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T G Wegmann

Publications and source records attributed to T G Wegmann.

At least 37 records · Page 2Linked to original sources
PubMed1993

Monoclonal antibodies directed against a widespread oncofetal antigen: the alpha-fetoprotein receptor.

Accumulating evidence based on alpha-fetoprotein (AFP) cell binding and uptake has shown the presence of a receptor for AFP on the surface of fetal and neoplastic cells. In order to further study this receptor, monoclonal antibodies (MAbs) made against pooled human mammary tumor membrane extracts were screened for their ability to inhibit the binding of radiolabeled AFP to the Ichikawa and TA3/Ha malignant cell lines. IgM-producing clones 167H.1 and 167H.4 were found to inhibit the binding of AFP to its receptor. Conversely, the MAb reaction was inhibited by an excess of AFP but not by serum albumin at an equal molar concentration. The possibility that these MAbs recognize AFP has been ruled out. In addition, we describe a method for the purification of the AFP receptor which yielded fractions reactive to both 167H.4 and AFP. The results obtained strongly suggest that 167H.1 and 167H.4 are directed against the binding site for AFP on the AFP receptor. Using 167H.4 we found positive immunohistochemical staining in 6/6 human mammary tumor specimens whereas 3/3 benign mammary adenomas were negative. Immunostaining of fetal muscle with either 167H.4 or an anti-AFP antiserum yielded a similar staining pattern. The staining of live Ichikawa cells with 167H.4 showed a surface receptor distribution (capping) similar to the one described in previous reports using labeled AFP. The widespread expression of the AFP receptor observed previously is consistent with the results obtained using the MAbs described herein. The potential use of these MAbs for basic and clinical studies is discussed.

Animals↗
PubMed1992

The expression and localization of mRNA for colony-stimulating factor (CSF)-1 in human term placenta.

A 4-kb mRNA for colony-stimulating factor 1 (CSF-1) was detected in normal human placenta at term by Northern blot analysis. In-situ hybridization revealed that the mRNA for CSF-1 was localized in the mesenchymal cells of the chorionic villous stroma, but not in the trophoblasts or capillary epithelial cells. Because there are significant numbers of tissue macrophages (Hofbauer cells) in the placental stroma and because the receptor for CSF-1 (the c-fms proto-oncogene product) is known to be expressed by trophoblasts, our results suggest that CSF-1 produced by placental stromal cells may act as a growth and survival factor for human placental macrophages and trophoblasts.

Autoradiography↗
PubMed1991

Characterization of cytokine production by the metrial gland and granulated metrial gland cells.

The metrial gland and its population of bone marrow-derived, large, granulated, lymphocyte-like cells, termed granulated metrial gland (GMG) cells, are consistent but poorly understood, decidua-associated features of pregnancy in the mouse and other species. Decidua, a complex maternal tissue, is thought to be a source of cytokines important for placental development. Thus, it is important to determine if lymphokine or cytokine production is among the activities of the metrial gland and GMG cells. Media conditioned by culture of either metrial gland explants or migrating GMG cells were evaluated for various cytokine activities. At least four activities were present: CSF-1, IL-1, a factor promoting proliferation of DA-1 cells that was not GM-CSF, IL-3 or erythropoietin and an activity cytotoxic to the CSF-1-dependent macrophage cell line 5/10.14. CSF-1 and IL-1 appeared to be products of the GMG cells. Cytokines not present at detectable levels included IL-2, IL-4, TNF-alpha and TGF-beta. Qualitatively, the cytokine profiles remained constant throughout days 8-16 of gestation. mRNA from migratory GMG cells was isolated and assayed for eleven cytokine mRNAs by polymerase chain reaction-based amplification of cDNA synthesized from mRNA. GMG cell RNA contained transcripts for LIF and CSF-1 but did not contain transcripts for GM-CSF, G-CSF, IL-2, IL-3, IL-4, IL-6, IL-7, IFN-gamma or TNF-alpha. TGF-beta transcripts were detected in occasional samples at very low levels. Since GMG cells are highly mobile cells that migrate throughout the placenta and into trophoblast-lined maternal blood spaces, their function in pregnancy may involve the delivery of very localized differentiation or growth regulatory signals to the developing fetal trophoblast and placenta.

Animals↗
PubMed1991

The in situ expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA at the maternal-fetal interface.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced by cells in the placenta, is known to be a growth factor for trophoblast cells in vitro and when injected into pregnant mice at risk for mid-gestation fetal resorption, dramatically lowers the fetal death rate while stimulating placental and fetal growth. We describe here the localization of GM-CSF mRNA expression in murine placenta by in situ hybridization. It is found in small round cells (lymphoid-like) and endothelial cells in the maternal decidua. In addition, GM-CSF transcripts are located in cells of the spongiotrophoblast zone (trophoblast-like cells), but not in the labyrinthine zone. These results indicate that GM-CSF may be influencing the growth and function of the fetal placenta in a paracrine-autocrine manner. These results support earlier observations that link GM-CSF production during pregnancy to decidual T-lymphocytes and further suggest a placental source within the invasive trophoblast.

Animals↗
PubMed1990

Host natural suppressor activity regulates hemopoietic engraftment kinetics in antibody-conditioned recipient mice.

Resistance to semi-allogeneic or syngeneic hemopoietic stem cell engraftment can be reduced by treating the unirradiated host with anti-class I MHC antibody. In our previous studies we showed a direct correlation between such resistance and the level of natural suppressor (NS) activity in the host. Thus newborn mice that have high NS activity are very resistant to marrow engraftment, as are adults pretreated with CFA that increases NS activity in the bone marrow. We have now devised a method that allows us to follow hemopoietic engraftment kinetics within the marrow cavity itself by assaying individual CFU-granulocyte/macrophage progenitor cells for their host or donor origin over the immediate post-transplant period. By using this method, we find a close correlation between the rate of marrow engraftment and reduction in host NS activity. Marrow engraftment does not correlate with the reduction of either total host bone marrow cellular content or CFU-granulocyte/macrophage progenitor cell levels. NS activity is mediated by Thy-1-, partially radiosensitive, nylon wool nonadherent cells without NK activity. Adoptively transferred Thy-1-, irradiated spleen cells containing NS activity induced by pretreatment with CFA delayed engraftment kinetics in the marrow cavity. Thus hemopoietic engraftment in the marrow cavity appears to be controlled by an inhibitory regulatory activity that is reflected in the in vitro NS assay. These studies suggest new regulatory targets for selective host conditioning to eliminate resistance to marrow transplantation.

Animals↗
PubMed1990

The effects of anti-CD4 and anti-CD8 antibody treatment on placental growth and function in allogeneic and syngeneic murine pregnancy.

During pregnancy, maternal immune recognition of paternal alloantigens has been shown to result in an increased influx of maternal T cells into the spleen, draining lymph nodes and decidua. In previous studies we have shown that polyclonal or monoclonal anti-T cell antibody treatment of allogeneically pregnant mice results in decreased placental proliferation and phagocytosis in vivo. In the present study we compare the effect of such antibody treatment during allogeneic and syngeneic pregnancy. We show that monoclonal anti-CD8 treatment of both types of pregnant females reduces placental proliferation and phagocytosis. Anti-CD4 antibody treatment, on the other hand, only affects placental proliferation, indicating that there is a complex network of immune interactions affecting placental growth and function.

Animals↗
PubMed1990

Expression of novel cytokine transcripts in the murine placenta.

It is increasingly apparent that lymphohematopoietic cytokines play a unique role during gestation. For example, placentally derived cells, including trophoblast and choriocarcinomas, respond to granulocyte-macrophage (GM)/colony-stimulating factor (CSF) and to colony-stimulating factor 1 (CSF-1), both formerly considered to be hematopoietic cytokines. It has been shown that CSF-1 is produced by the uterine epithelium and GM-CSF by the decidua. However, evidence is emerging that placentally derived cytokines may also influence reproductive function, and the question arises whether anything unique about their expression allows them to function in this particular environment. We have therefore analyzed the expression of cytokine genes in the murine placenta using a panel of cDNA probes that detect GM-CSF, CSF-1, tumor necrosis factor (TNF), interleukin (IL)-1, IL-2, IL-3, and IL-5. We report here the detection of mRNA encoding IL-1, TNF, and CSF-1 that are identical in size to those found in macrophage and fibroblast cell lines. In contrast, five distinct GM-CSF transcripts, four of which are larger than T-cell GM-CSF transcripts, were present. These novel transcripts ranged in size from 5.2, 3.9, 2.4, and 2.1 to 1 kb. Restriction analysis did not reveal any major structural alterations in the placental GM-CSF gene. Thus, the unique placental GM-CSF mRNAs detected most likely result from modified transcription of the GM-CSF gene in the placenta rather than transcription from a modified placental GM-CSF gene. Transcription of enkaryotic genes involves a number of regulatory mechanisms that can generate functionally and structurally diverse polypeptides from a single gene. Modified transcription of the GM-CSF gene in the placenta may serve to generate functionally diverse cytokines which provide the growth and differentiation signals that help to sustain pregnancy. This observation may clarify the unique role played by GM-CSF in reproductive function.

Animals↗
PubMed1990

Control of fetal survival in CBA x DBA/2 mice by lymphokine therapy.

In this study, we examined the effect of injecting various cytokines. We report here that tumour necrosis factor (TNF)alpha, gamma-interferon and interleukin 2 (IL-2) can, in some circumstances, increase fetal resorption rates in abortion-prone (CBA/J x DBA/2) and non-abortion prone (CBA/J x BALB/c,C3H x DBA/2) matings: 1000 units TNF enhanced resorptions from 43 to 79% in CBA x DBA/2, from 7 to 89% in CBA x BALB/c, from 5 to 47% in C3H x DBA/2. The effect was both gestational age- and dose-dependent. Gamma interferon and R-IL-2 enhanced resorptions from 38 to 68% and 76% respectively in the CBA/J x DBA/2 mating combination, whereas the rates in CBA/J x BALB/c matings were enhanced from 6 to 44% and 55%. Lipopolysaccharide (LPS), which is known to lead to the release of TNF-alpha, had a similar effect, leading to gestational age- and dose-dependent enhancement of resorptions up to 100%. However, cytokines of the CSF family, including IL-3 and GM-CSF, increased the chances of fetal survival when injected into abortion-prone mice, e.g. reducing resorption rates in the abortion-prone CBA/J x DBA/2 mating combination from 55 to 22% (IL-3), and 47 to 8% (GM-CSF). They also increased fetal and placental weight and, in particular, expanded the spongiotrophoblast zone in the placenta. The latter observations may be due to a direct trophic influence on placental cells, perhaps through a cytokine cascade, or an indirect effect due to inhibition of natural killer (NK)-like cells, or both. Whatever the mechanism, these results may find practical application in influencing reproductive outcome in women and other species.

Animals↗
PubMed1989

Delayed activation of quiescent donor hematopoietic stem cells in the host marrow cavity by anti-host monoclonal antibody.

To understand the mechanisms controlling hematopoietic engraftment in untreated, normal recipients, we investigated the fate of parental, donor hematopoietic stem cells after apparent graft failures in unconditioned F1 hybrid recipient mice. By administering an anti-host H-2K monoclonal antibody, which targets host cells but spares the donor, we found that chimerism could be induced by delayed conditioning in animals with apparent graft failure. Engraftment kinetics in the host were followed by typing individual colony forming unit--granulocyte/macrophage (CFU-GM) colonies for their origin and showed that parental cells, which were otherwise virtually absent, become promptly detectable within the marrow cavity after antibody administration. Marrow transfers to secondary hosts suggested that parental stem cells were present in the marrow of the untreated recipients. These findings establish that the elimination of all parental cells cannot account for the absence of peripheral blood chimerism in the unconditioned F1 hybrid recipient. Thus, viable and functional donor stem cells, which remain quiescent in the host marrow, can be activated by a selective conditioning regimen and can rescue an apparent graft failure. The selective activation in vivo of marked stem cells in an unirradiated microenvironment may be a useful system to study the regulation of cellular proliferation within the marrow cavity.

Animals↗
PubMed1989

The role of natural suppressor and natural killer activities in resistance to hemopoietic transplantation in unirradiated hosts.

We report here that bone marrow stem cell engraftment in unirradiated hosts correlates with levels of natural suppressor (NS) activity in the host at the time of transplantation. This is shown in the antibody-facilitated murine chimeras, in which conditioning consists of a single injection of anti-host MHC antibody, which results in long term hemopoietic engraftment in P----F1 and syngeneic donor-host combinations. The data establish that, in two independent situations, engraftment is reduced in hosts with elevated NS activity. Resistance to engraftment in antibody-conditioned adult hosts is increased by prior administration of CFA, which also increases NS activity. Likewise, neonatal animals, which are highly resistant to antibody-facilitated engraftment, exhibit a spontaneously-increased level of NS activity. This resistance declines with the ontogenic waning of splenic NS activity. Conversely, administration of facilitating antibody decreases host bone marrow NS activity, while anti-MHC antibodies that fail to facilitate engraftment do not reduce it. NK activity, on the other hand, correlates poorly with resistance or susceptibility to marrow engraftment in these situations. These results suggest that immunoregulatory functions associated with hemopoiesis may control engraftment of donor stem cells in unirradiated hosts.

Animals↗
PubMed1988

Maternal T cells promote placental growth and prevent spontaneous abortion.

Transplantation immunologists have long been intrigued by the natural allograft that results from normal mammalian pregnancy. Its general success contrasts with the rejection problems associated with most artifactual organ transplantation and raises intriguing questions concerning the nature of the mechanisms involved in that success. This area of research has recently taken on added momentum because it is now clear that immunological maneuvers can prevent recurrent spontaneous abortion in mice, horses and humans [1-3]. The purpose of this review is to discuss some of these recent developments, which lead to the surprising conclusion that maternal T cells, rather than being potentially detrimental to the fetal allograft, promote its growth and viability during normal pregnancy. This review will address these questions by considering: (a) the nature of the exposure of fetal alloantigens to the maternal circulation in the chimeric zone of the placenta; (b) the evidence for maternal immune recognition of the fetal alloantigens; and (c) the consequences of that recognition with respect to the prevention of spontaneous abortion. As in other areas of immunology the T cell emerges as the most important component of this immune recognition.

Abortion, Habitual↗
PubMed1988

[Role of the placenta in maintaining the fetal allograft].

Present knowledge of the alloantigenic status of the placenta, which makes it a natural semi-allogeneic allograft is briefly surveyed. The systemic immunoregulatory mechanisms operating during normal allopregnancy which are not a prerequisite for a successful pregnancy are recalled. The placenta--dependent local mechanisms, e.g. trophoblast dependent decidual suppressor cells, factor mediated and factor independent resistance to cell mediated lysis, are surveyed as well as some of the mechanisms of action of trophoblast regulatory factors, namely suppressor cell induction and inhibition of IL-2 dependent cell growth/activation. The main feature of the CBA x DBA/2 model of spontaneous abortions in mice, and its prevention by anti Balb/c leukocyte immunisation are described. It was shown that anti-T cell depletion prevents the anti-abortive effects of immunisation. Such a treatment is also able to restore normal placental weight in auto-immune MRL lpr mice, which are known to display excess seric CSF beta-like activity (CSFs being in vitro efficient growth factors for trophoblasts). Transfer of such cells into the MHC compatible CBA/J prevents resorbtions upon a subsequent mating with DBA/2. Thus, direct effects of CSFs beta 1 and beta 2 as anti abortifacient (IL3 and GM CSF) are described together with the abortificacient effects of TNFs and NKs activators.

Abortion, Spontaneous↗
PubMed1987

The immunostimulatory effect of T cells and T cell lymphokines on murine fetally derived placental cells.

Evidence for maternal immune recognition of the fetus can be found during pregnancy, yet the conceptus remains unharmed. Indeed, in some cases immunizing the mother with cells sharing histocompatibility antigens with the fetus is beneficial to fetal survival. This could be due to the effect of maternally derived lymphokines on placental growth and function, according to the immunostimulation hypothesis. We demonstrate here that placental cells in culture proliferate upon the addition of T cell-derived lymphokines. The lymphokine activity has been separated from IL 2 and B cell growth factor, and copurified with IL 3 and granulocyte-macrophage colony-stimulating factor (CSF-GM). Recombinant CSF-GM and recombinant IL 3 showed a similar effect. The placental cells that proliferate in culture are of fetal origin and are characterized by strong adherence, phagocytosis, nonspecific esterase staining, and response to the macrophage-specific colony-stimulating factor CSF-1. In addition, treatment of pregnant females with anti-thymocyte serum as well as anti-Ly-2.1 monoclonal antibody, at gestational times before Ly-2 antigen appearance in the fetus, leads to a reduction of the proliferative and phagocytic capacity of day 12 placentae. These results clearly demonstrate that maternal T cells act upon fetally derived placental cells to improve their proliferative and phagocytic potential, and thus provide evidence for the immunostimulatory role of these cells during pregnancy.

Animals↗
PubMed1987

Immunological and para-immunological mechanisms in spontaneous abortion: recent insights and future directions.

Unexplained spontaneous abortion in humans is currently thought to be related to genetic or immunologic factors. Animal models of spontaneous abortion have been used to try to gain some insight into the problems in humans. From studies of animal models there is increasing evidence that a variety of mechanisms may initiate pregnancy failure and participation of immunologic effectors may be a secondary event. Recent studies indicate that murine abortion that occurs spontaneously (without deliberate immunization by the investigator) may be initiated by para-immunologic host effector cells such as NK cells, macrophages and their toxins that possess selective toxicity which is not antigen-specific. The potential importance of local non-specific suppressive mechanisms in the uterus is also highlighted by their ability to block non-specific para-immune effector cell activation, and by their potential relationship to growth factors in decidual supernatants that promote placental cell growth in vitro. Levels of non-specific suppression do not appear low when fetal death can be attributed to a genetic mutation. The concept that different tissue components of the feto-placental unit serve as targets of different immunologic and para-immunologic effectors is defined. The new insights into the pathophysiology of murine abortion and its correction can provide a useful framework for further analysis of the role of para-immunologic effector mechanisms in unexplained abortion in humans and in non-murine veterinary conditions.

Abortion, Spontaneous↗
PubMed1987

Immunological competence and host-specific tolerance of antibody-facilitated bone marrow chimeras.

We have generated murine antibody-facilitated (AF) bone marrow chimeras in the genetic combination P1----(P1 X P2)F1 by the simultaneous injection of P1 bone marrow cells and anti-P2 MHC monoclonal antibody into normal (unirradiated) adult (P1 X P2)F1 recipients. These mice have normal life spans and appear to be healthy, with no overt signs of graft-versus-host disease. We have undertaken an extensive survey of the ability of stable, long-term AF chimeras to generate immune responses in vitro and in vivo. Both T and B lymphocyte functions have been analyzed in proliferative and effector cell assays. The AF chimeras respond normally to mitogenic as well as antigenic stimuli, and exhibit normal capacities for cellular collaboration in the generation of immune responses. However, splenic lymphocytes from AF chimeras are substantially and specifically hyporesponsive or nonresponsive to host, P2-encoded, alloantigens in in vitro assays of cell-mediated immunity. This host-specific tolerance is exhibited by the cytotoxic T lymphocyte lineage; T helper cells necessary for the generation of a cytotoxic response may also have decreased reactivity to host determinants. We conclude that our protocol for the production of AF chimeras does not compromise the immune system of chimeric animals but does allow the maintenance of host-specific tolerance, after stable equilibrium has been attained.

Animals↗