Defects in the vasoactive intestinal peptide (VIP)/VPAC system during early stages of the placental-maternal leucocyte interaction impair the maternal tolerogenic response.

Successful embryo implantation occurs followed by a local inflammatory/T helper type 1 (Th1) response, subsequently redirected towards a tolerogenic predominant profile. The lack of control of this initial local inflammatory response may be an underlying cause of early pregnancy complications as recurrent spontaneous abortions (RSA). Considering that vasoactive intestinal peptide (VIP) mediates anti-inflammatory and tolerogenic effects in several conditions we hypothesized that VIP might contribute to tolerance towards trophoblast antigens during the early interaction of maternal leucocytes and trophoblast cells. In this study we investigated VIP/VPAC system activity and expression on maternal peripheral blood mononuclear cells (PBMCs) after interaction with immortalized trophoblast cells (Swan-71 cell line) as an in-vitro model of feto-maternal interaction, and we analysed whether it modulates maternal regulatory T cell (T(reg))/Th1 responses. We also investigated the contribution of the endogenous VIP/VPAC system to RSA pathogenesis. VIP decreased T-bet expression significantly, reduced monocyte chemotactic protein-1 (MCP-1) and nitrite production in co-cultures of PBMCs from fertile women with trophoblast cells; while it increased the frequency of CD4(+) CD25(+) forkhead box protein 3 (Foxp3)(+) cells, transforming growth factor (TGF)-ß expression and interleukin (IL)-10 secretion. These effects were prevented by VIP-specific antagonist. Interestingly, PBMCs from RSA patients displayed significantly higher T-bet expression, lower T(reg) frequency and lower frequency of VIP-producer CD4 lymphocytes after the interaction with trophoblast cells. Moreover, the patients displayed a significantly lower frequency of endometrial CD4(+) VIP(+) cells in comparison with fertile women. VIP showed a Th1-limiting and T(reg) -promoting response in vitro that would favour early pregnancy outcome. Because RSA patients displayed defects in the VIP/VPAC system, this neuropeptide could be a promising candidate for diagnostic biomarker or surrogate biomarker for recurrent spontaneous abortions.

Is the paternal mononuclear cells' immunization a successful treatment for recurrent spontaneous abortion?

PROBLEM: Alloimmunization as a treatment for recurrent spontaneous abortion (RSA) is still controversial due to the lack of enough controls to evaluate its effectiveness. The present study was conducted to compare the live birth rate in the presence or absence of immunotherapy. METHOD OF STUDY: Ninety-two women with RSA (79 primary [PA] and 13 secondary aborters[SA]) received immunotherapy. Thirty-seven RSA couples not receiving paternal alloimmunization, constituted the "control" group. RESULTS: The pregnancy rate in alloimmunized was 58 vs 46% in the control group. The live birth increased from 71% in the controls to 88% after immunotherapy. The alloimmunization induced mixed lymphocyte reaction blocking factors (MLR BFs) in 79% of women. However, they were also present in 83% of immunized women experiencing a new abortion. CONCLUSION: These results indicate that alloimmunization may be useful in the treatment of RSA.

Long-term treatment of chronic chagasic cardioneuropathy with a mixture of gangliosides: effect on evolution of circulating antiGM1 antibodies.

Chagas disease involves a cardiac impairment, being the first alterations of autonomic disorders which affect heart rate and blood pressure control. At this stage, diminished heart rate responses to atropine and propranolol are observed. Prior studies have shown that short term ganglioside treatment improves the responses to these agents, but there is no information about the long term effect of gangliosides and the evolution of antiGM1 titers. The effects of long term treatment with gangliosides on autonomic tests in patients with chagasic cardiodisautonomy and the evolution of antiGM1 titers were studied in 90 patients (57 men, 33 women, aged 25-60 years) with positive serology for Chagas disease and electrocardiogram showing sinusal bradycardia and incomplete right branch block, without cardiomegaly, with autonomic alterations by postural and Valsalva's tests. All patients were submitted to a test that consisted of intravenous injection of atropine 0.04 mg/kg followed 3 min later by intravenous injection of propranolol 0.2 mg/kg. During these tests heart rate and blood pressure were recorded continuously. Subsequently, 30 patients were treated with 100 mg/day of a mixture of gangliosides by intramuscular injection during 15 days in a row, followed by 40 mg/day during another 75 days. Another 30 patients received continuous treatment for 12 months. The remaining 30 patients were controls. The antiGM1 antibody circulating titers were determined before the treatment, at the third and 12th month. Seventy-four patients completed the study. Before treatment, the heart rate increased, though slightly, after the injection of atropine. After 3 months of ganglioside treatment a statistically significant increase in the response to atropine was recorded. In the controls at 12 months, the response to atropine remained increased without differences between the patients treated for 3 and 12 months. The control patients did not show any modification of the heart rate response during 12 months. Both ganglioside-treated groups showed an increase in the response to propranolol. The antiGM1 titer distribution was similar in both healthy subjects and chagasic patients. None of the patients had positive antiGM1 titers in basal conditions nor significant modifications after the ganglioside treatment. Chagasic cardioneuropathy was not associated in this study with high antiGM1 antibody titers. Chagasic patients showed a diminished heart rate response to atropine as well as to propranolol. Ganglioside treatment determined an increased heart rate response, particularly after atropine. Increased heart rate response was maintained until 1 year, without differences between the patients treated for 3 and 12 months. No changes in the antiGM1 titers were observed during the ganglioside treatment.

Pregnant women with impaired tolerance to an oral glucose load in the afternoon: evidence suggesting that they behave metabolically as patients with gestational diabetes.

OBJECTIVE: In previous studies we observed the existence of a circadian variation of the blood glucose response to oral glucose in pregnant women with higher values at 4 PM. Some women with increased risk of diabetes with normal oral glucose tolerance tests at 8 AM also had values above maximum normal levels at 4 PM. The aim of this trial was to determine the clinical significance of this impaired tolerance in the afternoon. STUDY DESIGN: Seventy-seven pregnant women with normal risk of diabetes (65 of normal weight and 12 overweight), 75 with increased risk of diabetes (26 overweight), and 12 patients with gestational diabetes were incorporated in the study. All women underwent two oral glucose tolerance tests (1.5 gm/kg) at 31 to 32 weeks' gestation at 8 AM and 4 PM with a 1-week interval. At 33 weeks' gestation a whole-day blood glucose profile was performed with usual food intake; samples were withdrawn before each meal and at 30, 60, and 120 minutes after each meal. The weight of the newborns was recorded. RESULTS: (1) Results of oral glucose tolerance tests confirmed a circadian variation of the response in all groups; (2) 37 women with increased risk of diabetes had higher values after oral glucose tolerance testing than the normal threshold at 4 PM but not at 8 AM; (3) among women with normal risk of diabetes all values were within the normal range despite the circadian variation; (4) blood glucose levels during whole-day profiles were normal in women with normal risk of diabetes and with increased risk of diabetes with normal oral glucose tolerance testing at 4 PM, whereas all women with increased risk of diabetes and impaired tolerance in the afternoon showed hyperglycemic episodes; (5) the percentage of newborns with high weight (>90th percentile) among women with increased risk of diabetes and abnormal oral glucose tolerance tests at 4 PM was similar to the percentage found in women with gestational diabetes and much higher than the one observed in women with normal oral glucose tolerance tests in the afternoon. CONCLUSIONS: The impairment of the response to oral glucose tolerance testing seen in some patients with increased risk of diabetes at 4 PM but not at 8 AM seems of clinical significance in view of the abnormal whole-day blood glucose profile these women had and the weights of the newborns.