Transplantation Immunology, Signal Transduction
Our current research efforts are focused on understanding the mechanism of chronic allograft rejection. The development of anti-HLA antibodies following transplantation is associated with transplant atherosclerosis, a manifestation of chronic allograft rejection. We postulate that anti-HLA antibodies are pathogenic in chronic rejection by binding to HLA class I molecules on endothelium and smooth muscle of the allograft and transducing signals that stimulate cell proliferation. Our studies have shown that when anti-HLA antibodies bind to distinct HLA-A and -B locus molecules on endothelial and smooth muscle cells there is increased tyrosine phosphorylation of intracellular proteins, induction of fibroblast growth factor receptor expression and cell proliferation. These studies suggest anti-HLA antibodies can play a key role in the initiation of proliferative signals, which stimulate the development of myointimal hyperplasia associated with chronic rejection of human allografts. Our current efforts are focused on elucidating the class I signal transduction pathway. Understanding this mechanism will permit the development of new therapeutic modalities for the treatment and prevention of transplant atherosclerosis and extending the functional life of transplanted organs. An additional focus of our research is in the development of methods for immunologic evaluation of the immune response in transplant patients. We are currently developing assays to measure both the humoral and cellular alloimmune response to the graft. These tests include monitoring of anti-HLA antibodies to identify patients at risk of rejection, monitoring the T cell indirect allorecognition pathway for the diagnosis of chronic rejection, study of immune and inflammatory gene expression during allograft rejection and identification of T suppressor cells which down regulate the immune response to alloantigens. We plan to expand this work to develop cDNA microarrays and protein arrays to search for new bio-markers for the early diagnosis of cardiac, renal and liver transplant rejection.
- Practice Plan Board, UCLA, Department of Pathology, term 2000-2003.
- Chair, Quality Assurance and Standards Committee, American Society for Histocompatibility and Immunogenetics, term 1999-2001.
- Editorial Board of Human Immunology, 2000-present.
- Editorial Board of Transplant Immunology, 1999-present.
- Bian H, Harris PE, Mulder A, Reed EF. Anti-HLA antibody ligation to HLA class I molecules expressed by endothelial cells stimulates tyrosine phosphorylation, inositol phosphate generation, and proliferation. Human Immunol 1997; 53:90-97.
- Harris PE, Bian H, and Reed EF. Induction of high affinity FGF receptor expression and proliferation in human endothelial cells by anti-HLA antibodies: A possible mechanism for transplant atherosclerosis. Journal of Immunology 1997; 159:5697-5704.
- Bian H, Harris PE, Reed EF. Ligation of HLA class I molecules on smooth muscle cells with anti-HLA antibodies induces tyrosine phosphorylation, FGF receptor expression and cell proliferation. International Immunology 1998; 10:1315-1323.
- Nath N, Bian H, Reed EF, Chellapan SP. HLA class I- mediated induction of cell proliferation involves cyclin E-mediated inactivation of Rb function and induction of E2F activity. J lmmunol 1999; 162:5351-5358.
- Bian H, Reed EF. Alloantibody mediated signal transduction in endothelial cells and smooth muscle cells; enhancement by INFO and TNF. J Immunol 1999; 163:1010-1018.
- Bian H, Reed EF. Anti-HLA class I antibodies transduce signals in endothelial cells resulting in FGF receptor translocation, down regulation of ICAM-1 and cell proliferation. Transplant Proc 2001; 33:1115-6.
- Jin YP, Sing RP, Du ZY, Ayyappan K, Rajasekaran ER, Reed EF. Ligation of HLA Class I molecules on endothelial cells induces phosphorylation of src, paxillin and focal adhesion kinase in an actin dependent manner. J of Immunol 2002; 168:5415-5423.