The mechanisms underlying the survival of the fetal allograft with its paternal MHC antigens remain to be explained. This proposal focuses on the basal plate region of the murine placental. We have shown that fetal class I MHC-bearing trophoblast and maternal decidual cells are intimately intermixed in this tissue. CD8+ T- cells are both necessary and sufficient to mediate graft rejection across a class I MHC barrier. It is unclear why class I MHC positive trophoblast are not recognized and lysed by CD8+ cytotoxic T-cells (CTL). Our results with the placental listeriosis model indicate that local T-cell and macrophage functions are nonspecifically impaired. We believe this suppression reflects local mechanisms which also prevent lysis of trophoblast. Other data suggests that trophoblast-enriched placental cells cannot be lysed by primed allo-MHC specific CTL. These observation may be due to interaction of other factors in the effector and target populations used for these studies or may reflect target-mediated suppression of the effector cell. This proposal will test the ability of purified subpopulations of trophoblast and other placental cells to both stimulate and suppress specific stages in the activation and effector phases of CTL function. Experiments will: (1) re-examine the question of resistance to lysis using class I MHC-bearing basal plate trophoblast and a panel of cloned allo-class I MHC specific clones to determine which stage (if any) in the lytic program is impaired and (2) further explore our own data suggesting that local suppressive influences can prevent T-cell dependent effector mechanisms by testing the ability of subpopulations of basal plate cells to inhibit CTL functions. Our laboratory has a longstanding interest in the suppression of immune response during the perinatal period as evidence by published work over the past 67 years. As a specialist in placental pathology with training in cellular immunology I can address questions with depend equally on anatomical understanding of tissues and a knowledge of contemporary concepts in immunology. Dr. Virginia Pappiannou (see letter) will help prepare trophoblast target cells bearing only paternal MHC antigens by blastocyst transfer, Dr. Carol Reiss (see letter) will provide a panel of cloned CTL specific for discrete domains on H2Dd and H2Ld class I MHC, and senior research scientists in my department will act as secondary sponsors taking an active role in my development as an independent investigator.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Clinical Investigator Award (CIA) (K08)
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Maternal and Child Health Research Committee (HDMC)
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Brigham and Women's Hospital
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