Cytokine expression patterns in acute and chronic liver allograft rejection  

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Olivia M. Martinez and Sheri M. Krams

Transplant Immunobiology Laboratory, Department of Surgery, Stanford University School of Medicine

The immune pathways of liver allograft rejection are mediated by lymphoid cells which infiltrate the graft and become activated following recognition of donor alloantigen. The growth, function, and survival of activated lymphocytes is dependent upon a family of secreted proteins termed cytokines. Our laboratory has studied the expression of cytokines within the liver during acute and chronic allograft rejection with the goal of elucidating the cellular mechanisms of allograft rejection. Molecular analyses of intragraft cytokine transcripts as well as measurement of cytokine proteins in bile revealed a heterogeneous cytokine pattern during acute liver allograft rejection. Significant elevations in IL-4, IL-5, and IL-10 mRNA and/or protein are detected in rejecting allografts as compared to stable grafts. Of these cytokines, IL-5 is the most specific and sensitive indicator of acute liver allograft rejection. In situ hybridization localized the expression of IL-5 mRNA to cells within the inflammatory infiltrate. The production of IL-5 within the liver is strongly associated with eosinophilia in the graft and the peripheral blood. Moreover, activated eosinophils can be identified adjacent to bile duct epithelial cells. Because IL-5 is a potent eosinophil growth and differentiation factor these findings suggest that production of IL-5 within the liver may lead to the release of cytotoxic mediators by eosinophils within the portal region. To further characterize cytokine pathways in graft rejection we have defined the phenotype of lymphocytes which produce IL-5 in response to alloantigen in vitro. The major source of alloantigen-induced IL-5 are CD3+CD25+ cells which express the activation antigen CD30. CD30+ T cells also produce abundant IFN-g and IL-10. Thus, CD30+ T cells may function as a regulatory cell subset in acute liver allograft rejection. During chronic liver allograft rejection the intragraft cytokine profile is characterized by upregulation of the T cell derived cytokines IL-2, IFN-g, and IL-5 and the growth factor PDGF-b. Studies are underway using microarray analyses to further define the cytokine patterns in chronic liver allograft rejection.

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