Additional potential enhancer regions, are located in the first, second and third introns. We have identified specific nucleotide sequences that interact with DNA binding proteins for these regions. Our studies are also focused on identifying the biochemical signaling events that contribute to the IFN-gamma gene expression and determining if alterations in specific DNA binding proteins have occurred in these cell lines in response to treatment. As a second experimental approach, we have developed lines of transgenic mice which express IFN-gamma in the bone marrow. Analysis of the founder line indicates that these mice have a pronounced B cell deficiency as the bone marrow, spleen and lymph nodes lack both preB and mature B cells.
Germinal centers are absent and both the spleen and bone marrow have a disrupted architecture.
Our data indicate that abnormal bone marrow expression of IFN-gamma results in alterations in many arms of the hematopoietic system and results in a severe B cell depletion. Efforts within the CMIS have focused on a molecular analysis of the effects of FAA in vitro in order to elucidate the mechanisms by which it enhances cytokine gene expression and subsequent enhanced immune responsiveness to tumor challenge in mice but has failed in human clinical trials. Efforts are concentrated on identifying the biochemical and molecular pathways involved in this gene induction and those regulatory regions of the specific cytokine genes that are required for enhanced gene expression in response to FAA in order to be able to FAA derivatives which may have therapeutic potential in human disease. This document was prepared by John Ortaldo, Ph.D. .