Donor T cell activation initiates small bowel allograft rejection through an IFN-gamma-inducible protein-10-dependent mechanism

• Published in: The Journal of immunology (1950) 2002-04, Vol.168 (7), p.3205-3212
• Main Authors: Zhang, Zheng, Kaptanoglu, Levent, Haddad, Wael, Ivancic, David, Alnadjim, Ziad, Hurst, Stephen, Tishler, Darren, Luster, Andrew D, Barrett, Terrence A, Fryer, Jonathan
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Cell Migration Inhibition; Cell Movement - immunology; Chemokine CXCL10; Chemokines - biosynthesis; Chemokines, CXC - biosynthesis; Chemokines, CXC - genetics; Chemokines, CXC - immunology; Chemokines, CXC - physiology; Cytokines - biosynthesis; Down-Regulation - immunology; g-Interferon-inducible protein 10; Graft Rejection - immunology; Graft Rejection - pathology; Graft Rejection - prevention & control; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Intestine, Small - immunology; Intestine, Small - metabolism; Intestine, Small - transplantation; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Mice, Transgenic; RNA, Messenger - biosynthesis; Spleen - cytology; Spleen - immunology; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Transplantation, Homologous - immunology; Transplantation, Homologous - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.7.3205

The poor success in controlling small bowel (SB) allograft rejection is partially attributed to the unique immune environment in the donor intestine. We hypothesized that Ag-induced activation of donor-derived T cells contributes to the initiation of SB allograft rejection. To address the role of donor T cell activation in SB transplantation, SB grafts from DO11.10 TCR transgenic mice (BALB/c, H-2L(d+)) were transplanted into BALB/c (isografts), or single class I MHC-mismatched (L(d)-deficient) BALB/c H-2(dm2) (dm2, H-2L(d-)) mutant mice (allografts). Graft survival was followed after injection of control or antigenic OVA(323-339) peptide. Eighty percent of SB allografts developed severe rejection in mice treated with antigenic peptide, whereas 30 days regardless of OVA(323-339) administration. Activation of donor T cells increased intragraft expression of proinflammatory cytokine (IFN-gamma) and CXC chemokine IFN-gamma-inducible protein-10 mRNA and enhanced activation and accumulation of host NK and T cells in SB allografts. Treatment of mice with neutralizing anti-IFN-gamma-inducible protein-10 mAb increased SB allograft survival in Ag-treated mice (67%; p < 0.05) and reduced accumulation of host T cells and NK cells in the lamina propria but not mesenteric lymph nodes. These results suggest that activation of donor T cells after SB allotransplantation induces production of a Th1-like profile of cytokines and CXC chemokines that enhance infiltration of host T cells and NK cells in SB allografts. Blocking this pathway may be of therapeutic value in controlling SB allograft rejection.