Despite decades of work in humans and animal models, the role of maternal/fetal microchimerism (the long term survival of rare cells from mothers in children or children in mothers) in reproductive immunology, pathogenesis of autoimmunity, and transplantation tolerance remains a largely unexplored area. A picture has begun to emerge, however-that maternal microchimerism somehow teaches the developing adaptive immune system how to balance the need for pathogen resistance against the requirement to protect sensitive tissues from autoimmune destruction. A key discovery in the course of the previous funding period was the finding in a mouse model of a link between the level of maternal microchimerism and the level of T regulatory cells specific for non-inherited maternal antigens or NIMA in adult mice. This discovery was paralleled by similar findings in healthy adult humans, suggesting general principles in mammals and not simply a 'mouse phenomenon'. Therefore we propose the hypothesis that maternal/fetal cell exchanges result in lifelong microchimerism that may evoke either tolerance or sensitization, depending on the ability of the chimerism to successfully infiltrate professional antigen-presenting cell [APC] lineages and thereby tip the balance in favor of T regulator vs. T effector cell induction. This hypothesis will be tested by means of 3 Specific Aims: 1)[Human] to determine in healthy families of different ethnic backgrounds the NIMA-specific immune status of individual family members, how this status is related to maternal microchimerism, and which alloantigen- specific T cells contribute to NIMA tolerance [T regulatory cell] or sensitization [T effector cell];2) [Mouse] to determine the role of particular Mc+ lineages in NIMA-specific tolerance or sensitization, and whether recipient only, or both recipient and donor (passenger) CD4 and CD8 T cells influence the NIMA effect on organ allograft outcome (the mutual regulation hypothesis);and 3) [Human] to determine if pre-transplant fetal/maternal immune status of recipient and/or donor predicts renal allograft outcome in HLA-haplo-identical living-related donor renal transplantation. Since the first submission of this competitive renewal application, we have discovered that mouse heart transplant tolerance to a "NIMA"-expressing donor can be accurately predicted prior to transplantation by simply measuring the level of indirect pathway anti- NIMA Treg activity [Dutta et al., AJT 2011, in press]. The significance of the research is that if successful, it will not only identify the key cellular components of natural allotolerance in mice and humans, but it will also enable transplant surgeons to select live-related patient-donor combinations with a high probability of successful outcome while avoiding sensitization in clinical tolerance trials.

Public Health Relevance

Successful pregnancy depends on natural mechanisms of immunologic tolerance that insure the health of the fetus and mother until delivery. However, even after separation, mother and baby continue to harbor small numbers of fetal or maternal cells in their body, in apparent defiance of surveillance by the host immune system. This study seeks to determine the mechanisms of fetal-maternal cell acceptance, and whether acquired tolerance to this natural transplant can be exploited for the benefit of the organ transplant recipient. We will also investigate the role of ethnicity in the response to maternal cells and whether this can help explain the lower rates of kidney graft survival observed in African-American and Hispanic non- Caucasian subjects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066219-07
Application #
8372382
Study Section
Special Emphasis Panel (ZRG1-IMM-N (02))
Program Officer
Prabhudas, Mercy R
Project Start
2005-07-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
7
Fiscal Year
2013
Total Cost
$312,588
Indirect Cost
$99,842
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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
Jankowska-Gan, Ewa; Sheka, Adam; Sollinger, Hans W et al. (2012) Pretransplant immune regulation predicts allograft outcome: bidirectional regulation correlates with excellent renal transplant function in living-related donor-recipient pairs. Transplantation 93:283-90
Szabolcs, Paul; Burlingham, William J; Thomson, Angus W (2012) Tolerance after solid organ and hematopoietic cell transplantation. Biol Blood Marrow Transplant 18:S193-200
Haynes, L D; Jankowska-Gan, E; Sheka, A et al. (2012) Donor-specific indirect pathway analysis reveals a B-cell-independent signature which reflects outcomes in kidney transplant recipients. Am J Transplant 12:640-8
Fan, L; Benson, H L; Vittal, R et al. (2011) Neutralizing IL-17 prevents obliterative bronchiolitis in murine orthotopic lung transplantation. Am J Transplant 11:911-22
Dutta, Partha; Burlingham, William J (2011) Microchimerism: tolerance vs. sensitization. Curr Opin Organ Transplant 16:359-65
Dutta, P; Dart, M; Roenneburg, D A et al. (2011) Pretransplant immune-regulation predicts allograft tolerance. Am J Transplant 11:1296-301
Mezrich, Joshua D; Fechner, John H; Zhang, Xiaoji et al. (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185:3190-8
Rajesh, Deepika; Zhou, Ying; Jankowska-Gan, Ewa et al. (2010) Th1 and Th17 immunocompetence in humanized NOD/SCID/IL2rg(null) mice. Hum Immunol :

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