Abstracts
2002 Digestive Disease Week

# 105718 Abstract ID: 105718 Donor T Cell Activation Initiated Small Bowel Allograft Rejection Is Dependent upon IFN-? Inducible Protein-10
Zheng Zhang, Terrence A Barrett, Levent Kaptanoglu, David Ivancic, Andrew D Luster, Jonathan P Fryer, Chicago, IL; Charlestown, MA

Small bowel transplantation has been limited by difficulties in controlling small bowel (SB) allograft rejection. This is partially attributed to the unique immune environment of the donor intestine, which harbors large numbers of donor lymphoid cells including T cells. We hypothesized that antigen-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-2Ld+) were transplanted into BALB/c (isografts), or single class I MHC mismatched (Ld deficient) BALB/c H-2dm2 (dm2, H-2Ld-) mutant mice (allografts). Graft survival was followed after injection of control or antigenic OVA323-339 peptide. We found that 80% of SB allografts developed severe rejection in mice treated with antigenic peptide, whereas less than 20% of allografts were rejected in mice treated with control peptide (P<0.05). Isografts survived >30 days regardless of OVA323-339 administration. Analysis of graft tissues and cell composition in host spleens and graft associated-mesenteric lymph nodes (MLN) or lamina propriae (LP) demonstrated that donor T cell activation increased intragraft mRNA expression of IFN-? and CXC chemokines including IFN-? inducible protein-10 (IP-10), and this correlated with enhanced host T cell activation and accumulation of host T and NK cells in SB allografts. In addition, donor T cell activation enhanced accumulation of donor T cells in the host spleen (POD 8). To evaluate the role of IP-10 in the rejection initiated by donor T cell activation, the dm2 recipients of DO11.10 SB grafts were treated with control or neutralizing anti-IP-10 mAb in addition to OVA323-339 peptide injection. We found that SB allograft survival was significantly prolonged in 67% of antigen-treated mice (p<0.05) compared to control group. Anti-IP-10 mAb also reduced infiltration of host CD4+ T cells(7% to 3%), CD8+ T cells (25% to 13%) and NK (6% to 2.5%) cells in the graft. Furthermore, donor T cell expansion in host spleen was abrogated in antigen-treated mice given anti-IP-10 mAb (12% to 0.3%). These results suggest that activation of donor T cells can mediate SB allograft rejection by inducing production of IP-10 that enhances host T cell priming and infiltration of host T cells and NK cells in SB allograft. Blocking this pathway may be of therapeutic value in controlling SB allograft rejection.