Aberrant cytokine production by peripheral blood mononuclear cells in recurrent pregnancy loss?

BACKGROUND: Successful pregnancy may depend on a Th2-type cytokine response, whilst, conversely, a poor pregnancy outcome may be associated with an increase in Th1 cytokines and a concomitant decrease in Th2 cytokines. This prospective study was designed to elucidate whether a failure of the cytokine shift pre-dated miscarriage and was therefore likely to be an aetiological factor in recurrent pregnancy loss (RPL). METHODS: Cytokine production by stimulated peripheral blood mononuclear cells from 46 pregnant women who had previously suffered idiopathic RPL during early pregnancy was compared with 25 gestationally age-matched pregnant controls and 11 non-pregnant women. RESULTS: Production of IFN-gamma was lower in pregnant than in non-pregnant women and even lower in RPL pregnant women (P = 0.0191). IL-10 was increased in pregnant women compared with non-pregnant controls, and further increased in RPL patients (P = 0.026). IL-4 was also increased in women with RPL (P = 0.0001). No differences in IFN-gamma, IL-10 or IL-4 secretion were observed in RPL patients who subsequently miscarried compared with those who successfully completed the pregnancy. RPL women with a successful reproductive outcome had similar concentrations of TNF-alpha to pregnant women, RPL women who subsequently miscarried had significantly lower levels than either pregnant women (P = 0.02) or non-pregnant controls (P = 0.0004). CONCLUSIONS: Contrary to our hypothesis, the cytokine shift, which appears to characterize normal pregnancy, was accentuated rather than diminished in RPL pregnant women.     

Correlation of plasma hormone levels and peripheral circulating lymphocyte subpopulations during human pregnancy

Using monoclonal antibodies (OKT3, OKT4, OKT8) peripheral blood lymphocyte subsets were determined in 40 normal primiparous pregnant women and compared with those of 31 nonpregnant controls. In pregnant women plasma concentrations of estradiol, progesterone, human placental lactogen (HPL), beta subunit of human chorionic gonadotropin (beta HCG), and alpha-fetoprotein were measured by means of radioimmunoassay. We studied if correlations between peripheral lymphocyte subsets and plasma hormone levels might exist. We observed in pregnant women from 10 to 40 wk of amenorrhea a decrease in the percentage of OKT3 and OKT8 cells, and during the course of pregnancy an increase in the percentage of OKT4 cells. This increase inversely correlated with plasma beta HCG levels and directly correlated with plasma HPL levels.     

A selective increase in plasma soluble vascular cell adhesion molecule-1 levels in preeclampsia.

PROBLEM: The study was conducted to determine whether altered plasma levels of soluble intercellular adhesion molecule (ICAM)-1 and soluble vascular cell adhesion molecule (VCAM)-1 are involved in the pathogenesis of preeclampsia. METHOD OF STUDY: Maternal plasma samples were collected from 20 patients with preeclampsia, 20 matched normotensive patients with uncomplicated pregnancies. and ten healthy nonpregnant women. Samples were assayed for soluble VCAM-1 and soluble ICAM-1 by specific enzyme-linked immunosorbent assay. RESULTS: Both soluble VCAM-1 and soluble ICAM-1 were detectable in the plasma of all preeclamptic, normotensive pregnant, and nonpregnant women. The mean plasma level of soluble VCAM-1 was significantly higher in preeclamptic women compared to normotensive pregnant women (1831 ng/mL +/- 534 ng/mL vs. 1254 ng/mL +/- 386 ng/mL, respectively; P < 0.05). However, the plasma level of soluble VCAM-1 was unchanged during the third-trimester of normal pregnancy compared to nonpregnant women. The mean plasma level of soluble ICAM-1 in preeclamptic and normotensive pregnant women were increased when compared to nonpregnant women. However, the mean plasma level of soluble ICAM-1 was comparable in women with preeclampsia and normotensive pregnancy. CONCLUSIONS: The selective increased plasma levels of soluble VCAM-1 in patients with preeclampsia provide evidence for endothelial activation and suggest distinct pathways for neutrophil and endothelial activation in preeclampsia.     

Abnormal first trimester serum interleukin 18 levels are associated with a poor outcome in women with a history of recurrent miscarriage

PROBLEM: How the maternal immune system adapts to tolerate the fetus is not fully understood, but a successful pregnancy is associated with the production of Th2-type cytokines and miscarriage is associated with the production of Th1-type cytokines. METHOD OF STUDY: Levels of interferon (IFN)-gamma, interleukin (IL)-4, IL-12 and IL-18 were measured in serum from 205 pregnant women of whom 115 pregnant women had a history of recurrent miscarriage. RESULTS: Compared with healthy pregnant women those who miscarried had increased serum levels of the Th1-associated cytokines IFN-gamma, IL-12 and IL-18. CONCLUSIONS: Increased levels of IL-18 appeared to be critical in early pregnancy and were able to discriminate between pregnancies that continued and those that end in miscarriage.     

Nitric oxide production increases during normal pregnancy and decreases in preeclampsia

To investigate the changes in nitric oxide (NO) production during and after normal pregnancy and in pregnancies complicated by preeclampsia, we measured serum nitrates and nitrites (NOx) concentrations and serum iron markers in 347 subjects. Serum NOx concentrations were determined after reduction of nitrates to nitrites using the Griess reaction. Serum iron and serum ferritin were assayed using an automatic chemical analyzer and a chemiluminescence method. Serum NOx concentrations were significantly higher in the first trimester (117.3 +/- 31.4 microM) than in nonpregnant women (23.8 +/- 7.1 microM). High NOx concentrations persisted throughout normal pregnancy, irrespective of serum ferritin concentrations, and returned to nonpregnant levels by 9-12 wk postpartum. Mean NOx concentrations in preeclamptic women were 43.1 +/- 12.7 microM, which were significantly lower than those in the gestation age-matched normal pregnant women (249.7 +/- 51.3 microM). In summary, NO production increases with advancing gestation during normal pregnancy and decreases in preeclampsia, regardless of serum ferritin concentrations. Elevated NOx concentrations during pregnancy return to normal within 12 wk after delivery.     

Immunoassay of type IV collagenase/gelatinase (MMP-2) in human plasma.

We have developed a sensitive and specific sandwich type enzyme-linked immunosorbent assay (ELISA) to detect type IV collagenase (MMP-2) in human plasma which employs the combination of affinity purified rabbit polyclonal antibodies and mouse monoclonal antibodies to human MMP-2. The MMP-2 ELISA detects latent and activated MMP-2, MMP-2 complexed with TIMP and MMP-2 complexed with alpha 2 macroglobulin (65% efficiency). To determine whether physiologic conditions associated with increased connective tissue turnover are accompanied by increased MMP-2 levels in plasma, we compared enzyme levels in pregnant and nonpregnant women. Plasma MMP-2 (mean +/- standard deviation) was significantly increased (p less than 0.05) in the second half of pregnancy (650 +/- 312) as compared to early pregnancy (356 +/- 139) or the nonpregnant state (387 +/- 193). As a result of the linkage between type IV collagenase production by cancer cells and the metastatic phenotype, the assay of MMP-2 in plasma is of potential clinical value in cancer.     

Intravascular volume expansion and fetal outcome in pregnant Nigerians with hemoglobin SS and SC

In a comparative study of physiological changes in pregnant Nigerians, plasma volume measurements were performed in 75 healthy Nigerian women. They comprised 40 women with hemoglobin genotype AA (20 pregnant and 20 nonpregnant) and 35 women with hemoglobin genotype SS or SC (15 pregnant and 20 nonpregnant). Plasma volume was determined in the left lateral position using the Evans blue dye dilution technique (described by Dacie and Lewis) in the nonpregnant, at 16 and 36 weeks of gestation, and at 8 weeks postpartum.     

Up-Regulated Expression of CD56+, CD56+/ CD16+, and CD19+ Cells in Peripheral Blood Lymphocytes in Pregnant Women With Recurrent Pregnancy Losses

PROBLEM : To analyze immunophenotypic profiles of peripheral blood and humoral autoimmune responses in women with a history of recurrent spontaneous abortions (RSA). METHOD : Peripheral blood lymphocyte subsets by flow cytometry and autoantibodies to phospholipids and nuclear components by ELISA were measured in non pregnant and pregnant women with RSA of unknown etiology. Thirty-five pregnant and eighty-one nonpregnant women with RSA were studied. Seventeen nonpregnant and twenty-two pregnant normal controls were included. RESULTS : Natural killer (NK) cells (CD56+) were significantly elevated in nonpregnant women with RSA as compared with nonpregnant controls. Pregnant women with RSA demonstrated significantly increased NK (CD56+, CD56+/CD16+) and B cells (CD19+) as compared with pregnant controls. Women who miscarried the index pregnancy demonstrated significantly lower CD3+ cells in comparison with normal controls. Women with RSA and antiphospholipid antibodies showed significantly elevated NK cells when compared with women without antiphospholipid antibodies. Women with autoantibodies to nuclear components demonstrated significantly elevated CD19+/CD5+ cells when compared to women without autoantibodies to nuclear components. CONCLUSIONS : Women with RSA demonstrate an abnormal cellular immune response by increasing peripheral natural killer cells and B cells as compared with normal controls.     

Calcium and vitamin D status of pregnant teenagers in Maiduguri, Nigeria.

This study investigates parameters related to calcium and bone metabolism by determining the concentrations of total calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone, and phosphorous in young pregnant women. The patient population was 30 pregnant Nigerian teenage women grouped by trimester (10 per group), 10 women immediately following delivery, and 21 healthy age-matched controls. On the basis of serum prealbumin levels, the general nutrition of the pregnant women was found to be significantly below that of the more privileged and better-educated nonpregnant controls. The mean total calcium concentration in sera of the third-trimester women was 8.83 mg/dL, which was significantly below that of the controls (9.77 mg/dL) and the first-trimester group (9.30 mg/dL). Despite the 10% to 15% decline in the serum level of total calcium during pregnancy, the parathyroid hormone level decreased markedly from 0.60 to 0.61 ng/mL in the first and second trimesters to 0.41 ng/mL in the third trimester. Serum vitamin D and 1,25-dihydroxyvitamin D levels in the second and third trimesters were within the normal range. These data indicate that toward the end of gestation, pregnant teenagers in northern Nigeria appear to become calcium deficient and do not exhibit the expected increase in serum parathyroid hormone levels normally seen in pregnant women.     

Changes in cytokine production and composition of peripheral blood leukocytes during pregnancy are not associated with a difference in the proliferative immune response to the fetus

We analyzed peripheral blood from women at term pregnancy for leukocyte composition, in vitro proliferative responses and cytokine production after nonspecific and fetus-specific stimulation. Maternal peripheral blood mononuclear cells (PBMCs) were collected and stimulated with umbilical cord blood (UCB) of the mother's own child, third-party UCB, nonspecific stimulus phytohemagglutinin, and anti-CD3 antibody, with PBMCs of nonpregnant women (cPBMC) as controls. Nine combinations of patient, child, third party child, and controls were selected on basis of sharing one human leukocyte antigen (HLA)-DR antigen. The response of mPBMC upon specific stimulation with fetal antigens was similar to that of cPBMC. No differences were found when comparing the mother's response upon stimulation to her own child with stimulation to that with a control child. Nonspecific stimulation with phytohemagglutinin and anti-CD3 antibody did not reveal a difference in proliferation rate between mPBMC and cPBMC. However, mPBMC contained a higher percentage of CD14(+) cells (p = 0.001) and activated T cells (CD25(dim), p < 0.0001), but a lower percentage CD16(-)CD56(bright) natural killer (NK) cells (p = 0.001) and CD16(+)CD56(+) NK cells (p = 0.003). mPBMC produced more interleukin (IL)-6, IL-10, and IL-17 compared with cPBMC (p < 0.05). We found differences in lymphocyte composition and cytokine production between mPBMC and cPBMC. These differences did not result in quantitative changes in proliferative responses during pregnancy compared with responses in nonpregnant controls.     

IFN-γ production in response to IL-18 or IL-12 stimulation by peripheral blood mononuclear cells of atopic patients

BACKGROUND: Several studies have shown that interleukin (IL)-4 and interferon-gamma (IFN-gamma) are important for the regulation of immunoglobulin E (IgE) production and that IL-18 and IL-12 induce IFN-gamma. OBJECTIVE: IFN-gamma production in response to IL-18 or IL-12 stimulation was investigated in peripheral blood mononuclear cells (PBMCs) of atopic patients with various levels of serum IgE. METHODS: Cytokine production from PBMCs was measured following stimulation with a non-specific stimulator (phytohemagglutinin: PHA), IL-18 or IL-12 in 12 healthy controls and 26 atopic patients with various serum IgE levels. RESULTS: IFN-gamma production by IL-18-stimulated PBMCs was positively correlated with IFN-gamma production by IL-12-stimulated PBMCs (P < 0.05). However some atopic patients showed discrepancy between the levels of IFN-gamma production stimulated by IL-12 and by IL-18. CONCLUSIONS: The results shown here suggest the presence of abnormalities in the IL-12 and/or IL-18 signalling pathways, such as genetic defects in the atopic patients.     

Lymphocyte subsets and mitogen stimulation of blood lymphocytes in preeclampsia.

PROBLEM: The question of whether there are differences in systemic immune reactivity in severe preeclampsia compared with normal pregnancy was addressed. METHOD OF STUDY: During the third trimester, blood samples were taken from 12 pregnant women with severe preeclampsia. Five of the preeclamptic pregnancies were analyzed separately because they were treated with dexamethasone before the blood samples were taken. The seven dexamethasone-treated preeclamptic pregnant women were analyzed and compared with six uncomplicated pregnancies. A control group consisted of 15 nonpregnant females. Lymphocyte subsets were identified by flow cytometry. The function of peripheral blood mononuclear cells (PBMCs) was studied as proliferative responses to mitogens alone and in combination with immunomodulating drugs. RESULTS: An increased number of B lymphocytes (CD19+) (P < 0.05) and natural killer (NK) cells (P < 0.05) was noticed in severe preeclampsia compared with normal pregnancy. The proliferative response of PBMCs in phytohemagglutinin (PHA)-stimulated cultures in autologous serum from patients with severe preeclampsia was reduced (P < 0.05) compared with normal pregnancy. The addition of indomethacin and cimetidine significantly stimulated (P < 0.05) the proliferative responses. The enhancing effect of cimetidine was not found in dexamethasone-treated preeclamptic patients. CONCLUSIONS: The presence of systemic immunosuppression in severe preeclampsia is demonstrated as a reduced proliferative response of PBMCs to PHA, which could be partly restituted by indomethacin or cimetidine, indicating immunosuppressor activity that is mediated by prostaglandin and histamine. Increased levels of B lymphocytes and NK cells were also noticed.     

Sleep in normal late pregnancy.

Twelve women in their third trimester of pregnancy and 10 age-matched nonpregnant controls underwent complete polysomnography for one night in the laboratory. Seven of the original women returned for a second study 3-5 months postpartum. During late pregnancy, women showed increased wake after sleep onset (WASO) and a lower sleep efficiency in comparison with the control group. The percentage of rapid eye movement (REM) sleep was significantly decreased and the percentage of stage 1 significantly increased compared to the nonpregnant group. At 3-5 months postpartum, a significant reduction in WASO and increased sleep efficiency were noted. However, only a slight increase was noted in REM sleep during the postpartum period compared to the prepartum period. The most frequent sleep complaints in the pregnant group were restless sleep, low back pain, leg cramps and frightening dreams. In summary, in accordance with their complaints, women in their third trimester demonstrated polysomnographic patterns of sleep maintenance insomnia.     

Etiological implication of autoantibodies to zona pellucida in human female infertility.

PROBLEM: Autoantibodies to zona pellucida (ZP) have been implicated as a cause of infertility in woman by three lines of clinical and laboratory evidence. METHOD: First, positive anti-zona activities, as assessed by the passive hemagglutination reaction (PHAR) using bovine red blood cells sensitized with porcine zona antigen, were detected in 45 of 1,872 serum samples collected from infertile women, but in only three (two nonpregnant and one pregnant) of 592 serum samples from control subjects. Their incidence in 320 women with unexplained infertility (5.6%) was much higher than that in 1,552 women with infertility of known cause (1.7%, P < 0.01), which was comparable to the incidence observed in 193 age-matched fertile nonpregnant and pregnant women (1.5%, P < 0.05). None of the serum samples from 292 age-matched adult men and 100 children of between 5 and 10 years old gave a positive PHAR. Second, follow-up study for a minimum of 2 years with treatment revealed that no pregnancy occurred in 11 infertile women with a consistently positive PHAR, and only three pregnancies in 19 infertile women with a fluctuating positive PHAR. Third, three of seven serum samples from women who gave a consistently positive PHAR produced strong immunofluorescence reactions on human ZP even after adsorption with porcine and human AB blood cells. Pre-exposure of human ZP to the sera showing positive immunofluorescence, including that of one patient undergoing an in vitro fertilization program, greatly diminished the number of spermatozoa of normal quality that bound to and penetrated across human ZP. CONCLUSIONS: The observed high incidence of anti-zona activities and long-term resistancy to treatment in women with unexplained infertility may be closely correlated with inhibition of sperm-egg interaction by anti-zona autoantibodies produced in these women.     

T helper 1-type immunity to trophoblast antigens in women with a history of recurrent pregnancy loss is associated with polymorphism of the IL1B promoter region

Recurrent pregnancy loss (RPL) is a common disorder during early gestation. Recent evidence suggests that T helper 1 (Th1)-type immunity is associated with unsuccessful pregnancy especially in women with RPL of otherwise unknown etiology, while Th2-type immunity is associated with pregnancy success. Interleukin (IL)-1 may influence Th1/Th2 immune responsiveness and has been implicated in the establishment of successful pregnancy. In the present study, we investigated polymorphism of the IL-1beta gene (IL1B) in women with a history of RPL. Significant increases in the frequencies of IL1B promoter region variants IL1-511C and IL1B-31T were found in women with a history of RPL. Increased frequencies of these two variants and their homozygotes were found only in cases having evidence of Th1 immunity to trophoblast as determined by IFN-gamma production of peripheral blood mononuclear cells (PBMCs) stimulated with a trophoblast cell-line extract. Significantly higher IFN-gamma production by PBMCs in response to trophoblast correlated with variant IL1B-511C and its homozygocity in women with RPL. These results suggest that variants -511C and -31T in the IL1B promoter region confer risk for RPL associated with Th1 immunity to trophoblast antigens.     

Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites

Pregnant women are highly susceptible to malaria infection because of their low immunity and are at increased risk of maternal illness or death, in addition to spontaneous abortion, stillbirth, premature delivery, and low birth weight. However, the detailed pathogenesis of maternal malaria remains unclear. In this study, we evaluated a mouse model that shows similar severe pathological features of pregnant women during Plasmodium falciparum infection and investigated the pathogenesis of maternal malaria. Pregnant mice immunized by infection with an attenuated parasite, Plasmodium berghei XAT, were more susceptible to virulent P. berghei NK65 challenge/infection than were nonpregnant mice and showed high levels of parasitemia and a poor pregnancy outcome associated with placental pathology, such as accumulation of parasitized red blood cells, in the late phase of pregnancy. Notably, the pregnant immune mice challenged/infected with P. berghei NK65 developed liver injury associated with microvesicular fatty infiltration in late pregnancy. The pathological features were similar to acute fatty liver of pregnancy. Higher levels of gamma interferon and nitric oxide (NO) were found in plasma from pregnant immune mice infected with P. berghei NK65 than in plasma from nonpregnant mice. These findings suggest that development of liver injury and placental pathology in pregnant immune mice challenged/infected with P. berghei NK65 is accompanied by enhanced production of proinflammatory cytokines.     

Elevation of Transforming Growth Factor-β1 Is Associated with Recurrent Miscarriage

To investigate the significance of transforming growth factor-1 (TGF-1) in reproduction we have compared plasma levels in normal pregnant women and patients suffering miscarriages. We examined 188 normal pregnant women and 12 pregnant women with miscarriages. Eight women with severe recurrent miscarriages (mean ± SD of previous number of miscarriages; 10.4 ± 2.4 times) were also examined before conception; 34 nonpregnant women served as controls. Plasma TGF-1 level increased with the gestational week and returned within the normal range 1 month after delivery. The levels among pregnant women with miscarriages (mean ± SD; 2.44 ± 0.83 ng/ml) were significantly higher than those of pregnant controls (1.74 ± 0.95 ng/ml) of matched gestational weeks; levels among nonpregnant women with severe recurrent miscarriages were extremely elevated (4.1 ± 3.04 ng/ml) compared to the control value (1.34 ± 0.59 ng/ml). These data suggest that TGF-1 may be necessary to maintain pregnancy but also may be a risk factor for recurrent miscarriages.     

Maternal and newborn immunization with a human immunodeficiency virus-1 immunogen in a rodent model

We examined immunization with an inactivated, gp120-depleted human immunodeficiency virus (HIV) antigen in incomplete Freund's adjuvant (IFA), also containing a sequence of immunostimulatory (ISS) DNA, during the last trimester of pregnancy and neonatally in a rat model. Pregnant rats were immunized in the third trimester and their litters were immunized during the newborn period. In addition, litters of rats from non-immunized mothers were immunized during the neonatal period. As another control, pregnant rats were immunized and their litters analysed. Supernants from peripheral blood mononuclear cells (PBMCs) were assayed from newborns at 4 weeks of age for HIV-specific interferon-gamma (IFN-gamma), HIV-specific regulated on activation, normal, T-cell expressed, and secreted (RANTES), and serum for p24 antigen-specific immunoglobulin G (IgG) production. In the animals whose pregnant mothers were immunized and were also immunized during the neonatal period, we observed HIV-specific IFN-gamma production and HIV-specific RANTES production, but weak p24 IgG antibody production. Animals immunized only during the neonatal period developed the highest levels of HIV-specific IFN-gamma production, but somewhat lower levels of HIV-specific RANTES and p24 IgG antibody production. The group of animals whose mothers had received immunizations during the last trimester of pregnancy, but were not immunized during the neonatal period, developed the strongest p24 IgG antibody levels, but little or undetectable HIV-specific IFN-gamma or RANTES production. Neonatal immunization resulted primarily in cell-mediated immune responses, while animals born to mothers who were immunized during the last trimester had primarily an antibody-mediated immune response. Immunization of pregnant animals followed by neonatal immunization resulted in a mixed cell-mediated/antibody type profile in the neonatal animal. Future studies should provide insights into neonatal immunity and potential vaccine approaches to prevent neonatal infection and perinatal transmission.     

Maternal antigen presenting cells are a source of plasmatic HLA-G during pregnancy: longitudinal study during pregnancy

The aim of this work was to investigate the longitudinal evolution of plasmatic soluble HLA-G (sHLA-G: shed HLA-G1 plus HLA-G5) during pregnancy, and if peripheral maternal antigen presenting cells (APC) can be a source of sHLA-G. Blood samples were obtained from 45 volunteers during normal pregnancy, 8 of them monthly; from 8 pregnant volunteers in the first weeks of pregnancy who had later a miscarriage, and from 14 healthy nonpregnant control women. Monocytes obtained during pregnancy showed a moderately HLA-G cell surface expression and stimulation with interferon (IFN)-gamma increased this expression. Monocytes-derived dendritic cells obtained from pregnant women during the first and third trimester of pregnancy secreted more sHLA-G than those obtained from nonpregnant women. Plasmatic sHLA-G concentration in pregnant women was significatively higher than in nonpregnant women, with a peak in the third month. We can conclude that maternal APC are a source of sHLA-G. Women who experienced miscarriage had previously very low or undetectable plasmatic sHLA-G levels in the second month of pregnancy. Data suggest that undetectable sHLA-G could be a risk of complications.     

Effect of pregnancy and human immunodeficiency virus infection on intracellular interleukin-2 production patterns

Human immunodeficiency virus type 1 (HIV-1) infection decreases the production of interleukin-2 (IL-2) from CD4+ and CD8+ T cells. Recombinant IL-2 (rIl-2) has been given to HIV-infected individuals to generate significant increases in CD4+ T-cell counts. There are limited data regarding the effects of pregnancy and HIV infection on IL-2 production in humans. To investigate the effects of human pregnancy, HIV infection, and HIV therapy on IL-2 production, we evaluated 61 women. Intracellular IL-2 production by CD4+ T cells from nonpregnant HIV-infected women was significantly lower than in that in uninfected women (45% +/- 8% versus 52% +/- 8%, P = 0.04). In contrast, there was no difference in levels of intracellular IL-2 production between HIV-infected and uninfected pregnant women. These observations suggest that pregnancy may down-regulate IL-2 production regardless of HIV infection status. Future studies should evaluate IL-2 production patterns in larger cohorts of women so that the physiological significance of IL-2 down-regulation in pregnancy can be further evaluated. This information is essential to assess the possible use of IL-2 supplementation therapy as a means of enhancing immune responses among HIV-infected pregnant women.