Soluble factors (cytokines) produced by lymphocytes and monocytes exert a wide range of immunologic activities that could alter the allograft response. While the nature of the cells infiltrating rejecting organs has been extensively studied, their pattern of cytokine production and the influence of these factors on the rejection process are less well evaluated. To define the dynamics of cytokine production in the allograft situation and its functional consequences, 4 specific aims are proposed: 1) Develop quantitative molecular biology techniques for measuring cytokine production in situ using as an initial model murine graft-vs-host disease. By Northern blot analysis, in situ hybridization and bioassay techniques, cytokine production at the mRNA as well as protein level will be assessed. 2) Assess functional properties of monocytes in spleens of mice undergoing GVH disease, since these cells are prominent in rejecting organs and are targets of cytokine action. Monocyte function will be correlated with levels of various factors measured. 3) Assess B cell expression in GVH disease. Certain forms of GVH are associated with autoantibody production and we wish to determine whether this pattern of preferential antibody expression is related to the pattern of cytokine production. We will also evaluate cyclosporine sensitivity of B cells in this disease model. 4) With techniques developed in the GVH model, we will investigate cytokine mRNA production in various solid graft models studied in this Program Project. Together these studies should clarify the role of a series of potent immunoregulatory molecules that could modify the course of transplant rejection.
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