EXPRESSION OF CHEMOKINES AND CHEMOKINE RECEPTORS IN HUMAN CARDIAC ALLOGRAFTS: ASSOCIATION WITH CD3+ T CELL INTILTRATES AND REJECTION

Abstract

167 Chemokines function in the recruitment as well as in the activation of leukocytes. Recent studies in animal models suggest that they play an important role in acute and chronic allograft rejection. However, little is reported on the expression or function of chemokines in human allografts. In this study we have examined the expression of RANTES (Ran), MCP-1, Mig, IP-10, SDF-1, lymphotactin (Lt), and eotaxin mRNA in human cardiac allograft biopsies by semiquantitative RT-PCR. The expression of the chemokine receptors CCR1, CCR3, CCR5 and CXCR3 were examined in separate biopsies by immunohistochemistry. Biopsies taken at the same time as the study biopsies were examined for the clinicopathologic diagnosis of rejection using the ISHLT scoring system. A total of 44 biopsies (n=44 patients) were examined by RT-PCR. Rejection grade 1A was found in 6 biopsies and grade 2 in 5 biopsies. No rejection was found in 33 biopsies. The expression of chemokines are summarized in the (Table) as the percentage of biopsies expressing the chemokine.TableA total of 27 biopsies were examined by immunohistochemistry. CCR3 was found on resident cells and on infiltrating mononuclear cells in most biopsies, without any association with rejection. CCR5 was found in 41 % of biopsies on occasionally infiltrating leukocytes, and was not associated with the histological diagnoses. In contrast, the expression of CXCR3 and CCR1 was associated with the presence of CD3+ T cell infiltrates (p<0.05). Furthermore, in the absence of CXCR3- or CCR1-expressing infiltrates there was no evidence of rejection. In addition, in most biopsies with CD3+ T cell infiltrates and rejection CXCR3- and CCR1-expressing cells were present. Thus, the expression of eotaxin, SDF-1 and lymphotactin, as well as of CCR3 is common in human cardiac allograft biopsies and is not associated with the clinicopathologic diagnosis. In contrast, RANTES and IP-10 as well as their receptors CCR1 and CXCR3 may be associated with acute rejection. Since chronic rejection is associated with MCP-1 and Mig expression, we speculate that the lack of expression of MCP-1 and Mig in low-grade rejection may be of functional significance for long term outcome.