The pregnant uterus is an immunologically privileged site. Despite major histocompatibility complex (MHC) and minor H differences, rejection of the fetus by mother is rare and acceptance of migrant maternal cells by the offspring is common. We recently showed a strong neonatal tolerance effect of maternal antigen exposure in mice. This effect, which required both gestation and lactation-phase exposure, resulted in acceptance of maternal antigen + heart allograft for >100 days in 40-50% of recipients, without chronic rejection. The goal of the proposed work will be to test the hypothesis that maternal microchimerism arising by transplacental migration of maternal stem cells and sustained by oral exposure to maternal antigens in the neonate, induces allotolerance while reinforcing self antigen-specific tolerance. This hypothesis will be tested by means of three specific aims: 1) We will determine the influence of maternal exposure upon the development and phenotype of maternal antigen specific T regulatory and T effector cells in an F1 backcross breeding model that results in transplant tolerance to maternal antigens; 2) We will examine the strain differences in mouse F1 back-cross breeding models that exhibit either tolerance or rejection of heart allografts carrying the non-inherited maternal antigens; in particular we will analyze the role of maternal hematopoeitic microchimerism in sustaining neonatally induced tolerance or sensitization in the adult, the extent of parenchyma! cell microchimerism, and the role of intercellular membrane transfer associated with dendritic cells of the offspring; and 3) We will investigate the peculiar resistance of the long-term surviving, maternal antigen + heart allograft to chronic rejection by testing the hypothesis that maternal microchimerism induces T regulatory cells that can suppress autoimmunity to cardiac myosin in susceptible mouse strains. SUMMARY: We believe that if successful, this proposal will advance our understanding of the mechanism(s) of neonatal tolerance to maternal antigens, an area of great significance for the health of mother and baby, especially in autoimmune disease-susceptible individuals. It will also provide fundamental new insights in the field of allo-tolerance, the """"""""holy grail"""""""" of transplant immunology. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066219-03
Application #
7447830
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Prabhudas, Mercy R
Project Start
2006-06-15
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$277,120
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Zhang, Jue; Chu, Li-Fang; Hou, Zhonggang et al. (2017) Functional characterization of human pluripotent stem cell-derived arterial endothelial cells. Proc Natl Acad Sci U S A 114:E6072-E6078
Morelli, Adrian E; Bracamonte-Baran, William; Burlingham, William J (2017) Donor-derived exosomes: the trick behind the semidirect pathway of allorecognition. Curr Opin Organ Transplant 22:46-54
Bracamonte-Baran, William; Florentin, Jonathan; Zhou, Ying et al. (2017) Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance. Proc Natl Acad Sci U S A 114:1099-1104
Tomita, Yusuke; Satomi, Miwa; Bracamonte-Baran, William et al. (2016) Kinetics of Alloantigen-Specific Regulatory CD4 T Cell Development and Tissue Distribution After Donor-Specific Transfusion and Costimulatory Blockade. Transplant Direct 2:e73
Sackett, S D; Brown, M E; Tremmel, D M et al. (2016) Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation. Transplant Rev (Orlando) 30:61-70
Ling, Changying; Li, Qiyao; Brown, Matthew E et al. (2015) Bioengineered vocal fold mucosa for voice restoration. Sci Transl Med 7:314ra187
Burlingham, William J; Jankowska-Gan, Ewa; Kempton, Steve et al. (2015) Patterns of Immune Regulation in Rhesus Macaque and Human Families. Transplant Direct 1:e20
Sullivan, J A; Jankowska-Gan, E; Shi, L et al. (2014) Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses. Am J Transplant 14:1512-22
Lockridge, Jennifer L; Zhou, Ying; Becker, Yusof A et al. (2013) Mice engrafted with human fetal thymic tissue and hematopoietic stem cells develop pathology resembling chronic graft-versus-host disease. Biol Blood Marrow Transplant 19:1310-22
Jankowska-Gan, Ewa; Hegde, Subramanya; Burlingham, William J (2013) Trans-vivo delayed type hypersensitivity assay for antigen specific regulation. J Vis Exp :e4454

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