stimulated lymphocyte proliferation assay, and (3) purity by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Results indicate that (1) human early pregnancy factor has a basic molecular weight of 14 kd, (2) early pregnancy factor has immunosuppressive activity, (3) polymers of early pregnancy factor also appear to be present in the embryo growth media, and (4) immunosuppressive factors other than early pregnancy factor are also secreted by preimplantation human embryos. Early pregnancy factor and other factor(s) produced by the preimplantation embryo may play a role in suppressing maternal cellular immune responses, thereby preventing maternal rejection of the embryo.

Immunologic and neuroendocrine interactions in pregnancy.

The neuroendocrine system helps in the success of the fetal graft by suppressing maternal cellular immune response against the foreign paternal histocompatibility (HLA) antigens. In addition, placenta absorbs the antibodies directed against the paternal HLA antigens, thus inhibiting the humoral rejection of the fetal graft. In contrast, neuropeptides released in the maternal blood stream under adverse mental states may stimulate lymphocyte blastogenesis and natural killer (NK) cell activity resulting in premature loss of the fetus. Further, homozygosity of a lethal gene which is in linkage disequilibrium with HLA genes may have a role in some unexplained fetal deaths.

Human embryo associated immunosuppressor factor(s) from pre- and post-implantation stages share some similarities.

The present study demonstrates that embryo associated immunosuppressive factor(s) (EASF) secreted by the human embryo at pre- and post-implantation stages share some similarities. Human EASF was partially purified from embryo growth media of in vitro fertilized ova and from first trimester pregnancy sera. Non-pregnancy sera were fractionated in parallel. During each step of purification the fractions were tested for immunosuppressive properties using concanavalin A-stimulated lymphocyte proliferation assay. Analysis of EASF positive fractions on SDS-PAGE identified 14 kDa and 24 kDa molecules in embryo growth media and pregnancy sera. No such molecules were found in control sera, suggesting that these factors are embryo associated. The relationship of pre- and post-implantation EASF was also analyzed by EASF binding assay using murine anti-EASF antibody, which was raised against EASF isolated from embryo growth media. Results show that murine antibody bound to EASF purified from pregnancy sera, but not to identical fractions from control sera, indicating that these post-implantation EASF possess some similarity with pre-implantation EASF. Results also indicate that a species of suppressor factors present in embryo growth media and pregnancy sera were unique for their origin. Presence of these three EASFs at various stages of gestation may play a role in suppressing maternal cellular immune responses thereby preventing maternal rejection of the embryo.