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

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.