Induction of abortion in mice with a monoclonal antibody specific for suppressor T-lymphocyte molecules (original) (raw)
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Reproduction, 1990
The concentrations of T-cell suppressor factor (TsF) were examined by competitive binding assays in the uterus, spleen, and regional lymph nodes draining the uterus in Day-5 pregnant mice or in ovariectomized mice given hormone treatments to induce conditions of delayed implantation or implantation. The amounts of immunoreactive TsF on Day 5 of pregnancy were 2\m=.\055\ m=+-\0\m=.\302,0\m=.\803\ m=+-\0\m=.\088, 0\m=.\426\ m=+-\ 0\m=.\136 ng TsF/mg extractable protein for the regional lymph nodes, spleen and uterus, respectively, during Day 5 of pregnancy. When implantation was prevented by ovariectomy on Day 4 followed by treatment with only progesterone, amounts of TsF (as a % of Day 5 value) were decreased to 57% in the uterus and increased to 141% in the spleen and 180% in the regional lymph nodes. When implantation was then initiated with the addition of oestradiol-17\g=b\ to the progesterone treatment, amounts of TsF were increased to 206% in the uterus, 318% in the spleen, and remained unchanged at 180% in the regional lymph nodes. These experiments suggest that the amounts of TsF in the uterus and spleen are dependent upon the implantation process, whereas amounts of TsF in the regional lymph nodes are independent of this event.
Abnormal T-Cell Reactivity against Paternal Antigens in Spontaneous Abortion
The American Journal of Pathology, 2005
Mammalian pregnancy is thought to be a state of immunological tolerance. The mechanisms underlying this phenomenon are still poorly understood. Here, we determined whether an inappropriate function of T regulatory (Treg) cells is involved in the pathogenesis of spontaneous abortion. We evaluated spleen and decidual lymphocytes from CBA/J mice undergoing immunological abortion (DBA/2J-mated) or having normal pregnancy (BALB/c-mated) on day 14 of gestation for ex vivo cytokine production after PMA or paternal antigen (alloantigen) stimulation. Treg activity was characterized by quantifying CD4 ؉ CD25 ؉ cells, foxp3 expression, and interleukin-10 secretion. Decidual lymphocytes from abortion CBA/J mice contained a significantly higher frequency of interferon-␥-producing T cells specific for paternal antigens compared to those from normal pregnancy (7.8% versus 2.7%, P < 0.05). Compared to virgin CBA/J females, normal pregnant mice showed strongly elevated numbers of CD4 ؉ CD25 ؉ and interleukin-10 ؉ Treg cells in the thymus whereas significantly lower frequencies of Treg cells were observed in abortion mice. Very interestingly, CD4 ؉ CD25 ؉ Treg cells from normal pregnant and nonpregnant CBA/J mice could inhibit both proliferation and interferon-␥ secretion of lymphocytes from abortion mice in vitro whereas in vivo prevention of fetal rejection could only be achieved after adoptive transfer of Treg cells from normal pregnant mice. Our data suggest that pregnancy-induced Treg cells play a vital role in maternal tolerance to the allogeneic fetus.
Cellular Immunology, 1989
Expression of certain autologous lymphocyte-activating antigenic determinants on the developing embryo is known to provide a stimulus for maternal anti-fetal autoproliferative responses. If left unregulated these responses could exert negative influences on the reproductive process by converting to autoaggressive forms of immune reactivity. In normal circumstances, immunological reactions of this nature are therefore likely to be under the control of pregnancy-associated immunoregulatory elements found within the maternal/fetal environment. In the present investigation we describe a naturally occurring splenic inhibitory cell type devoid of conventional T, B, and macrophage surface markers associated with syngeneic murine pregnancy that is capable of exerting potent immunosuppressive effects on an in vitro expression of fetal/newborn T cell autoreactivity, namely the autologous mixed lymphocyte reaction (AMLR). Maternal spleen cells inhibitory for AMLR were found to be highly resistant to cytotoxic pretreatment with a panel of conventional antisera directed against T cell-specific antigenic determinants. The non-T nature of the natural splenic suppressor cell was further indicated by experiments showing that purified spleen T cells had no inhibitory activity. Pregnancy spleen cell populations that were effectively depleted of macrophages retained full ability to inhibit AMLR. Maternal suppressor activity could be localized to the spleen cell population bearing receptors for the B cell-specific lectin, soybean agglutinin (SBA). A panel of monoclonal antibodies prepared against enriched populations of suppressor cells was screened and selected for specific reactivity using an ELISA against glutaraldehyde-fixed SBA+ spleen cell subpopulations from pregnant versus virgin animals. Several of the monoclonals developed against suppressor-enriched spleen cell populations from &pregnant as well as allopregnant animals were effective in reducing or eliminating suppressor cell activity following cytotoxic pretreatment in the presence of complement. The novel set of anti-suppressor monoclonal antibodies described here should prove useful in furthering the isolation and characterization of pregnancy-associated suppressor cells and in determining their relationship to natural suppressor cell populations described in other Systems.
Scandinavian Journal of Immunology, 1987
Pregnant and neonatal/l'ctal mice have been shown to harbour niuurnlly occurring inhibitory cells ot" both T and non-T type. Non-T suppressor ceils present in the spleen of priniipurous pregnant and newborn animals inhibit proliferative responses in auinlogous and aliogcneie mixed lymphocyte reactions. Sueh cells can be positively selected for hy agglutination with the B cell-specific lectin soybean agglutinin (SBA). We generated rat IgG monoclonal antibodies against unique cell surface structures on the non-T inhibitory cells, and cylotoxic pretreatment of spleen cells from pregnant or neonaial/felal mice largely abrogates iheir suppressive activity on proliferative responses. Furthermore, in vivo administration of such antibodies to pregnant inbred and oulbred mice results in termination of the pregnancy or decreased litter size. Since injection of anti-T cell igO monoclonal antibodies does not interfere with the delivery of normal sized litters it is evident from these studies that the non-T immunoregulatory cells, in contrast to T-inhibitory cells, are of greal importance in ensuring immunological homeostasis in the fetat-placental environment during pregnancy in mice.
Lymphocytes immunotherapy for preserving pregnancy: Mechanisms and Challenges
American Journal of Reproductive Immunology, 2018
Due to the expression of paternal antigens by the embryo, pregnancy is considered as a semi‐allograft and so immunological dysregulation is considered as one of the important causes in repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It has been revealed that lymphocytes immunotherapy (LIT) could be an appropriate approach to prevent pregnancy loss in such patients. Various mechanisms have been suggested for effectiveness of LIT such as enhancing expression of anti‐paternal cytotoxic antibodies (APCA), progesterone‐induced blocking factor (PIBF), anti‐idiotypic antibodies (Ab2), and mixed lymphocyte reaction blocking antibodies (MLR‐Bf), as well as reduction in the T helper 1/T helper 2 ratio and deviation in the pattern of cytokines production. However, there are controversial results about the beneficial effect of LIT treatment in RIF and RPL patients. In the current study, we reviewed findings of LIT in RIF and RPL patients with a focus on possible mechanis...
Kinetics of Regulatory T Cells During Murine Pregnancy
American Journal of Reproductive Immunology, 2007
Problem The semi-allogeneic fetus is usually tolerated by the maternal immune system. This was proposed to be modulated by CD4+CD25+foxp3+ regulatory T cells (Treg). We aimed to determine the kinetics of Treg during murine gestation and investigate whether changes in Treg levels respond to hormonal variations during pregnancy or generated changes in the local indolamine dioxygenase (IDO) expression.Method of study We included in our studies the well-known CBA/J × DBA/2J abortion-prone combination using CBA/J × BALB/c as controls. CBA/J × C57/BL6 and BALB/c × C57/BL6 were included as further controls. Animals were killed on days 0, 2, 5, 8, 10, and 12 of pregnancy to measure the levels of Treg, pregnancy-related hormones and IDO expression.Results A Treg augmentation in normal pregnancy combinations could be observed on day 2 in several organs contrary to the observations made in abortion-prone mice. No differences in hormonal levels could be seen among all groups. IDO was expressed exclusively in placenta starting from day eight, showing no variations among the groups.Conclusion Differences in Treg levels and pregnancy outcome do not correlate with changes in hormonal levels. In addition, as Treg augmentation takes place early and it is observed mainly in the decidual component of the fetal–maternal interface, IDO does not seem to be the pathway underlying Treg protective activity as proposed for humans.