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The Contribution of Chemokines and Chemokine Receptors to the Rejection of Fetal Proislet Allografts

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Abstract:

Chemokines regulate the recruitment of leukocytes to sites of inflammation and may therefore play an important role in lymphocyte trafficking between draining lymph nodes and pancreatic islet tissue allografts. The intragraft expression of α- and β-chemokine mRNA during the rejection of BALB/c proislet (fetal precursor islet tissue) allografts in CBA/H mice was assessed quantitatively and semiquantitatively by RT-PCR analyses. Allograft rejection was associated with the strongly enhanced (from day 4) and prolonged expression (up to day 10) of the α-chemokine IP-10 and enhanced intragraft mRNA expression of the β-chemokines MCP-1, MIP-1α, MIP-1β, RANTES, and eotaxin. Peak transcript expression was identified at day 4 (IP-10, MCP-1), day 5 (eotaxin), day 6 (MIP-1α, MIP-1β), and day 14 (RANTES). To examine the role of β-chemokine receptors in allograft rejection, additional allografts to CCR2−/− , CCR5−/−, and wild-type CCR+/+ mice were analyzed by histology, immunohistochemistry, and morphometry. In CCR5−/− mice, the intragraft recruitment of T cells and macrophages was slower and allograft destruction was delayed; in CCR2−/− mice, the initial entry of macrophages was retarded but graft survival was not prolonged. These findings suggest that IP-10 regulates the initial influx of T cells into proislet allografts, MCP-1/CCR2 signaling controls initial macrophage entry, and the MIP-1α, MIP-1β, and RANTES/CCR5 pathway contributes to the rejection response by subsequently amplifying the recruitment of T cell subpopulations required for graft destruction.

Keywords: Allograft; Chemokines; Fetal; Islet; Rejection; mRNA

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/000000004783983611

Affiliations: 1: *Division of Immunology and Genetics, The John Curtin School of Medical Research, The Australian National University, G.P.O. Box 334, Canberra, A.C.T., 2601, Australia 2: †Section of Molecular Genetics and Microbiology The University of Texas at Austin, Austin, TX 78712

Publication date: January 1, 2004

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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