ABSTRACT
The use of biological therapies for treating autoimmune diseases is increasing. These therapies are sometimes administered to pregnant women as part of a planned therapeutic regimen or to women with unexpected or unplanned pregnancies. The safety of biological therapies in this setting is a major issue. Here, we describe three young pregnant patients with autoimmune disorders: two patients with rheumatoid arthritis and one with idiopathic thrombotic thrombocytopenic purpura. These patients were exposed to rituximab (anti-CD20 monoclonal antibody) or abatacept (fusion protein CTLA4Ig) during the first trimester of their pregnancies. No significant adverse effects or complications were observed during the pregnancies, and all three patients delivered healthy newborns. In the rituximab cases, this result might be explained in part by the very low transplacental maternofetal transfer of rituximab during the first trimester of pregnancy. Despite these favorable outcomes, the use of these two biological agents must follow international recommendations. Their use is not currently allowed during pregnancy except in cases where the potential benefit to the mother justifies the potential risk to the fetus. In the case of exposure to the single agent rituximab during the first trimester, current data suggest that the low risk to the fetus may be outweighed by the potential benefit to the mother.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/adverse effects , Autoimmune Diseases/drug therapy , Immunoconjugates/adverse effects , Pregnancy Complications/drug therapy , Abatacept , Adult , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/drug therapy , Autoimmune Diseases/complications , Female , Humans , Immunosuppressive Agents/adverse effects , Pregnancy , Pregnancy Outcome , Pregnancy Trimester, First , Purpura, Thrombotic Thrombocytopenic/complications , Purpura, Thrombotic Thrombocytopenic/drug therapy , Risk , RituximabABSTRACT
Liver receptor homolog 1 (LRH-1) is an orphan nuclear receptor that synergizes with beta-catenin/T cell factor 4 signaling to stimulate intestinal crypt cell renewal. We evaluated here the impact of haploinsufficiency of LRH-1 on intestinal tumorigenesis by using two independent mouse models of human colon tumorigenesis. Haploinsufficiency of LRH-1 blunts intestinal tumorigenesis in the ApcMin/+ mice, a genetic model of intestinal cancer. Likewise, Lrh-1+/- mice are protected against the formation of aberrant crypt foci in the colon of mice exposed to the carcinogen azoxymethane. LRH-1 gene expression is reduced in tumors that express elevated levels of the proinflammatory cytokine TNF-alpha. Reciprocally, decreased LRH-1 expression in Lrh-1+/- mice attenuates TNF-alpha expression. Compared with normal human colon, expression and subcellular localization of LRH-1 is significantly altered in neoplastic colon. In combination, these data suggest a role of LRH-1 in the initiation of intestinal tumorigenesis both by affecting cell cycle control as well as through its impact on inflammatory pathways.
Subject(s)
Cell Cycle/physiology , Inflammation/metabolism , Intestinal Neoplasms/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Azoxymethane/pharmacology , Carcinogens/pharmacology , Disease Models, Animal , Female , Heterozygote , Humans , Intestinal Neoplasms/chemically induced , Intestinal Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Receptors, Cytoplasmic and Nuclear/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
LRH-1 is an orphan nuclear receptor predominantly expressed in tissues of endodermal origin, where it controls development and cholesterol homeostasis. We show here that LRH-1 induces cell proliferation through the concomitant induction of cyclin D1 and E1, an effect that is potentiated by its interaction with beta-catenin. Whereas beta-catenin coactivates LRH-1 on the cyclin E1 promoter, LRH-1 acts as a potent tissue-restricted coactivator of beta-catenin on the cyclin D1 promoter. The implication of LRH-1 in cell proliferation highlights an unanticipated crosstalk between LRH-1 and the beta-catenin/Tcf4 signaling pathway, which is relevant for the renewal of intestinal crypt cells.
