The overall goal of this research is to understand the mechanisms of maternal immune tolerance to the allogeneic fetus in pregnancy. The intimacy between the maternal immune system and the fetal allograft is an unparalleled physiological situation in which paternally inherited fetal antigens expressed by the fetus are unfailingly tolerated in normal pregnancy. The studies proposed herein further investigate previous observations that both murine and human pregnancy results in highly specific recognition of paternally- inherited fetal alloantigens. This holds true for both major and minor histocompatibility antigens. In this proposal, we will employ a murine model of a transgenic fetal minor histocompatibility antigen in combination with maternal CD4+ and CD8+ lymphocytes that specifically react to this antigen to investigate maternal lymphocyte responses and induction of tolerance to fetal antigen. We also investigate the expression, timing and presentation of fetal minor histocompatibility antigens in the human placenta.
Our Specific Aims are: 1. Determine the phenotypic and functional properties of mHAg-specific T cells generated during murine pregnancy. 2. Determine the phenotypic and functional properties of antigen presenting cells displaying fetal antigen to T cells during pregnancy. 3. Investigate the expression and functional significance of fetally-derived mHAg in human pregnancy. Collectively, these studies will yield important new insights into the responses of maternal lymphocytes to fetal antigen that lead to immunological adaptation and harmonious coexistence of mother and fetus. This knowledge could in turn, give new light into the pathogenesis of pregnancy failure, and proved a basis for the development of therapeutic agents, not only co combat infertility, but also cancer, autoimmune disease and transplant rejection.

Public Health Relevance

Numerous medical situations arise from either inappropriate immune tolerance to antigen, such as cancer, or inappropriate immune intolerance to antigen, such as failed pregnancy, autoimmune disease, and transplantation rejection. Pregnancy represents a perfect balance of coexistence between a foreign graft and the maternal immune system that has adapted to promote the growth of the fetus rather than reject it. Understanding the events surrounding this unique physiological situation will yield insight on how infertility, cancer and autoimmune disease may be alleviated.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD045611-10
Application #
8466341
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
2004-01-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$283,562
Indirect Cost
$94,521
Name
University of Kansas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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Warren, Bryce D; Kinsey, William K; McGinnis, Lynda K et al. (2014) Ovarian autoimmune disease: clinical concepts and animal models. Cell Mol Immunol 11:510-21
Linscheid, Caitlin; Petroff, Margaret G (2013) Minor histocompatibility antigens and the maternal immune response to the fetus during pregnancy. Am J Reprod Immunol 69:304-14
Perchellet, Antoine L; Jasti, Susmita; Petroff, Margaret G (2013) Maternal CD4ýýý and CD8ýýý T cell tolerance towards a fetal minor histocompatibility antigen in T cell receptor transgenic mice. Biol Reprod 89:102
Ma, Kimberly K; Petroff, Margaret G; Coscia, Lisa A et al. (2013) Complex chimerism: pregnancy after solid organ transplantation. Chimerism 4:71-7
Hunt, J S; Petroff, M G (2013) IFPA Senior Award Lecture: Reproductive immunology in perspective--reprogramming at the maternal-fetal interface. Placenta 34 Suppl:S52-5
Kshirsagar, S K; Alam, S M; Jasti, S et al. (2012) Immunomodulatory molecules are released from the first trimester and term placenta via exosomes. Placenta 33:982-90

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