Faculty

Research Description

Research Description

The studies in our laboratory focus on the immunobiology of pregnancy. Recent experiments have highlighted the role of uteroplacental macrophages in creating a safe environment for fetal development. We demonstrated that macrophages down-regulate their production of potentially harmful inflammatory substances such as tumor necrosis factor-alpha and nitric oxide. Conversely, our current experiments show that uteroplacental macrophages are high producers of interleukin-10 (IL-10), an anti-inflammatory cytokine believed to be mainly responsible for the immunosuppressive environment of the pregnant uterus. These observations raise the question of how macrophages and perhaps other types of leukocytes as well are programmed into an immunosuppressive profile for the benefit of semiallogeneic pregnancy.

Progesterone is clearly one of the regulatory molecules, but we are also interested in the possibility that soluble isoforms of the major histocompatibility antigen produced in placentas from RNA splice variants derived from the HLA-G gene are of equal importance. To evaluate this possibility, we produced recombinant eukaryotic and prokaryotic soluble HLA-G1 and -G2. Use of these isoforms in DNA array technology and northern blot hybridization experiments demonstrated that they drive mononuclear leukocytes into immunosuppressive patterns. For example, T lymphocytes reduce production of a critical cell surface molecule, CD8, and macrophages increase their production of IL-10. In parallel studies, we demonstrated that decidual macrophages exhibit receptors for HLA-G, the ILT-2 and ILT-4 proteins. These two receptors signal inhibitory pathways leading to prevention of cytotoxicity. We are now using a baboon model to investigate the functional roles of HLA-G in implantation and initiation of pregnancy. We have demonstrated that a very similar gene, Paan-AG, is expressed in the baboon placenta.

In a final project, we are investigating the roles of tumor necrosis factor (TNF) superfamily members in placental immune privilege as well as in the growth and differentiation of placental cells. A series of papers from our laboratory have reported on an abundance of TNF superfamily ligands and their receptors in human placentas. We have demonstrated temporal changes during placental development as well as differential expression by cell lineage. Current experiments focus on two less-well known members of this family, TRAIL and LIGHT. Experimental approaches include use of knockout mice and use of both primary cultures of placental trophoblast cells and trophoblast cell lines in immunological, biochemical and molecular strategies for defining functions. Our expectations are that these powerful cytokines will ultimately be found to have key roles in maternal-fetal immune interactions and to modulate gene expression during organ development and demise.