title: The role of chemokines and their receptors in the rejection of pig islet tissue xenografts.
abstract: The mechanism by which inflammatory cells are recruited to pig islet tissue (proislet) xenografts was investigated by examining the intragraft mRNA expression of murine alpha- and beta-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-1alpha (MIP-1alpha) (3 to 5 days) and subsequent expression of eotaxin (days 4 to 10), MIP-1beta (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-1alpha), the influx of CD4 T cells (MCP-1, MIP-1alpha, MIP-1beta, IP-10 and RANTES) and the characteristic infiltrate of eosinophils (eotaxin and RANTES) associated with islet xenograft rejection. Inhibition of beta-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-1alpha, MIP-1beta 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-1alpha and MIP-1beta 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.
authors.affiliation: Division of Molecular Medicine, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Solomon
authors.forename: William A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: David A
authors.initials: DA
authors.lastname: Mann
authors.forename: Charmaine J
authors.initials: CJ
authors.lastname: Simeonovic
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology; D054357:Chemokine CXCL10; D018925:Chemokines / Q000235:genetics / Q000276:immunology*; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology*; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D015848:Interleukin-5; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D015847:Interleukin-4