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 being evaluated. The mechanisms of self-tolerance to tumor antigens are being examined by developing models in transgenic mice that express tumor-derived proteins of known immunogenicity under the control of tissue-specific promoters. These models are making it possible to use technologies such as gene expression arrays to identify abnormalities in tolerant T cells and to begin testing molecular strategies for correction. The mechanisms responsible for the development of tolerance and/or failure to eradicate persistent viral infections is being evaluated in a murine model employing isolates of LCMV that are either cleared by the host or establish chronic infection. Methods to modulate the effector functions of T cells are being developed using retroviral-mediated gene transfer to either introduce new functions or to interfere with expression of inhibitory/regulatory proteins by expression of siRNA molecules.

Immunity to the human pathogenic virus HIV is being studied with the goal of defining methods to generate or augment protective immune responses. These studies include an evaluation of candidate vaccines for HIV in an experimental macaque model. Previous studies in CMV led to clinical trials in which immunosuppressed leukemia patients who were at high risk for fatal CMV infection were treated by infusion of CMV-specific cytolytic T cell clones selected for recognition of an immunodominant protective epitope and have been expanded to large numbers in vitro. Such studies have demonstrated the feasibility and efficacy of reconstituting immunity in humans by the adoptive transfer of antigen-specific T cell clones. Therapy of HIV infection is currently being explored using T cell clones specific for virion proteins, and the activity of such clones is being evaluated by both monitoring viral load and examining T cell activity in situ in biopsy specimens. T cell therapy of human malignancy is also being evaluated, in particular melanoma and leukemia, by transferring T cell clones targeted at selected antigenic epitopes. 

Ho WY, Blattman JN, Dossett ML, Yee C, Greenberg PD. Adoptive immunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction. Cancer Cell 3:431-7, 2003.

Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99:16168-73, 2002.

Cheng LE, Greenberg PD. Selective delivery of augmented IL-2 receptor signals to responding CD8+ T cells increases the size of the acute antiviral response and of the resulting memory T cell pool. J Immunol 169:4990-7, 2002.