Donor T cell activation initiates small bowel allograft rejection through an IFN-gamma-inducible protein-10-dependent mechanism.
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 <20% of allografts were rejected in mice treated with control peptide (p < 0.05). Isografts survived >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.
Zhang
Zheng
Z
Department of Surgery, Northwestern University Medical School, Chicago, IL 60611, USA.
Kaptanoglu
Levent
L
Haddad
Wael
W
Ivancic
David
D
Alnadjim
Ziad
Z
Hurst
Stephen
S
Tishler
Darren
D
Luster
Andrew D
AD
Barrett
Terrence A
TA
Fryer
Jonathan
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000276:immunology; D054357:Chemokine CXCL10; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D007421:Intestine, Small / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D012333:RNA, Messenger