Rapid data-driven model reduction of nonlinear dynamical systems including chemical reaction networks using ℓ1-regularization.

Large-scale nonlinear dynamical systems, such as models of atmospheric hydrodynamics, chemical reaction networks, and electronic circuits, often involve thousands or more interacting components. In order to identify key components in the complex dynamical system as well as to accelerate simulations, model reduction is often desirable. In this work, we develop a new data-driven method utilizing ℓ1-regularization for model reduction of nonlinear dynamical systems, which involves minimal parameterization and has polynomial-time complexity, allowing it to easily handle large-scale systems with as many as thousands of components in a matter of minutes. A primary objective of our model reduction method is interpretability, that is to identify key components of the dynamical system that contribute to behaviors of interest, rather than just finding an efficient projection of the dynamical system onto lower dimensions. Our method produces a family of reduced models that exhibit a trade-off between model complexity and estimation error. We find empirically that our method chooses reduced models with good extrapolation properties, an important consideration in practical applications. The reduction and extrapolation performance of our method are illustrated by applications to the Lorenz model and chemical reaction rate equations, where performance is found to be competitive with or better than state-of-the-art approaches.

Plasmodium genetic loci linked to host cytokine and chemokine responses.

Both host and parasite factors contribute to disease severity of malaria infection; however, the molecular mechanisms responsible for the disease and the host-parasite interactions involved remain largely unresolved. To investigate the effects of parasite factors on host immune responses and pathogenesis, we measured levels of plasma cytokines/chemokines (CCs) and growth rates in mice infected with two Plasmodium yoelii strains having different virulence phenotypes and in progeny from a genetic cross of the two parasites. Quantitative trait loci (QTL) analysis linked levels of many CCs, particularly IL-1ß, IP-10, IFN-γ, MCP-1 and MIG, and early parasite growth rate to loci on multiple parasite chromosomes, including chromosomes 7, 9, 10, 12 and 13. Comparison of the genome sequences spanning the mapped loci revealed various candidate genes. The loci on chromosomes 7 and 13 had significant (P<0.005) additive effects on IL-1ß, IL-5 and IP-10 responses, and the chromosome 9 and 12 loci had significant (P=0.017) interaction. Infection of knockout mice showed critical roles of MCP-1 and IL-10 in parasitemia control and host mortality. These results provide important information for a better understanding of malaria pathogenesis and can be used to examine the role of these factors in human malaria infection.

New candidate vaccines against blood-stage Plasmodium falciparum malaria: prime-boost immunization regimens incorporating human and simian adenoviral vectors and poxviral vectors expressing an optimized antigen based on merozoite surface protein 1.

Although merozoite surface protein 1 (MSP-1) is a leading candidate vaccine antigen for blood-stage malaria, its efficacy in clinical trials has been limited in part by antigenic polymorphism and potentially by the inability of protein-in-adjuvant vaccines to induce strong cellular immunity. Here we report the design of novel vectored Plasmodium falciparum vaccines capable of overcoming such limitations. We optimized an antigenic insert comprising the four conserved blocks of MSP-1 fused to tandemly arranged sequences that represent both allelic forms of the dimorphic 42-kDa C-terminal region. Inserts were expressed by adenoviral and poxviral vectors and employed in heterologous prime-boost regimens. Simian adenoviral vectors were used in an effort to circumvent preexisting immunity to human adenoviruses. In preclinical studies these vaccines induced potent cellular immune responses and high-titer antibodies directed against MSP-1. The antibodies induced were found to have growth-inhibitory activity against dimorphic allelic families of P. falciparum. These vectored vaccines should allow assessment in humans of the safety and efficacy of inducing strong cellular as well as cross-strain humoral immunity to P. falciparum MSP-1.

Inhibitory activity of tea polyphenol and Hanseniaspora uvarum against Botrytis cinerea infections.

AIMS: To investigate the effect of tea polyphenol (TP) and Hanseniaspora uvarum alone or in combination against Botrytis cinerea in grapes and to evaluate the possible mechanisms involved. METHODS AND RESULTS: TP alone was effective in controlling grey mould in grape at all concentrations. TP at 0.5 and 1.0% in combination with H. uvarum (1 x 10(6) CFU ml(-1)) showed a lower infection rate of grey mould. TP at 0.01% or above significantly inhibited the spore germination of B. cinerea. TP at 0.1% showed inhibition ability on mycelium growth of B. cinerea. The addition of TP did not affect the growth of H. uvarum in vitro and significantly increased the population of H. uvarum in vivo. CONCLUSIONS: TP exhibited an inhibitory effect against B. cinerea and improved the biocontrol efficacy of H. uvarum. The inhibitory effects of spore germination and mycelial growth of B. cinerea and the increased populations of H. uvarum in vivo may be some of the important mechanisms of TP. SIGNIFICANCE AND IMPACT OF THE STUDY: The results suggested that TP alone or in combination with biocontrol agents has great potential in the commercial management of postharvest diseases of fruits.

Inhibitory activity of tea polyphenol and Candida ernobii against Diplodia natalensis infections.

AIMS: To investigate the effect of tea polyphenol (TP) and Candida ernobii alone or in combination against postharvest disease (Diplodia natalensis) in citrus fruit and to evaluate the possible mechanisms involved. METHODS AND RESULTS: TP at concentrations of 0.1%, 0.5% and 1.0% alone, or in combination with C. ernobii (1x10(6) CFU ml(-1)), showed a lower infection rate of stem-end rot. TP at the concentration of 0.5% or above significantly inhibited the spore germination of D. natalensis. TP at the concentration of 1.0% showed inhibitary ability on mycelium growth of D. natalensis. The addition of TP did not affect the growth of C. ernobii in vitro and significantly increased the population of C. ernobii in vivo. CONCLUSIONS: TP exhibited an inhibitory effect against D. natalensis and improved the biocontrol efficacy of C. ernobii. It was direct because of the inhibitory effects of TP on spore germination and mycelial growth of D. natalensis in vitro and indirect because of the increased populations of C. ernobii in vivo. SIGNIFICANCE AND IMPACT OF THE STUDY: The results suggested that TP alone or in combination with biocontrol agents has great potential in commercial management of postharvest diseases in fruits.

Immunogenicity in rhesus of the Plasmodium vivax mosquito stage antigen Pvs25H with Alhydrogel and Montanide ISA 720.

Pvs25 is an ookinete surface protein from Plasmodium vivax that is the target of transmission-blocking antibodies. Two immunogenicity trials in rhesus monkeys with a recombinant form of the protein, Pvs25H, were undertaken. Monkeys were vaccinated with Pvs25H adsorbed to Alhydrogel or emulsified in Montanide ISA 720 at 0, 4 and 27 weeks (study 1) or in Montanide ISA 720 at 0 and 18 weeks (study 2) with 1.5 or 15 microg Pvs25H in 0.1 or 0.5 mL of emulsion (four combinations). Immunogenicity was assessed by ELISA and by membrane-feeding experiments using P. vivax-infected blood from human volunteers (studies 1 and 2) or from chimpanzees (study 1). Both vaccine trials generated antibodies that blocked transmission of P. vivax to mosquitoes. Antibody titres and transmission blocking were higher with Montanide ISA 720 than with Alhydrogel in the first trial and with the 15 microg Pvs25H/0.5 mL ISA 720 combination in the second trial.

Interaction between two domains of the P. yoelii MSP-1 protein detected using the yeast two-hybrid system.

Several model systems of plasmodia have demonstrated the potential of the merozoite surface protein, MSP-1, to induce protective immunity. However, little is known about the function of this protein or its interaction with other surface molecules that may also serve as immunological targets. To identify potentially significant inter- and intra-molecular interactions involving MSP-1, we have utilized the yeast two-hybrid system. A cDNA activation domain library was constructed from the erythrocytic stages of the murine malarial parasite Plasmodium yoelii yoelii 17XL. A 795 bp region of Py17XL MSP-1 (bait), homologous to the Plasmodium falciparum MSP1(33) fragment, was inserted into a Gal4p DNA binding domain vector and used to screen the activation domain library (target). Several randomly selected clones that demonstrated bait-target interaction were found to express overlapping regions of Py17XL MSP-1. Deletion constructs further localized the peptide fragments retaining interaction indicating that a region within the MSP-1(38) fragment interacts with the MSP-1 bait domain. Subsequent studies confirmed this interaction, as both peptides were co-precipitated from cell lysate by a peptide tag-specific antibody. It was observed that the interaction of these two fragments significantly increased the half-life of the MSP-1(38) within yeast cells. The specific interaction described here demonstrates the potential of this approach to elucidate additional inter- or intra-molecular interactions of Py17XL MSP1 and other malarial proteins.

Efficacy of two alternate vaccines based on Plasmodium falciparum merozoite surface protein 1 in an Aotus challenge trial.

In an attempt to produce a more defined, clinical-grade version of a vaccine based on Plasmodium falciparum merozoite surface protein 1 (MSP1), we evaluated the efficacy of two recombinant forms of MSP1 in an Aotus nancymai challenge model system. One recombinant vaccine, bvMSP1(42), based on the 42-kDa C-terminal portion of MSP1, was expressed as a secreted protein in baculovirus-infected insect cells. A highly pure baculovirus product could be reproducibly expressed and purified at yields in excess of 8 mg of pure protein per liter of culture. This protein, when tested for efficacy in the Aotus challenge model, gave significant protection, with only one of seven monkeys requiring treatment for uncontrolled parasitemia after challenge with P. falciparum. The second recombinant protein, P30P2MSP1(19), has been used in previous studies and is based on the smaller, C-terminal 19-kDa portion of MSP1 expressed in Saccharomyces cerevisiae. Substantial changes were made in its production process to optimize expression. The optimum form of this vaccine antigen (as judged by in vitro and in vivo indicators) was then evaluated, along with bvMSP1(42), for efficacy in the A. nancymai system. The new formulation of P30P3MSP1(19) performed significantly worse than bvMSP1(42) and appeared to be less efficacious than we have found in the past, with four of seven monkeys in the vaccinated group requiring treatment for uncontrolled parasitemia. With both antigens, protection was seen only when high antibody levels were obtained by formulation of the vaccines in Freund's adjuvant. Vaccine formulation in an alternate adjuvant, MF59, resulted in significantly lower antibody titers and no protection.

Plasmodium: immunization with carboxyl-terminal regions of MSP-1 protects against homologous but not heterologous blood-stage parasite challenge.

A leading candidate for a vaccine targeted at the erythrocytic stages of plasmodial parasite development is the merozoite surface protein-1 (MSP-1). We have previously shown that the carboxyl-terminal region of MSP-1 derived from Plasmodium yoelii yoelii 17XL, expressed as a fusion protein with glutathione S-transferase (GST-PYC2), can immunize mice against an otherwise lethal homologous challenge infection. This protection has been shown to be predominantly mediated by antibodies. We report here on the efficacy of immunization with MSP-1 carboxyl regions when the challenge is a heterologous rodent parasite species. The course of parasitemia was not altered in mice immunized with GST-PYC2 and challenged with 10(4) heterologous Plasmodium chabaudi adami parasites, as both control and immunized mice developed infections that peaked at day 7 and then rapidly declined. Similarly, mice immunized with GST-PYC2 and challenged with 10(5) Plasmodium berghei ANKA parasites displayed virulence similar to that seen in infection control mice. The homologous region of the P. chabaudi adami MSP-1 gene was similarly expressed as a fusion protein with GST. Mice immunized with GST-PCC2 and challenged with 10(4) parasites showed significant protection against homologous P. chabaudi adami infection but no protection whatsoever against heterologous P. yoelii yoelii 17XL infection. These in vivo results correlate with the observation that sera generated by immunization with the carboxyl region of MSP-1 recognizes this protein from homologous, but not heterologous, radiolabeled parasite protein preparations.

Frequent detection of tumor cells in hematopoietic grafts in neuroblastoma and Ewing's sarcoma.

Many poor-risk neuroblastomas and tumours of the Ewing's sarcoma family (ET) recur despite autologous transplants. Recurrence may be due to tumor cells contained in the BM harvests or PBSC harvests. The objectives of this prospective study were to: (1) determine the incidence and degree of tumor cell contamination in paired BM and PBSC harvests; and (2) determine the efficacy of tumor cell purging by immunomagnetic CD34+ cell selection. 198 samples from 11 consecutive patients with neuroblastoma or Ewing's sarcoma were analyzed. We assayed tumor contamination by RT-PCR assay for PGP 9.5, plus immunohistochemistry for neuroblastoma-specific antigens (the latter in neuroblastoma only). None of these patients had tumor cells detected in their BM by clinical histology immediately before BM or PBSC harvests. However, 82% of PBSC and 89% of backup BM harvests were contaminated with tumor by RT-PCR and/or immunocytochemistry assays. Unselected PBSC and BM harvests contained similar quantities of tumor cells (median, approximately 200000 cells). Cyclophosphamide plus G-CSF mobilization did not affect the incidence or level of contamination in PBSC harvests, as compared to blood obtained before mobilization. Immunomagnetic CD34+ cell selection depleted tumor cells by a median of 3.0 logs for PBSC, and 2.6 logs for BM harvests.

Comparison of humoral immune responses elicited by DNA and protein vaccines based on merozoite surface protein-1 from Plasmodium yoelii, a rodent malaria parasite.

Immunization with DNA vaccines encoding relevant Ags can induce not only cell-mediated immune response but also humoral immune responses against pathogenic microorganisms in several animal models. Our previous results demonstrated that, when the C terminus (PyC2) of Plasmodium yoelii merozoite surface protein-1 (MSP-1), a leading vaccine candidate against erythrocytic stages of malaria, was expressed as a fusion protein (GST-PyC2) with glutathione S-transferase (GST), it elicited Ab-mediated protective immune responses in BALB/c mice. In our present study, we wished to examine the humoral responses to a DNA vaccine (V3) encoding GST-PyC2. The GST-PyC2 expressed in V3-transfected Cos 7 cells was recognized by a protective monoclonal Ab to PyC2 (mAb302), although the secreted product had undergone N-linked glycosylation. When BALB/c mice were immunized with V3 plasmid, anti-PyC2 Abs were successfully induced. These Abs immunoprecipitated native PyMSP-1 protein and competed with mAb302 for binding to its epitope at a level similar to those elicited by GST-PyC2 protein immunization. However, these Abs had significantly lower titers and avidities, and different isotype profiles and protective capacities against a lethal erythrocytic stage challenge, than those resulting from immunization with GST-PyC2 protein. Most surprising was the finding that, in contrast to protein immunization, there was no significant increase in the avidity of either GST-specific or PyC2-specific IgG Abs during the course of DNA immunization. This suggests that there may be little or no affinity maturation of specific Abs during DNA immunization in this system.

Effects of L-triiodothyronine and the thyromimetic L-94901 on serum lipoprotein levels and hepatic low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and apo A-I gene expression.

The mechanisms by which thyroid hormone (triiodothyronine (T3)) and a thyromimetic, 2-amino-3-(3,5-dibromo-4-[4-hydroxy-3-(6-oxo-1,6-dihydro-pyridazin -3-ylmethyl)-phenoxyl]-phenyl)propionic acid (L-94901), lower plasma low density lipoprotein (LDL) cholesterol and raise plasma high density lipoprotein (HDL) cholesterol levels was investigated in thyroidectomized and sham-operated rats. Thyroidectomy resulted in a 77% increase in plasma LDL cholesterol, a 60% decrease in plasma triglycerides, and a modest reduction in HDL cholesterol. Daily oral dosing with T3 (10-170 nmol/kg) or L94901 (100-1000 nmol/kg) for 7 days decreased plasma LDL cholesterol in thyroidectomized rats by 60-80%, respectively. This reduction in LDL cholesterol was accompanied by a dose-dependent increase in HDL cholesterol levels of up to 60%. Thus, the ratio of LDL to HDL was decreased from 1.01 to 0.12 after treatment with L-94901 and to 0.25 after dosing with T3. In sham-operated animals, T3 and L-94901 lowered LDL cholesterol by 61 and 46%, respectively, and increased HDL cholesterol by 25 and 53%, respectively. Immunoblotting analysis of liver membranes prepared from thyroidectomized or sham-operated rats demonstrated that LDL receptor protein levels were increased by up to eight-fold. Northern blotting analysis revealed similar large increases in hepatic LDL receptor mRNA levels that accounted for the increases in LDL receptor protein levels. Hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA, protein, and activity were increased 2- to 3-fold. The T3- and L-94901-mediated increases in serum HDL levels were associated with 2- to 3-fold increases in apo A-I mRNA levels. In contrast with most other hypocholesterolemic agents, T3 and L-94901 significantly increase HDL cholesterol levels in addition to decreasing LDL cholesterol levels due to induction of hepatic apo A-I and LDL receptor gene expression.

Fc receptors are not required for antibody-mediated protection against lethal malaria challenge in a mouse model.

The mechanisms by which Abs mediate protection during blood-stage malaria infections is controversial, with some evidence pointing to the direct effect of Abs on parasite invasion and growth, while other studies suggest that Abs act in cooperation with monocytes to achieve parasite inhibition. To determine whether the effector phase of protection in vivo to the rodent parasite Plasmodium yoelii yoelii requires Fc receptor bearing cells, we passively transferred immune sera into FcR gamma-chain knockout mice. Inflammatory macrophages from these knockout mice were unable to mediate phagocytosis or Ab-dependent cell-mediated cytotoxicity (ADCC) through Fc gamma RI, Fc gamma RII, or Fc gamma RIII. Passive transfer of either P. y. yoelii hyperimmune sera or anti-GST-PYC2 sera directed to the major merozoite surface protein (MSP-1) of this parasite enabled both BALB/cByJ mice and FcR gamma-chain-deficient mice to resist lethal P. y. yoelii 17XL (Py17XL) challenge. mAb302, a protective IgG3 Ab, also passively protected both strains of mice. Most of these samples contain Ab isotypes that would not be able to protect mice if their protective effects required Ab-dependent cell-mediated cytotoxicity. These results establish that, in this infection, protection is directly mediated by Abs and does not require the participation of Fc receptors.

Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer.

PURPOSE: We evaluated weekly single-agent intravenous (IV) vinorelbine as salvage therapy for metastatic breast cancer. After the first five patients, all received elective growth factor support with granulocyte colony-stimulating factor (G-CSF; filgrastim) in an attempt to maximize delivered dose-intensity (DDI). Objective tumor response, DDI, and toxicity were assessed, as well as time to progression (TTP) and survival. PATIENTS AND METHODS: This single-center nonrandomized trial enrolled 40 patients. Anthracycline exposure and subsequent progression were common to all patients, and 38 of 40 were paclitaxel-refractory. Vinorelbine was given initially at 30 mg/m2/wk, then at 35 mg/m2/wk in a phase I/II design, which involved first intermittent (6 days of 7) and then continuous (daily) administration of G-CSF at 5 micrograms/kg. RESULTS: The maximum-tolerated starting dose was 35 mg/m2/wk with continuous G-CSF support. The mean DDI was 27.7 mg/m2/wk for all patients. There were two complete responses (CRs) and eight partial responses (PRs) in 40 assessable patients for an overall response rate of 25% (95% confidence interval [CI], 13% to 41%). The median TTP was 13 weeks and median survival time 33 weeks. The dose-limiting toxicity was neutropenia, with dose delay or reduction required in 14 of 27 patients entered at 35 mg/m2. Febrile neutropenia that required hospitalization was unusual (three of 40 patients, 8%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in nine patients (23%) and 26 patients (65%) required RBC transfusions for anemia. Seven patients (18%) had reversible grade 3/4 nonhematologic complications, primarily related to neurotoxicity. Grade > or = 3 mucositis was absent. CONCLUSION: Concurrent administration of weekly vinoralbine and daily G-CSF is feasible and permits an increase in DDI for vinorelbine of 43% to 76% over that reported in series without growth factor support. The response rate, TTP, and survival data are encouraging for therapy given to heavily pretreated patients with metastatic breast cancer. Vinorelbine is not cross-resistant with paclitaxel and should be considered for further trials in the dose-intensified mode made possible by G-CSF, alone or combined with other agents.

Protective efficacy against malaria of a combination sporozoite and erythrocytic stage vaccine.

Most malariologists believe that optimal malaria vaccines will induce protective immune responses against different stages of the parasite's life cycle. A multiple antigen peptide (MAP) vaccine based on the Plasmodium yoelii circumsporozoite protein (PyCSP) protects mice against sporozoite challenge by inducing antibodies that prevent sporozoites from invading hepatocytes. A purified recombinant protein vaccine based on the P. yoelii merozoite surface protein-1 (PyMSP-1) protects mice against challenge with infected erythrocytes, presumably by inducing antibodies against the erythrocytic stage of the parasite. We now report studies designed to determine if the PyMSP-1 vaccine protects against challenge with sporozoites, the stage encountered in the field, and if immunization with a combination of the PyCSP and PyMSP-1 vaccines provides additive or synergistic protection against sporozoite challenge. In two experiments, using TiterMax or Ribi R-700 as adjuvant, 3 of 19 mice immunized with the PyMSP-1 vaccine were completely protected against sporozoite challenge. The remaining mice had significantly delayed onset and lower levels of peak parasitemia than did control mice (11.1 +/- 2.8% vs. 36.7 +/- 1.6% in experiment #2, P < 0.01). Immunization with the combination vaccine reduced by approximately 50% the level of antibodies induced to PyCSP and PyMSP-1, as compared to that induced by the individual components. However, in two experiments, there was evidence of additive protection. Six of 19 (31.6%) immunized with the PyCSP vaccine, 3 of 19 (15.8%) immunized with the PyMSP-1 vaccine, and 10 of 19 (52.6%) immunized with the combination were completely protected against sporozoit challenge. This modest increase in protection in the combination group may be a reflection of additive anti-PyCSP and anti-PyMSP-1 immunity, since mice in the combination group had diminished levels of antibodies to each components. These studies indicate that considerable work may be required to optimize the construction, delivery, and assessment of multi-stage malaria vaccines.

Maternal serum creatine kinase does not predict tubal pregnancy.

PURPOSE: Our purpose was to validate prospectively the predictive value of maternal serum creatine kinase in the evaluation of ectopic pregnancy. METHODS: Fifty-one consecutive pregnant first-trimester patients who presented for suspected abnormal pregnancy were enrolled. Maternal serum samples were obtained and assayed for creatine kinase. Patients were subsequently evaluated for abnormal pregnancy by serial quantitative hCG levels, transvaginal ultrasonography, and surgery when appropriate. A receiver operating characteristic (ROC) curve was generated comparing intrauterine to extrauterine (ectopic) pregnancy. RESULTS: Of 51 patients, 18 had an ectopic pregnancy, 16 had a spontaneous abortion, and 17 had an ongoing intrauterine pregnancy. The ROC curve revealed that maternal serum creatine kinase had no ability to predict ectopic pregnancy. CONCLUSIONS: Maternal serum creatine kinase is not a reliable predictor of tubal pregnancy.

Evaluation of patients with abnormal uterine bleeding.

An accurate, efficient diagnosis of disorders responsible for abnormal uterine bleeding depends on a systematic consideration of all the possible causes. Careful history and physical and pelvic examinations provide the framework for evaluation. Many adjunctive diagnostic aids can be used to evaluate women with abnormal uterine bleeding. These tests include complete blood cell count, pregnancy test, hormone levels (estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, dehydroepiandrosterone sulfate), thyroid function tests, liver function tests, and coagulation profile. The need for these tests are individualized and based primarily on the patient's presentation. In women of reproductive age a complication of pregnancy should always be ruled out. Ectopic pregnancies can be life threatening. The prognosis in women with trophoblastic disease can be altered by a delay in establishing the correct diagnosis. Ultrasonographic studies, particularly transvaginal ultrasonography and hysteroscopy, have played an increasing role in the evaluation of patients with abnormal uterine bleeding over the past decade, especially for cases of intrauterine space-occupying lesions, including endometrial polyps, submucosal myomas, and retained placental fragments. Suspicion of reproductive tract malignancies is heightened in patients > 35 years old, those with a history of oligoovulation or anovulation suggestive of long-term unopposed estrogen exposure, those who are obese, and those who do not respond to first-line medical management. Diagnostic techniques available for the evaluation of these cases include endometrial biopsy, dilatation and curettage, transvaginal ultrasonography, and hysteroscopy. These procedures not only allow accurate diagnosis but may permit immediate therapeutic measures to be taken when organic causes are discovered. In summary, the key to the evaluation of abnormal uterine bleeding is a through history and physical and pelvic examinations governed by the differential diagnosis of excessive uterine bleeding and the selected use of adjunctive diagnostic tests and procedures only when absolutely necessary.

Comparison of immunosuppressive properties of hydatidiform mole decidua and trophoblast extracts.

PROBLEMS: The immunologic privilege afforded the fetus relies upon immunoregulation within the maternal-fetal interface. Trophoblast and decidua-derived immunoregulatory factors enforce this privilege by locally suppressing maternal responses to trophoblast antigens. The relative contribution of trophoblast or decidua immunosuppressive factors to pregnancy immunotolerance are not well characterized. The purpose of this study was to compare the suppressive effects of hydatidiform mole trophoblast and decidua extracts on interleukin-2-dependent proliferation. METHOD: Tissue extracts were prepared from hydatidiform mole trophoblast and decidua following uterine evacuation. Samples were submitted to interleukin-2-dependent and -independent cell proliferation assays. RESULTS: Hydatidiform mole trophoblast extract significantly (P < 0.05) suppressed interleukin-2-dependent proliferation but did not affect interleukin-2-dependent cell proliferation. In contrast, molar decidua extract suppressed both cell lines. CONCLUSIONS: Human hydatidiform mole trophoblast contains factor(s) that specifically abrogate interleukin-2-dependent clonal expansion of murine cytotoxic T-cells. In contrast, extracts of molar decidua suppressed both interleukin-2-dependent and -independent responses. This indicates that the trophoblast antagonizes critical interleukin-2-mediated immunologic responses, but that the decidua uses nonspecific antiproliferative mechanisms for immunoregulation.