Immune Tolerance; Sigma Receptor as a Therapeutic Target

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DESCRIPTION (provided by applicant): The goal of this project is to gather evidence in support of a novel strategy for the induction of immune tolerance, namely to use sigma 1 receptor as a potential therapeutic target. Sigma 1 receptor is defined as a specific binding site for various psychoactive drugs such as haloperidol and pentazocine. This receptor has been recently cloned and characterized. It is a membrane-bound protein found primarily in intracellular sites. It is expressed in various tissues including immune cells and placenta. There is compelling evidence for an immunosuppressive role of sigma 1 receptor-specific ligands. The role of this receptor in immune function has received increasing attention in recent years as it has become apparent that progesterone is a putative endogenous ligand for this receptor. The goal of this project is to delineate the molecular events involved in the immunosuppressive function of sigma 1 receptor and to investigate the possible role of progesterone in the maintenance of maternal tolerance toward placental allograft. This project will test the following hypotheses: 1) Progesterone and several pharmacological ligands suppress the function and proliferation of T lymphocytes by acting as specific ligands for the sigma 1 receptor; 2) sigma 1 receptor produces its effects by influencing the function of other cellular proteins in T lymphocytes and placenta via protein-protein interaction; 3) Abolition of sigma 1 receptor gene expression by targeted disruption of the gene in a mouse model will lead to maternal intolerance of the placental allograft. Three specific aims are proposed to test these hypotheses. Specific Aim 1 is to study the expression of sigma 1 receptor in quiescent and activated T lymphocytes and to establish the role of this receptor in the suppression of T cell function. This will be done by analyzing the expression of sigma 1 receptor at the molecular and functional level in T lymphocytes before and after activation. The obligatory role of sigma 1 receptor in T cell function will be evaluated by analyzing the biological effects of sigma 1 receptor-specific ligands in sigma 1 receptor-positive (control) and sigma 1 receptor-negative (stable transfectants expressing antisense sigma 1 receptor mRNA) Jurkat cells. Specific Aim 2 is to identify the proteins in human placenta and in T lymphocytes that interact with sigma 1 receptor using the yeast two-hybrid system. Identification of the target proteins that interact with sigma 1 receptor will help to unravel the molecular mechanisms of cell signaling mediated by sigma 1 receptor. Specific Aim 3 is to determine, using sigma 1 receptor knockout mice, whether the absence of the receptor manifests itself as embryo lethality, an inability of the embryo to defend itself against maternal immune system, or as an inability of the maternal immune system to maintain tolerance toward the placental allograft. This project may have significant physiological, clinical, and therapeutic relevance. The proposed studies may lead to a better understanding of the induction of maternal tolerance toward placental allograft and may provide the basis for future efforts to examine the therapeutic potential of sigma 1 receptor-specific ligands as effective immunosuppressants.