Scientific Report 2005

Immunology

Adaptive and Innate Responses to Alloantigens

D.B. McKay, A. Shigeoka, E. Zambricki

Surgical and medical advances have provided an opportunity for life to patients who would otherwise succumb to end-stage organ disease. Despite remarkable technological advances, most efforts to prevent rejection of transplanted tissues and organs have relied on treatment with nonspecific immunosuppressive medications that are toxic and require life-long use. One experimental method has allowed survival of transplanted organs without the use of immunosuppressive medications: intravenous exposure of the organ recipient to donor antigens before transplantation. In several animal models and human clinical trials, exposure to donor antigens before transplantation downregulated the T-cell responses of recipients to donor antigens.One focus of our research is the intracellular signaling events that lead to the induction of peripheral T-cell tolerance by exposure to donor antigens. We found that intravenous infusion of semiallogeneic donor cells into recipient mice leads to a series of events that culminate in acquired unresponsiveness to donor antigens and tolerance to allografts. We discovered that several proximal T-cell receptor–coupled signaling molecules are altered in peripheral T cells of the recipient mice. We are investigating how these proximal molecules may be regulated in T cells from recipients that do not reject their transplanted organs. In addition, we are interested in the initial events that regulate activation of recipient T cells, namely the events that regulate the initial activation of the cells that present donor antigens.

In other research, we are investigating the mechanisms that mediate the expansion of activated T cells in response to transplantation antigens. The long-range goal of this project is to develop effective ways to block proliferative signals and thereby prevent allograft rejection. Transplantation of allogeneic tissues induces vigorous proliferation of host T cells specific for donor alloantigens. Activation and cell division of recipient T cells are differentially regulated by intracellular signals evoked through the ligation of cell-surface receptors. A classic example is the binding of IL-2 to its receptor, which culminates in 3 distinct intracellular signaling pathways, including 2 that are important for T cell proliferation: the Janus kinase–signal transducer and activator of transcription pathway and the Ras–MAP kinase pathway. A third pathway, the phosphatidylinositol-3´-kinase–Atk kinase pathway, induces both proapoptotic and antiapoptotic signals, explaining the dual role
of IL-2.

Antibodies that specifically block binding of IL-2 to its receptor have been used in clinical transplantation. We are evaluating the intracellular signaling mechanisms that lead to effective blockade of the ligation of the receptors of growth factors. In the microenvironment of an allogeneic organ, several growth factors may influence the proliferation of potentially alloreactive T cells, and understanding these factors may lead to better use of therapeutic blockade of growth factors.

Publications

McKay, D.B., Josephson, M.A., Armenti, V.T., August, P., Coscia, L.A., Davis, C.L., Davison, J.M., Easterling, T., Friedman, J.E., Hou, S., Karlix, J., Lake, K.D., Lindheimer, M., Matas, A.J., Moritz, M.J., Riely, C.A., Ross, L.F., Scott, J.R., Wagoner, L.E., Wrenshall, L., Adams, P.L., Bumgardner, G.L., Fine, R.N., Goral, S., Krams, S.M., Martinez, O.M., Tolkoff-Rubin, N., Pavlakis, M., Scantlebury, V. Women's Health Committee of the American Society of Transplantation. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am. J. Transplant. 5:1592, 2005.

Zambricki, E., Shigeoka, A., Kishimoto, H., Sprent, J., Burakoff, S., Carpenter, C., Milford, E., McKay, D. Signaling T-cell survival and death by IL-2 and IL-15. Am. J. Transplant. 5:2623, 2005.