ASTS-Approved Multiorgan Transplantation Fellowship

Basic Science Research Program

The process of the recognition of alloantigen, resulting in either graft rejection or tolerance to the graft, requires that T cells traffic to specific locations including the graft, secondary lymphoid organs, and other lymphoid tissue. Trafficking is controlled by the complex interaction of a variety of receptors and ligands including adhesion molecules and chemokines and their receptors. Recent studies in the laboratory show that proper trafficking is important for both rejection of, and tolerance to, allografts. Specific projects in the laboratory will investigate the cellular and molecular requirements for T cell trafficking during tolerance, and define novel molecules and pathways responsible for these important events. In particular, studies will focus on chemokine ligands and receptors, the novel molecule FTY720 that regulates EDG receptor enzymatic pathways, and the interaction of specific T cells and dendritic cells.

Bai, Y, Liu, J, Wang, Y, Honig, S, Qin, L, Boros, P, Bromberg, JS. L-selectin dependent lymphoid occupancy is required to induce alloantigen specific tolerance. J. Immunol, 2002, 168:1579-1589.

The interleukin-10 molecule is a highly immunosuppressive ligand that influences T, B, and antigen presenting cell functions. In general IL-10 down regulates a variety of immune responses, but with its pleiotropic effects may also stimulate other responses simultaneously. The laboratory is investigating cellular and molecular pathways of IL-10 in immunity. With regard to molecular investigations, IL-10 induces the JAK-STAT pathway and a variety of SOCS molecules, which in turn have important downstream effects on cellular activation or quiescence. Specific projects will investigate IL-10 signaling in T cell and macrophage differentiation. We have identified a unique subpopulation of CD4+ CD25+ suppressor T cells expressing very high levels of the IL-10 receptor, which they use as a growth factor. Investigations will characterize this cell type and its mechanism of action.

Ding, Y, Qin, L, Kotenko, SV, Pestka, S, Bromberg, JS. A single amino acid determines the immunostimulatory activity of IL-10. J. Exp. Med., 2000, 191:213-224.

Qin L, Ding Y, Tahara H, Bromberg JS. Viral IL-10 induced immunosuppression requires TH2 cytokines and impairs APC function within the allograft. J. Immunol., 2001 Feb 15;166(4):2385-2393.

Ding, Y, Qin, L, Tarcsafalvi, A, Kotenko, SV, Pestka, S, Moore, KW, Bromberg, JS. Differential IL-10R1 expression plays a critical role in IL-10-mediated immune regulation. J. Immunol., 2001, 167:6884-6892.

Gene transfer and gene therapy have the ability to deliver immunosuppressive molecules to allografts, resulting in local, antigen-specific immunosuppression, without the systemic side effects associated with conventional immunosuppression. The laboratory will investigate the cellular and molecular immunology of viral vectors in cardiac and islet allografts, to determine how innate and adaptive immune responses influence allograft and vector function. This approach will improve the utility of gene medicines in transplantation for prolongation of allograft survival.

Sung RS, Qin L, Bromberg JS. TNFalpha and IFNgamma induced by innate anti-adenoviral immune responses inhibit adenovirus-mediated transgene expression. Mol Ther., 2001 May;3(5 Pt 1):757-767.

Zhang, H, Fu, S, Busch, A, Chen, F, Qin, L, Bromberg, JS. Identification of TNF-alpha-sensitive sites in HCMVie1 promoter.
Exp. Molec. Pathol., 2001,Oct;71(2):106-114.

Wang, Y, Bai, Y, Price, C, Boros, P, Qin, L, Bielinska, AU, Kukowska-Latallo, JF, Baker, JF, Bromberg, JS. Combination of electroporation and DNA/dendrimer complexes enhances gene transfer into murine cardiac transplants. Am. J. Transplant., 2001, 1:334-338.

Yang, Z, Chen, M, Wu, R, Fialkow, LB, Bromberg, JS, McDuffie, M, Naji, A, and Nadler, JL. Suppression of autoimmune diabetes by viral interleukin 10 gene transfer. J. Immunol., 2002, 168:6404-6411.

While pancreatic endocrine islet transplantation is technically feasible, a number of hurdles remain, including the inability to purify and grow large quantities of islets or islet progenitors in order to transplant more individuals. The laboratory will investigate the use of embryonic stem cells or mature pancreatic progenitor cells as substrates for the identification and characterization of the stem cells and/or progenitor cells for pancreatic islets. A combination of cellular and molecular biology, gene trapping and flow cytometry will be used to purify and characterize these stem and progenitor cell populations to provide a high quality source of replenishable islets for transplantation and the cure of type I diabetes.