Between 1% and 3% of U. S. women suffer recurrent miscarriages. Although the cause of recurrent miscarriages in most women is unknown, an immune mechanism involving inappropriate and injurious recognition of the conceptus by the mother's immune system has been proposed. We have recently developed data in murine models indicating that innate immune mechanisms trigger abortion. Specifically, we have identified a novel role for complement activation as an early effector in the pathway leading to pregnancy loss associated with placental inflammation. Our work shows that complement activation is a central mechanism contributing to antiphospholipid antibody-induced pregnancy loss and fetal growth restriction and that complement activation is required for and precedes increases in TNF-alpha. In this application, we will test the hypothesis that complement activation is a necessary intermediary event in the pathogenesis of fetal loss in murine models of immunologically-mediated abortion representing both peri-implantation and postimplantation loss. Our overall goals are to elucidate the complement pathways that mediate recurrent spontaneous abortion and to define targets for interventions to prevent recurrent human miscarriage. Accordingly, our aims are: ? ? Aim 1. To define the role of complement in fetal loss in the DBA/2-mated female CBA/J murine model of spontaneous abortion. (a) To determine the temporal relationships between deposition of C3 (and of other complement components) and infiltration of inflammatory cells and production of TNF-q within decidua; (b) To identify the pathway(s) that initiate(s) complement activation and lead to C3 deposition in the decidua using complement deficient mice and specific complement inhibitors; (c) To determine whether diminished expression of murine complement regulatory proteins occurs in decidua and contributes to local complement activation; (d) To identify the complement pathway activation products and receptors that mediate fetal injury; (e) To determine which cellular and cytokine mediators of fetal loss contribute to deleterious complement activation in the deciduas. ? ? Aim 2. To define the role of complement in fetal loss in the DBA/2-mated TNF-a-treated female C57BL/6 model and to identify the specific complement activation products that mediate in vivo tissue injury and fetal loss. (a) To determine whether C3 is deposited within deciduas; whether C3 activation is required for abortion; and the relationship between TNF-alpha treatment, C3 deposition, and cellular infiltration; (b) To define the complement components or receptors that contribute to cytokine-dependent abortion using complement deficient mice and specific complement inhibitors ? ? If complement activation is a necessary mechanism in repeated pregnancy loss, elucidating the roles of specific complement components will provide a basis for developing new therapies, a rationale for choosing among them, and the capacity to improve patient outcomes. In addition, our studies will provide insights into mechanisms by which complement-induces disease and suggest means to prevent, arrest, or modify complement-mediated inflammatory disorders. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055007-02
Application #
6834641
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Macchiarini, Francesca
Project Start
2003-12-15
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$355,000
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
Lynch, Anne M; Eckel, Robert H; Murphy, James R et al. (2012) Prepregnancy obesity and complement system activation in early pregnancy and the subsequent development of preeclampsia. Am J Obstet Gynecol 206:428.e1-8
Qing, Xiaoping; Redecha, Patricia B; Burmeister, Melissa A et al. (2011) Targeted inhibition of complement activation prevents features of preeclampsia in mice. Kidney Int 79:331-9
Lynch, Anne M; Gibbs, Ronald S; Murphy, James R et al. (2011) Early elevations of the complement activation fragment C3a and adverse pregnancy outcomes. Obstet Gynecol 117:75-83
Lynch, A M; Salmon, J E (2010) Dysregulated complement activation as a common pathway of injury in preeclampsia and other pregnancy complications. Placenta 31:561-7
Lynch, A M; Murphy, J R; Gibbs, R S et al. (2010) The interrelationship of complement-activation fragments and angiogenesis-related factors in early pregnancy and their association with pre-eclampsia. BJOG 117:456-62
Lynch, Anne M; Murphy, James R; Byers, Tim et al. (2008) Alternative complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia. Am J Obstet Gynecol 198:385.e1-9
Lynch, Anne M; Gibbs, Ronald S; Murphy, James R et al. (2008) Complement activation fragment Bb in early pregnancy and spontaneous preterm birth. Am J Obstet Gynecol 199:354.e1-8
Sood, Rashmi; Zogg, Mark; Westrick, Randal J et al. (2007) Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers. J Exp Med 204:1049-56
Girardi, Guillermina; Yarilin, Dmitry; Thurman, Joshua M et al. (2006) Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 203:2165-75
Berman, Jessica; Girardi, Guillermina; Salmon, Jane E (2005) TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 174:485-90

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