Exposure to thioguanine during 117 pregnancies in women with inflammatory bowel disease

Background: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. Methods: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. Results: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. Conclusion: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Glatiramer acetate (copolymer-1, Copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells

Glatiramer acetate (GA; copolymer-1, Copaxone) suppresses the induction of experimental autoimmune encephalomyelitis and reduces the relapse frequency in relapsing-remitting multiple sclerosis. Although it has become clear that GA induces protective degenerate Th-2/IL-10 responses, its precise mode of action remains elusive. Because the cytokine profile of Th cells is often regulated by dendritic cells (DC), we studied the modulatory effects of GA on the T cell regulatory function of human DC. This study shows the novel selective inhibitory effect of GA on the production of DC-derived inflammatory mediators without affecting DC maturation or DC immunostimulatory potential. DC exposed to GA have an impaired capacity to secrete the major Th1 polarizing factor IL-12p70 in response to LPS and CD40 ligand triggering. DC exposed to GA induce effector IL-4-secreting Th2 cells and enhanced levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effect of GA is mediated via DC as GA does not affect the polarization patterns of naive Th cells activated in an APC-free system. Together, these results reveal that APC are essential for the GA-mediated shift in the Th cell profiles and indicate that DC are a prime target for the immunomodulatory effects of G

Macrophage support and suppression in rabbit T cell mitogenesis

The role of macrophages in mitogen-induced rabbit T cell proliferation has been investigated. The blastogenic response to the 3 mitogens, PHA, ConA and oxidative treatment by neuraminidase and galactose oxidase (NaGo) was tested. T cell proliferation was reduced by removal of low density or plastic adherent cells, including macrophages, and could be enhanced by the addition of peritoneal resident macrophages, indicating a macrophage requirement for rabbit T cell proliferation. However, PHA-induced proliferation could not be raised to the level expected. It was found that catalase and especially 2-ME could considerably enhance macrophage dependent proliferation, even at low macrophage concentrations. It is concluded therefore, that macrophages not only support but also suppress lymphocyte proliferation, namely by non-specific damage to lymphocytes through release of radicals and hydrogen peroxide. In addition, peritoneal, but not lymph node macrophages were found to suppress lymphocyte proliferation by prostaglandin production, although to a lesser extent. Experiments, done in the presence of blockers of macrophage-mediated suppression, showed that macrophages were able to magnify the PHA-induced T cell proliferation to the expected values. The experiments thus show that unactivated macrophages support and suppress lymphocyte proliferation at the same tim

Human epidermal Langerhans cells undergo profound morphologic and phenotypical changes during in vitro culture

Morphology, phenotype, and enzyme activity of highly enriched (80%) unlabeled human epidermal Langerhans cells (LC) have been studied, with emphasis on changes during a short-term culture of three days in vitro. All freshly isolated LC contained Birbeck granules and expressed high levels of CD1a, CD1c, and MHC class II molecules HLA-DR, -DP, and -DQ. They have a weak to moderate expression of RFD1, C3biR, Fc gamma R, p 150/95, MHC class I molecules HLA-ABC, and of the adhesion molecules LFA-3 and ICAM-1, whereas no expression of LFA-1 and several monocyte/macrophage markers were detected. Human LC undergo profound changes during in vitro culture. Birbeck granules, C3biR, Fc gamma R, and p 150/95 were completely lost and the expression of CD1a and CD1c was markedly decreased or lost. Expression of molecules that have essential functions in antigen presentation remained present at the same level (MHC class II molecules and ICAM-1) or was markedly enhanced (LFA-3 and MHC class I). Highly remarkable was the dramatically enhanced expression of interdigitating cell marker RFD1. The monocyte/macrophage markers initially absent remained absent and the enzyme activity initially present (including ATPase and nonspecific esterase) remained present. In conclusion, the results in this report stress rapid alterations of human LC during in vitro culture, resulting in transformation into cells that have phenotypical characteristics of potent antigen presenting cells that resemble interdigitating cell

Exposure to Thioguanine During 117 Pregnancies in Women With Inflammatory Bowel Disease.

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. METHODS: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes

Exposure to thioguanine during 117 pregnancies in women with inflammatory bowel disease

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease (IBD) is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and in birth. METHODS: In this multicenter case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most (78%) had Crohn's disease and the mean age at delivery was 31 years. In eighteen pregnancies (15%) IBD flared. Obstetric and infectious complications were seen in 15% (n=17) and 7% (n=8) of pregnancies, respectively. Ten pregnancies (8.5%) resulted in a first trimester miscarriage and one in a stillbirth at 22 weeks gestational age. Congenital abnormalities were observed in one induced abortion (trisomy 21) and in one of the live-born children (cleft palate) . In total 109 neonates were born from 101 singleton pregnancies and 4 twin pregnancies. In the singleton pregnancies, ten children were born prematurely and ten were born small for gestational age. Screening for myelosuppresion was performed in sixteen neonates (14.7%); two had anemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from 3 Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes