Philip D. Greenberg, MD
Professor of Medicine and Immunology
Email: click here
Phone: (206) 543-8306
Dr. Greenberg's laboratory is involved in studies elucidating the immunobiology of host T cell responses to infectious viruses and transformed cells. Analysis of T cell responses to pathogenic viral infections and tumors has demonstrated that reactive T cells are often rendered anergic or dysfunctional as a consequence of encounter with the antigen, and the basis for these defects are being explored and molecular strategies to restore and augment T cell function via genetic modification of T cells with vectors expressing novel proteins, dominant negative proteins, or RNAi are being evaluated. The mechanisms of tolerance to tumor antigens that are over-expressed pro-oncogenic self-proteins are being examined in transgenic mouse models that express tumor-derived proteins of known immunogenicity under the control of tissue-specific promoters; these models are making it possible to isolate and track antigen-specific tolerant cells, to use technologies such as gene expression arrays to identify abnormalities in tolerant T cells, and to begin testing molecular strategies for correcting defects. Immunity to human pathogenic viruses is being studied with the goal of defining methods to generate or augment protective immune responses. These studies include the development of transgenic/knock-in mice in which human genes are being expressed to create models that better typify human immune responses, and these mice, as well as TCR transgenic and B cell Ig-knockin mice developed in the lab, are being used to evaluate and improve the design of candidate HIV vaccines. Previous studies of human CMV immunobiology led to a clinical trial in which immunosuppressed leukemia patients at high risk for fatal CMV infection were infused with CMV-specific cytolytic T cell clones. The clones had been previously selected for recognition of an immunodominant protective epitope and expanded to large numbers in vitro, and this trial demonstrated that T cell transfer can reconstitute immunity in humans and provide protection from disease. This adoptive therapy approach with cloned T cells of known function and specificity is now being pursued to both elucidate the immunobiology of human malignancies and infections and to develop novel immune-based therapies. Clinical trials of adoptive T cell therapy are now underway in patients with leukemia. Methods to modulate the effector functions, survival, target avidity, and localization of T cells, and to impart desired antigen specificity are being developed using retroviral-mediated gene transfer, and such engineered T cell clones are now being evaluated in mouse models and will soon be tested in treatment of human disease.
Berger C, Xuereb S, Johnson DC, Watanabe KS, Kiem HP, Greenberg PD, Riddell SR. Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8(+) cytotoxic T lymphocytes. J Virol 74(10):4465-73, 2000.
Brodie SJ, Patterson BK, Lewinsohn DA, Diem K, Spach D, Greenberg PD, Riddell SR, Corey L. HIV-specific cytotoxic T lymphocytes traffic to lymph nodes and localize at sites of HIV replication and cell death. J Clin Invest 105(10):1407-17, 2000.
Riddell SR, Greenberg PD. T-cell therapy of cytomegalovirus and human immunodeficiency virus infection. J Antimicrob Chemother 45 Suppl T3:35-43, 2000.
Cooper LJ, Kalos M, Lewinsohn DA, Riddell SR, Greenberg PD. Transfer of specificity for human immunodeficiency virus type 1 into primary human T lymphocytes by introduction of T-cell receptor genes. J Virol 74(17):8207-12, 2000.