Accelerated Acute Rejection of the Intestinal Graft in CD28-Deficient Mice G. Dindelegan, M. Oltean, G. Kurlberg, N. Lycke, O. Nilsson, and M. Olausson ABSTRACT Objective. Multiple in vivo studies have shown that the pace and severity of graft rejection is little or not at all changed by deleting CD28 molecules in the recipient. These findings contrast with the effects of monoclonal antibody therapy aimed the same costimulatory target. The objective of the present study was to evaluate how the acute rejection process is affected in CD28-deficient mice using a fully allogeneic, highly immunologically reactive transplant model. Methods. Heterotopic vascularized small bowel transplants were performed in 24 recipient mice divided into 4 groups: 2 wild-type and 2 knockout groups. Each group consisted of 5 to 7 animals in which BalbC mice were used as intestinal donors to either wild-type C57BL6 or C57BL6 background CD28-deficient recipient mice. Selected endpoints were 3 and 6 postoperative days (POD). Intestinal rejection was evaluated by mucosal laser Doppler flowmetry (expressed in perfusion units) and histology (expressed in rejection grades). Results. Acute rejection occurred in both wild-type and CD28-deficient groups. At POD 3, no significant difference was noted between groups in terms of mucosal perfusion and histology. At POD 6, significant differences in graft mucosal perfusion and histology revealed a more aggressive rejection in the CD28-deficient group compared to the wild-type group. Conclusions. The present study showed that the severity of intestinal graft rejection responses was amplified by deleting CD28 molecules. Together with data from other studies, these results suggest a different pattern of distribution and/or activation of CD28/B7 receptors in various organs. I N RECENT YEARS, small bowel transplantation (SBT) has increasingly evolved as a valuable treatment for patients with intestinal failure. However, the clinical success of SBT is still limited compared with transplants of other organs. The explanation is the high immunogenicity of the intestine, leading to an increased rate of rejection, sepsis, and posttransplantation lymphoproliferative disorders. 1–3 The unusually strong immune response to the small intes- tine may be related to different mechanisms of rejection. T-cell activation plays a key role in sensitization and allograft rejection. Activation of T cells requires two con- current signals. The first signal is provided by the interac- tion of the T-cell receptor with its specific determinant. The second signal is made up of several elements that include the availability of some cytokines and interactions between certain costimulatory molecules and their ligands expressed by the stimulating cell population. One of the important pathways is the costimulatory signal delivered via the CD28/B7 pathway. Variability in rejection patterns depending on the trans- plant model and the grafted organ have been observed in From the University of Medicine and Pharmacy (G.D.), Cluj- Napoca, Romania, and Institute for Surgical Sciences, University of Gothenburg (M.Olt., G.K., N.L., O.N., M.Ola.), Gothenburg, Sweden. This study was supported by grants from The Swedish Re- search Council, Sahlgrenska University Hospital (LUA), Tore Nilsson Foundation, and Swedish Medical Society. Address reprint requests to George Dindelegan, MD, First Surgical Clinic, str. Clinicilor 3-5, 400006 Cluj-Napoca, Romania. E-mail: george.dindelegan@microsurgerycluj.ro 0041-1345/05/$–see front matter © 2005 by Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2005.01.078 360 Park Avenue South, New York, NY 10010-1710 82 Transplantation Proceedings, 37, 82– 86 (2005)