IP-10-induced recruitment of CXCR3 host T cells is required for small bowel allograft rejection.

Abstract

Chemokines mediate cell trafficking in inflammatory states such as allograft rejection. However, their role in small-bowel allograft rejection has not been defined. The aim of this study was to examine the roles of type 1 helper T-cell chemokines in small-bowel allograft rejection. Mucosal histology, chemokine messenger RNA (real-time polymerase chain reaction), and cell isolates were examined in small-bowel allografts and isografts. Interferon-gamma-inducible protein-10/CXC chemokine receptor (CXCR) 3 interactions were specifically evaluated by using allografts from interferon-gamma-inducible protein-10(-/-) donors and adoptive transfer of CXCR3(-/-) T cells into recombination activating gene (RAG)-1(-/-) recipients of small-bowel allografts. Type 1 helper T-cell cytokine (interferon-gamma) and chemokine (interferon-gamma-inducible protein-10, monokine induced by interferon-gamma, macrophage-inflammatory protein-1 alpha, and regulated on activation, normal T cells expressed and secreted) messenger RNA up-regulation was detected (real-time polymerase chain reaction) by postoperative day 3 in small-bowel allografts. Interferon-gamma-inducible protein-10(+/+) small-bowel allograft rejection was associated with a dramatic (>7-fold) increase in CXCR3(+) host T cells in the graft lamina propria. With interferon-gamma-inducible protein-10(-/-) small-bowel allografts, CXCR3(+) host T-cell infiltration of the graft lamina propria was markedly decreased and rejection was significantly delayed. Whereas adoptive transfer of wild-type B6 (CXCR3(+/+)) T cells into B6 (RAG-1(-/-)) recipients induced rapid rejection of CB6F1 small-bowel allografts, rejection was significantly delayed (29.2 +/- 8.7 days vs. 16.5 +/- 3.1 days; P < 0.01) in B6 (RAG-1(-/-)) mice reconstituted with T cells from B6 (CXCR3(-/-)) mice. Recruitment of CXCR3(+) host T cells by donor derived interferon-gamma-inducible protein-10 may precipitate small-bowel allograft rejection. These data highlight the importance of type 1 helper T cell-related chemokines in promoting cell-mediated rejection responses in small-bowel allografts and suggest that interferon-gamma-inducible protein-10 is an attractive therapeutic target for humanized monoclonal antibody strategies.