Background and Purpose: Graft vs host disease (GVHD) remains the major complication limiting the more widespread use of allogeneic bone marrow transplantation (BMT). Although T cells are required for the development of GVHD, the precise effector mechanisms responsible for pathogenesis in target host tissues remain unclear. The present studies were undertaken to investigate whether GVHD could be induced by an inoculum containing T cells which could not mediate cytotoxicity through either perforin or FasL dependent pathways (cytotoxically double deficient, CDD). Materials and Methods: Recipient mice were prepared by exposure to lethal total body irradiation and transplanted with MHC class I and II incompatible T cell depleted bone marrow containing the desired numbers of normal or cytotoxically deficient T cells. Animals were monitored for weight loss, mortality and clinical signs of GVHD. Bone marrow transplanted recipients receiving CDD allogeneic T cells exhibited weight loss and mortality post-transplant. At a dose of 5 x 106 CDD T cells, mortality was > 90%. Significant expansion of donor CDD T cells occurred post-BMT and inverted host splenic CD4/CD8 ratios characteristic of GVHD were also identified. Clinical changes characteristic of GVHD were exhibited by recipients of both CDD and cytotoxically normal T cells including haunched posture, ruffled fur and diarrhea. Conclusions: T cells which cannot effect perforin and FasL dependent cytotoxicity were capable of mediating graft vs host responses in MHC class I and II mismatched recipients. These responses induced weight loss and clinical signs as well as mortality. However, on a per cell basis, CDD donor cells were clearly less efficient in their capacity to induce GVHD. Thus, in the absence of perforin and FasL dependent killing, cytokines and/or cytotoxicity mediated by death receptors other than Fas can induce pathogenic changes characteristic of GVHD. These findings suggest that clinical BMT may be move successfully managed in the absence of these cell-mediated donor anti-host cytotoxic pathways.
|Original language||English (US)|
|Number of pages||5|
|State||Published - Dec 1 1998|
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)