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Relation Between Adenosine and T-helper 1/T-helper 2 Imbalance in Women With Preeclampsia

From the Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan; and the Center for Perinatal Biology, Loma Linda University, Loma Linda, California.

Address reprint requests to: Yoshio Yoneyama, MD, Nippon Medical School, Department of Obstetrics and Gynecology, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan; E-mail: Yoshi-1{at}nms.ac.jp.

	ABSTRACT

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OBJECTIVE: To evaluate the relationship between changes in plasma adenosine concentration and imbalances in the T-helper 1/T-helper 2 ratio in peripheral blood of women with preeclampsia.

METHODS: Plasma adenosine concentrations and the T-helper 1/T-helper 2 ratio were examined in the peripheral blood of 16 preeclamptic and normal pregnant women. The proportion of specific T-cell marker CD4-positive cells expressing intracellular cytokines, interferon- derived from T-helper 1 and interleukin-4 derived from T-helper 2 cells, were analyzed by flow cytometry. The ratio of interferon- secreting cells to interleukin-4 secreting cells was taken as the T-helper 1/T-helper 2 ratio in vivo. The effect of the adenosine-receptor blocker 8-sulfophenyltheophyl-line was also measured in vitro.

RESULTS: Mean plasma adenosine concentration in preeclampsia was significantly higher than that in normal pregnancy (0.68 ± 0.07 µmol/L versus 0.39 ± 0.06 µmol/L, P < .05). The proportions of interferon- secreting cells increased and interleukin-4 secreting cells decreased significantly in preeclampsia, and the T-helper 1/T-helper 2 ratio in preeclampsia was significantly higher than in normal pregnancy (18.1 ± 2.6 versus 9.9 ± 1.5, P < .05). The increase of the proportion of interferon- secreting cells after adenosine receptor blockade in preeclampsia significantly exceeded that of normal pregnancy. The T-helper 1/T-helper 2 ratio in preeclampsia was significantly greater than that in normal pregnancy (36% versus 17%, P < .05).

CONCLUSION: Increased plasma adenosine may be involved in the regulation of imbalances in the T-helper 1/T-helper 2 ratio in women with preeclampsia.

Cellular and humoral immunity and their effector cells are regulated by antigen-presenting cells, the T-helper cells, and by their secreted soluble messengers. The CD4-positive T-helper cells have been classified into three subsets based on their type of cytokine production. T-helper 1 cells synthesize mainly interleukin-2 and interferon-, which induce cellular immunity. T-helper 2 cells produce predominantly interleukin-4, -5, -6, and -10, which promote humoral immunity. T-helper 0 cells secrete both types of cytokines.¹

T-helper 2 cytokines predominate at the fetomaternal interface during normal pregnancy in animal species. Consequently, systemic immune responses influenced particularly by T-helper 2 have been proposed in pregnancy.² These cytokines appear to protect the fetus and placenta from being rejected and to aid in the maintenance of normal pregnancy. In humans, an important role for the T-helper 2 immune response has also been reported during normal pregnancy.^3,4 However, details regarding the mechanism of action remain incompletely understood. Because excessive T-helper 1 cell production has been shown to evoke rejection responses directed against fetoplacenal semiallografts,⁵ T-helper 1 dominance may be associated with pathologic conditions such as recurrent spontaneous abortions⁶ and preeclampsia.^3,7 Immune disorders have been implicated in the pathogenesis of preeclampsia, and imbalances in the T-helper 1/T-helper 2 ratio may play an important role in the production of leukocyte-endothelial adhesion molecules, which mediate adherence of inflammatory cells. Such imbalance may induce endothelial injury and eventually cause and/or worsen preeclampsia.⁸

Adenosine is a degradative metabolite of the adenine nucleotides, which is produced in response to ischemia and hypoxia in the placenta and other tissues. It has been implicated in many regulatory processes including regulation of local blood flow and metabolic rate. Adenosine also exerts powerful influences on immune-triggered cytokine production and may be speculated to shift the T-helper 1/T-helper 2 balance toward T-helper 2 dominance.^9,10 By this means, adenosine may exert a protective action at the maternal-fetal interface. In preeclamptic women, plasma adenosine concentrations are found to be significantly increased,¹¹ and there may be an associated imbalance in the T-helper 1/T-helper 2 ratio.^3,7 However, the exact relationship between elevated adenosine and the T-helper 1/T-helper 2 imbalance in women with preeclampsia has not been established.

To clarify the possible role of adenosine in modulating the T-helper 1/T-helper 2 imbalance, we measured plasma concentrations of adenosine and CD4-positive cells secreting interferon- (taken as an index of T-helper 1 cells¹²) and interleukin-4 (taken as an index of T-helper 2 cells¹²) in peripheral blood of women with preeclampsia. Thus, for purposes of this study, the ratio of interferon- secreting cells to interleukin-4 secreting cells was accepted as the T-helper 1/T-helper 2 ratio. The effects of adenosine-receptor blockade were also examined in vitro to test further the possible role of adenosine in modifying the T-helper 1/T-helper 2 ratio in women with preeclampsia.

	MATERIALS AND METHODS

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Subjects were recruited consecutively from the Obstetrics Outpatient Department of the Nippon Medical School Hospital beginning in 1999 and extending until April 2000. The study was approved by the Nippon Medical School Hospital Ethics Committee. Preeclampsia was defined as blood pressure higher than 140/ 90 mmHg on two or more occasions at least 6 hours apart with the patient at bed rest and proteinuria in excess of 300 mg protein per day. The entry criteria for the study were preeclamptic women whose blood pressure had been normal during the first 20 weeks’ gestation and with no previous history of hypertension or renal disease, a well-established gestational age corroborated by ultrasonography before 13 weeks’ gestation, a singleton fetus, no fetal structural anomaly, nonsmoker, a normal response to glucose tolerance testing, no evidence of recent infection (eg, rubella, toxoplasma, hepatitis B and C, cytomegalovirus, or syphilis), and the absence of uterine contractions.

Twenty-two women with preeclampsia meeting the eligibility criteria volunteered for the study, and 16 gave informed consent after being advised that they would not benefit directly from this research. Pregnant women without preeclampsia, matched for maternal age (within 0.7 year), parity, and gestational age (within 6 days), were selected to serve as a control group. Twenty-one patients were offered entry. Nineteen of these women satisfied the eligibility criteria, and 16 gave informed consent and constituted the control group.

The patients and control subjects were requested to abstain from caffeine intake for 7 days and were then studied after overnight fasting. One hour before the study, the women entered a quiet room and were placed in a semirecumbent position in bed. An indwelling 18-gauge catheter (Medikit Co., Tokyo, Japan) was placed in an antecubital vein. Care was taken to handle blood from preeclamptic and normal women in an identical fashion.

After the 1-hour period of accommodation, a 1-mL blood sample was withdrawn from the indwelling catheter into a heparinized syringe for measurement of plasma adenosine. An equal volume of sterile, ice-cold stop-solution was added to each sample near the tip of the sampling catheter. The stop-solution consisted of 20 µM of dipyridamole, 120 µM of erythro-9- (2-hydroxyl-3-nonyl) adenine hydrochloride, 60 µM of , ß-methylene adenosine-5'-diphosphate, and 5 mM of Na₂ ethylenediaminetetra-acetic acid (Sigma-Aldrich Japan K.K., Tokyo, Japan) in saline. Samples were transferred immediately to tared tubes on ice and then centrifuged without delay at 10,000 g for 5 minutes at 4C. The supernatant was deproteinized by centrifugation (1000 g for 1 hour, 25C) using an ultrafiltration cone (Centrifree, Millipore Corp., Bedford, MA). Deproteinized plasma was stored at -70C until analyzed.

Plasma adenosine concentrations were assayed with a high performance liquid chromatographic method with photodiode-array detection, as previously described.¹³ The detection limit was at least 5 nM, and the intra- and interassay coefficients of variation were 7.2% and 8.6%, respectively.

Flow cytometric determination of interferon- and interleukin-4 in the cytoplasm of peripheral CD4-positive T cells was performed using the Fastimmune cytokine detection system (Becton Dickinson Immunocytometry Systems, San Jose, CA). Briefly, blood samples were withdrawn into heparinized syringes and processed immediately. Aliquots (500 µL) were activated with phorbol 12-myristate 13-acetate (50 ng/mL) (Sigma-Aldrich Japan K.K.) and calcium ionomycin (0.5 µg/mL) (Sigma-Aldrich Japan K.K.) dissolved in proprietary media (Rosewell Park Memorial Institute #1640). Culture tubes were incubated in 5% CO₂ at 37C for 4 hours. Activation was performed in the presence of 10 µM of Brefeldin A (Sigma-Aldrich Japan K.K.), which inhibits intracellular transport processes. After incubation, the mononuclear cells were stained with 20 µL of peridin chlorophyll protein-conjugated monoclonal antibody specific for the cell surface antigen CD4 (Becton Dickinson Immunocytometry Systems) for 15 minutes at room temperature, and then washed twice with phosphate-buffered saline. They were treated with 1 mL of fluorescence-activated cell sorter lysing solution (Becton Dickinson Immunocytometry Systems) for 10 minutes to lyse the red blood cells. The suspension was then centrifuged at 500 g for 5 minutes at room temperature, and the supernatant was aspirated. Fluorescence-activated, cell-sorter permeabilizing solution (5 mL) (Becton Dickinson Immunocytometry Systems) was added, and the mixture was incubated for 10 minutes at room temperature to render the cells permeable. The cells were washed twice with phosphate-buffered saline. The treated cells were then stained with fluorescein-isothiocyanate-conjugated antihuman interferon- monoclonal antibody (Becton Dickinson Immunocytometry Systems) and phycoerythrin-conjugated antihuman interleukin-4 monoclonal antibody (Becton Dickinson Immunocytometry Systems) for 30 minutes at room temperature in the dark. Fluorescein-isothiocyanate-conjugated, isotype-matched immunoglobulin_2a and phycoerythrin-conjugated immunoglobulin₁ were used as controls for detecting nonspecific binding. After two washes with phosphate-buffered saline, the cells were resuspended in 1% paraformaldehyde in phosphate-buffered saline. Flow cytometry was performed using a FACSCalibur (Becton Dickinson Immunocytometry Systems).

The forward and side scatter gates for lymphocytes and the CD4-positive gate (logical gate) were set to exclude contaminating monocytes and dead cells from the analysis. The sorted cells were collected in sterile tubes, which had been precoated with fetal calf serum to prevent T-cell adhesion. The cells were counted, and the purity was verified. The purity of the sorted CD4-positive cells uniformly exceeded 99%. Fifty thousand cells were acquired in the list mode and analyzed with CELL Quest software (Becton Dickinson Immunocytometry Systems). The results were expressed as the percentage of cytokine-secreting cells in the total CD4-positive cell population.

Possible changes in the proportion of interferon- and interleukin-4 secreting cells were also examined after treatment of the cells with a nonspecific adenosine receptor blocker in vitro. Aliquots of heparinized venous blood were incubated with 10^-3 M of 8-sulfophenyl-theophylline (Sigma-Aldrich Japan K.K.) at 37C for 15 minutes. Phorbol 12-myristate 13-acetate and calcium ionomycin stimulation were then performed in the presence of Brefeldin A. Quantitation of interferon- and interleukin-4 secreting cells was performed by flow cytometry using the Fastimmune cytokine detection system (Becton Dickinson Immunocytometry Systems). The percentages of interferon- and interleukin-4 positive cells relative to the total CD4-positive cells were computed based on results of the fluorescence-activated cell sorter.

Data are presented as mean ± standard error of the mean. Statistic analyses were performed using Student t test for normally distributed data and the Mann-Whitney U test and Fisher exact test, as appropriate. Linear regression analysis was performed by the least-squares method. Differences were considered significant at P < .05.

	RESULTS

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The characteristics of the study population are given in Table 1. All subjects were married Japanese women of middle socioeconomic status who were nonsmokers. None of the patients in this study developed eclampsia or the hemolysis, elevated liver enzymes, and low platelets syndrome.

View this table: [in this window] [in a new window]   Table 2. Population of Total CD4-Positive T-cells Secreting Interferon- and Interleukin-4 and the T-helper 1/T-helper 2 Ratio in Peripheral Blood of Normal and Preeclamptic Women

View larger version (25K): [in this window] [in a new window]   Figure 1. Representative data from flow cytometry of CD4-positive T-cells in peripheral blood in normal pregnancy (A) and preeclampsia (B). CD4-positive T-cells were categorized by fluorescense-activated cell sorting (greater than 99% purity) as interferon- secreting (lower right quadrant), interleukin-4 secreting (upper left quadrant), or interferon- and interleukin-4 secreting (upper right quadrant). Numbers in the right upper corners are percentages of CD4-positive T-cell subset found in each quadrant. Yoneyama. Adenosine and T-helper Cells. Obstet Gynecol 2002.

View this table: [in this window] [in a new window]   Table 3. Changes in the Total CD4-Positive T-cells Secreting Interferon- and Interleukin-4 and the T-helper 1/T-helper 2 Ratio After Treatment of Blood With an Adenosine Receptor Blocker

	DISCUSSION

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The present study demonstrated that plasma adenosine concentrations increased 174% in preeclampsia compared with nonpreeclamptic women matched for gestational age and several other attributes. Such increases of adenosine are in agreement with earlier findings.¹¹ The elevation could reasonably be predicted because platelet activation, local tissue hypoxia and ischemia, the formation of microthrombosis, and increases in catecholamine concentrations are all well established causes for the release of adenosine into circulating blood. These events frequently occur in preeclampsia, and it is reasonable to conclude that plasma adenosine is elevated as a response to these events.

In the present study, interferon- secreting cells (index of T-helper 1) were found to predominate in preeclampsia, whereas interleukin-4 secreting cells (index of T-helper 2) were more numerous in normal pregnancy. Thus, the T-helper1/T-helper 2 ratio was significantly elevated in preeclampsia. This result is in agreement with the concept that a shift of T-helper 2 dominant to T-helper 1 dominant status may be associated with the pathogenesis of preeclampsia.^3,7 Other studies have yielded opposing findings, such as elevation in T-helper 2 cytokines, interlukin-4 and -6.^14,15 Differences between studies seem most likely to be explained by variations of study design, including the severity of preeclampsia and the method of cytokine analysis.

A new aspect of the present work relates to adenosine receptor blockade. Such blockade was found to significantly increase the proportion of interferon- secreting cells in both normal pregnancy and preeclampsia. This result suggests that adenosine may inhibit the activation of interferon- secreting cells during pregnancy in general. Moreover, the extent of the increase in the activation of interferon- secreting cells was more pronounced in preeclampsia than in normal pregnancy. In preeclampsia, the T-helper 1 cytokines and the T-helper 0 cytokines, which stimulate the activation of T-helper 1 cells, are elevated.^7,16 Because adenosine inhibits the effects of these cytokines,^17,18 removal of inhibition by 8-sulfophenytheophylline is one possible mechanism that might account for the greater response of the activation of interferon- secreting cells observed in women with preeclampsia. T-helper 1 cytokines are biologically active, and continued excessive T-helper 1 cell activation may eventually worsen preeclampsia. These observations taken together make credible the speculation that elevated plasma adenosine in preeclampsia reduces excessive T-helper 1 cytokine production and redresses imbalances in the T-helper 1/T-helper 2 ratio.

In this study, the adenosine receptor blocker 8-sulfo-phenyltheophylline did not alter interleukin-4 secreting cells significantly. The effect of adenosine on the T-helper 2 cytokine, interleukin-4 has not been established in detail. The nonspecific adenosine receptor antagonist theophylline suppresses the release of interleukin-4 by peripheral blood mononuclear cells,¹⁹ whereas the natural derivative of adenosine, cyclic 3',5'-adenosine mono-phosphate, does not affect interleukin-4 production.²⁰ Further studies are needed to clarify the effect of adenosine on the interleukin-4 production by T-helper 2 cells.

Other cytokines such as tumor necrosis factor- have also been implicated in the pathogenesis of preeclampsia.²¹ Because adenosine inhibits the interferon- production by tumor necrosis factor- and stimulates interferon-6 and interferon-10 production by T-helper 2 cells,^21,22 adenosine may minimize T-helper 1/T-helper 2 imbalances in preeclampsia by this means also.

A number of limitations should be emphasized in the use of numbers of CD4-positive T-cells with intracellular interferon- or interleukin-4 in making inferences regarding the functional changes in these cells in preeclampsia. Circulating T-cells that secrete intracellular cytokines in the peripheral blood do not necessarily reflect, for instance, the more important local immunologic environments in preeclampsia. The immunologic changes in the fetomaternal interface are likely to be of more importance than those in peripheral blood.^8,23 In addition to T-helper cells, other elements including monocytes, natural killer cells, and immunologic factors are involved in the pathogenesis of preeclampsia.⁸ The shift to the T-helper 1 dominance is found to induce apoptosis of trophoblasts,^4,24 and to correlate well with the severity of hypertension.²⁵ Thus, changes in the T-helper 1/T-helper 2 ratio are likely to reflect, at least in part, changes in the cell function in preeclampsia. Overall, the mechanisms by which adenosine may influence and possibly regulate the T-helper 1/T-helper 2 imbalance in preeclampsia are not fully understood, and further study is needed to clarify them.

	Footnotes

 
Supported by a Grants-in-Aid (No. 12470349) from the Ministry of Education, Science, and Culture.

PII S0029-7844(02)01657-5

Received August 14, 2001. Received in revised form November 26, 2001. Accepted December 11, 2001.

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