Early up-regulation of CXC-chemokine expression is associated with strong cellular immune responses to murine skin xenografts

Abstract

BACKGROUND: The dynamic pattern of the cellular infiltration and mRNA expression of chemokines in rat-to-mouse skin xenografts were examined to gain an understanding of the possible role of chemokines in the stronger cellular immune responses to xenografts compared with the allo-response. METHODS: The mean survival time of the xenografts was approximately 2 days less than that of allografts (10.7 +/- 0.9 days vs. 8.9 +/- 0.7 days, P < 0.05). In comparison with the allografts, the xenografts were characterized by a very early infiltration of monocytes/macrophages (day 3) and a larger number of CD4+ and CD8+ cells, as well as neutrophil infiltration in the early phase (day 5), and larger number of CD8+ and CD11b+ cells, as well as macrophage infiltration, in the later phase (day 7). Xenografts showed stronger interferon (IFN)-inducible 10-kDa protein (IP-10) and monokine induced by IFN (MIG) mRNA expression levels, which appeared earlier than in the allografts. In the later phase, strong expression of regulated on activation, normal T cell expressed and secreted was observed. Cytokine mRNA expression in the xenografts could be summarized by higher expression of IFN-gamma, interleukin (IL)1beta, IL6, and transforming growth factor -beta1 mRNA than in the allografts. These results suggest that the early increased CXC-chemokine expression, such as IP-10 and MIG, which has been known to be mainly produced by macrophages, may play a critical role in the stronger cellular xenograft rejection compared with allograft rejection. Therefore, MIG antiserum or CXCR3 antiserum was administered to the rat skin-engrafted mice every other day until rejection. RESULTS: Compared with the control normal rabbit serum-treated mice, either the MIG antiserum- or CXCR3 antiserum-treated mice showed a delayed rejection of approximately 2 days (8.3 +/- 0.5 days vs. 10.6 +/- 0.5 days or 10.8 +/- 1.9 days, respectively, P < 0.05). CONCLUSION: Overall, these results suggest that the more aggressive rejection of xenografts compared with allografts is due to the earlier expression of CXC-chemokines, IP-10 and MIG, and subsequent adjuvant effects of proinflammatory cytokines.