TY - JOUR
T1 - The role of chemokines and their receptors in the rejection of pig islet tissue xenografts
AU - Solomon, Michelle F.
AU - Kuziel, William A.
AU - Mann, David A.
AU - Simeonovic, Charmaine J.
PY - 2003/3
Y1 - 2003/3
N2 - The mechanism by which inflammatory cells are recruited to pig islet tissue (proislet) xenografts was investigated by examining the intragraft mRNA expression of murine α- and β-chemokines in CBA/H mice from days 3 to 10 post-transplant. Xenograft rejection was associated with early intragraft transcript expression for monocyte chemotactic protein-1 (MCP-1) (3 to 5 days), IP-10 (3 to 4 days) and macrophage inflammatory protein-1α (MIP-1α) (3 to 5 days) and subsequent expression of eotaxin (days 4 to 10), MIP-1β (days 4 and 5) and regulated on activation, normal T cell expressed and secreted (RANTES) (days 4 to 6) mRNA. This pattern was consistent with the early recruitment of macrophages (MCP-1, MIP-1α), the influx of CD4 T cells (MCP-1, MIP-1α, MIP-1β, IP-10 and RANTES) and the characteristic infiltrate of eosinophils (eotaxin and RANTES) associated with islet xenograft rejection. Inhibition of β-chemokine signaling in CCR2-/- mice (which lack the major co-receptor for MCP-1) resulted in retarded macrophage and CD4 T cell recruitment, enhanced eosinophil influx and a minor delay in rejection, compared with wildtype mice; there was little effect on leukocyte infiltration in xenografts harvested from CCR5-/- mice (lacking the co-receptor for MIP-1α, MIP-1β and RANTES). The impeded migration of leukocytes into xenografts in CCR2-/- hosts was associated with delayed intragraft expression of MCP-1 and RANTES mRNA; absence of MCP-1/CCR2-mediated signaling led to enhanced intragraft expression of MCP-1, MIP-1α and MIP-1β mRNA. These findings suggest that MCP-1 plays an important role in regulating macrophage and CD4 T cell infiltration to xenograft sites via the CCR2 signaling pathway. Additional treatment of xenografted CCR2-/- transplant recipients with anti-interleukin-(IL)-4 and anti-IL-5 mAbs further delayed xenograft rejection demonstrating the potential for combined antirejection strategies in facilitating pig islet xenotransplantation.
AB - The mechanism by which inflammatory cells are recruited to pig islet tissue (proislet) xenografts was investigated by examining the intragraft mRNA expression of murine α- and β-chemokines in CBA/H mice from days 3 to 10 post-transplant. Xenograft rejection was associated with early intragraft transcript expression for monocyte chemotactic protein-1 (MCP-1) (3 to 5 days), IP-10 (3 to 4 days) and macrophage inflammatory protein-1α (MIP-1α) (3 to 5 days) and subsequent expression of eotaxin (days 4 to 10), MIP-1β (days 4 and 5) and regulated on activation, normal T cell expressed and secreted (RANTES) (days 4 to 6) mRNA. This pattern was consistent with the early recruitment of macrophages (MCP-1, MIP-1α), the influx of CD4 T cells (MCP-1, MIP-1α, MIP-1β, IP-10 and RANTES) and the characteristic infiltrate of eosinophils (eotaxin and RANTES) associated with islet xenograft rejection. Inhibition of β-chemokine signaling in CCR2-/- mice (which lack the major co-receptor for MCP-1) resulted in retarded macrophage and CD4 T cell recruitment, enhanced eosinophil influx and a minor delay in rejection, compared with wildtype mice; there was little effect on leukocyte infiltration in xenografts harvested from CCR5-/- mice (lacking the co-receptor for MIP-1α, MIP-1β and RANTES). The impeded migration of leukocytes into xenografts in CCR2-/- hosts was associated with delayed intragraft expression of MCP-1 and RANTES mRNA; absence of MCP-1/CCR2-mediated signaling led to enhanced intragraft expression of MCP-1, MIP-1α and MIP-1β mRNA. These findings suggest that MCP-1 plays an important role in regulating macrophage and CD4 T cell infiltration to xenograft sites via the CCR2 signaling pathway. Additional treatment of xenografted CCR2-/- transplant recipients with anti-interleukin-(IL)-4 and anti-IL-5 mAbs further delayed xenograft rejection demonstrating the potential for combined antirejection strategies in facilitating pig islet xenotransplantation.
KW - Chemokines
KW - Rejection
KW - Xenograft
KW - mRNA
UR - http://www.scopus.com/inward/record.url?scp=0042367675&partnerID=8YFLogxK
U2 - 10.1034/j.1399-3089.2003.01146.x
DO - 10.1034/j.1399-3089.2003.01146.x
M3 - Article
SN - 0908-665X
VL - 10
SP - 164
EP - 177
JO - Xenotransplantation
JF - Xenotransplantation
IS - 2
ER -