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Post‐transplant upregulation of chemokine messenger RNA in non‐human primate recipients of intraportal pig islet xenografts

Post‐transplant upregulation of chemokine messenger RNA in non‐human primate recipients of... Abstract: Background: We have previously shown that pig‐to‐primate intraportal islet xenografts reverse diabetes, escape hyperacute rejection, and undergo acute cellular rejection in non‐immunosuppressed recipients. To gain a better understanding of mechanisms contributing to xenoislet rejection in non‐human primates we examined gene expression in livers bearing islet xenografts in the first 72 h after transplantation. Methods: Liver specimens were collected at sacrifice from seven non‐immunosuppressed rhesus macaques at 12, 24, 48 and 72 h after intraportal porcine islet transplantation. Following total RNA extraction, mRNA was quantified using SYBR green real‐time reverse transcription polymerase chain reaction (RT‐PCR) for species‐specific immune response genes. Data were analyzed using comparative cycle threshold (Ct) analysis, adjusted for specific primer‐efficiencies and normalized to cyclophilin expression. Results: Porcine insulin mRNA was detected in all liver samples. Cluster analysis revealed differential gene expression patterns at 12 and 24 h (early) compared with at 48 and 72 h (late) post‐transplant. Gene expression patterns were associated with histological findings of predominantly neutrophils and only a few lymphocytes at 12 and 24 h and an increasing number of lymphocytes and macrophages at 48 and 72 h. Transcript levels of CXCR3 and its ligands, interferon‐inducible protein 10 (IP‐10) and monokine induced by IFN‐γ (Mig), significantly increased between early and late time points together with expression of MIP‐1α, regulated on activation normal T expressed and secreted protein (RANTES) and MCP‐1. CCR5 showed only a marginal, non‐significant increase. Fas ligand, perforin and granzyme B transcripts were all elevated at 48 and 72 h post‐transplant. Conclusions: Our data suggest that CXCR3, with ligands IP‐10 and Mig, is involved in T cell recruitment in acute islet xenograft rejection in non‐human primates. Upregulation of RANTES and MIP‐1α transcripts in the absence of a significant CCR5 increase suggests a possible involvement of other chemokine receptors. MCP‐1 expression is associated with T cell and macrophage infiltration. Elevated cytotoxic effector molecule expression (Fas ligand, perforin, granzyme B) indicates T‐cell mediated graft destruction by cytotoxic and cytolytic mechanisms within 48 to 72 h after transplantation. These results identify the CXCR3‐mediated chemoattractant pathway as an immunosuppressive target in pig‐to‐primate islet xenotransplantation. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Xenotransplantation Wiley

Post‐transplant upregulation of chemokine messenger RNA in non‐human primate recipients of intraportal pig islet xenografts

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References (33)

Publisher
Wiley
Copyright
Copyright © 2005 Wiley Subscription Services, Inc., A Wiley Company
ISSN
0908-665X
eISSN
1399-3089
DOI
10.1111/j.1399-3089.2005.00228.x
pmid
15943778
Publisher site
See Article on Publisher Site

Abstract

Abstract: Background: We have previously shown that pig‐to‐primate intraportal islet xenografts reverse diabetes, escape hyperacute rejection, and undergo acute cellular rejection in non‐immunosuppressed recipients. To gain a better understanding of mechanisms contributing to xenoislet rejection in non‐human primates we examined gene expression in livers bearing islet xenografts in the first 72 h after transplantation. Methods: Liver specimens were collected at sacrifice from seven non‐immunosuppressed rhesus macaques at 12, 24, 48 and 72 h after intraportal porcine islet transplantation. Following total RNA extraction, mRNA was quantified using SYBR green real‐time reverse transcription polymerase chain reaction (RT‐PCR) for species‐specific immune response genes. Data were analyzed using comparative cycle threshold (Ct) analysis, adjusted for specific primer‐efficiencies and normalized to cyclophilin expression. Results: Porcine insulin mRNA was detected in all liver samples. Cluster analysis revealed differential gene expression patterns at 12 and 24 h (early) compared with at 48 and 72 h (late) post‐transplant. Gene expression patterns were associated with histological findings of predominantly neutrophils and only a few lymphocytes at 12 and 24 h and an increasing number of lymphocytes and macrophages at 48 and 72 h. Transcript levels of CXCR3 and its ligands, interferon‐inducible protein 10 (IP‐10) and monokine induced by IFN‐γ (Mig), significantly increased between early and late time points together with expression of MIP‐1α, regulated on activation normal T expressed and secreted protein (RANTES) and MCP‐1. CCR5 showed only a marginal, non‐significant increase. Fas ligand, perforin and granzyme B transcripts were all elevated at 48 and 72 h post‐transplant. Conclusions: Our data suggest that CXCR3, with ligands IP‐10 and Mig, is involved in T cell recruitment in acute islet xenograft rejection in non‐human primates. Upregulation of RANTES and MIP‐1α transcripts in the absence of a significant CCR5 increase suggests a possible involvement of other chemokine receptors. MCP‐1 expression is associated with T cell and macrophage infiltration. Elevated cytotoxic effector molecule expression (Fas ligand, perforin, granzyme B) indicates T‐cell mediated graft destruction by cytotoxic and cytolytic mechanisms within 48 to 72 h after transplantation. These results identify the CXCR3‐mediated chemoattractant pathway as an immunosuppressive target in pig‐to‐primate islet xenotransplantation.

Journal

XenotransplantationWiley

Published: Jul 1, 2005

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