Graft versus host disease (GVHD) is a major clinical problem complicating bone marrow transplantation. GVHD is dependent upon the presence of T-lymphocytes in the donor tissue. However, the actual role of these donor T cells in the pathogenesis associated with GVHD is still unclear. We have postulated that interferon (IFN) may play an important role in the pathogenesis associated with GVHD. Many of the pathogenic sequelae associated with GVHD can also be induced in vivo and in vitro by IFN. We have recently shown that mice undergoing acute GVHD have high levels of serum IFN. These results suggest that IFN may play a role in the pathogenesis associated with GVHD. My objective is to investigate the role of IFN in the pathogenesis associated with acute GVHD. We will characterize the cells producing IFN and determine the type(s) of IFN produced in different tissues obtained from mice undergoing acute GVHD. We will also characterize the T lymphocyte subpopulation(s) necessary for inducing IFN production in acute GVHD.
These specific aims will be addressed by measuring IFN from disrupted tissues obtained from mice at various times during GVHD and/or by culturing cells obtained from these mice in vitro and assessing these cultures for IFN production. Using cDNAs for IFNAlpha, IFNBeta, and IFNGamma, we will quantitate the amount of IFN mRNA present in different tissues and/or cells by dot blot hybridization and determine the tissue sites of IFN production by in situ hybridization. The surface phenotype of cells producing IFN in vivo will be determined with different well characterized monoclonal antisera using cell depletion experiments or by in situ hybridization using cDNA probes for different IFNs combined with immunocytochemistry. We will determine if acute GVHD can be altered by treating mice with antisera to different IFNs and/or by treating mice with different lymphokines. Mice transplanted with allogeneic lymphoid tissue will be given monoclonal antisera to different IFNs (IFNAlpha, IFNBeta, and/or IFNGamma) and GVHD assessed at various times. Transplanted mice will also be given one of the following: IFNAlpha, IFNBeta, IFNGamma, IL3, and/or CSF-1 and GVHD assessed at various times. Lastly, we will measure and characterize the types of IFN present in sera obtained from human bone marrow transplant patients undergoing GVHD. Findings from the studies proposed in this application will contribute to our knowledge of IFN and its role in GVHD and to the field of immunology and transplantation in general.
Showing the most recent 10 out of 13 publications
