Pre-transplant analysis of accommodation in donor pigs Introduction The promise of xenotransplantation has not been realized. Vigorous acute rejection, including anti- body mediated acute vascular rejection makes it currently unfeasible. The intense immune suppres- sion apparently necessary to prevent rejection would place the recipient at high risk for infections, including zoonotic infections [1]. The challenge therefore is to prevent acute xenograft rejection without severe immune suppression. One approach proposed to reduce the needed immune suppression is accommodation of organ xenografts. Accommodation would adapt or condition the xenograft to resist injury by pre- formed or induced antibodies [2–4]. Following prolonged exposure to low-level antibodies, endothelial cells in the grafts express proteins providing protection [5,6]. These changes in the xenograft should not, in theory, inhibit the ability of the immune system to react with infectious agents. Beschorner WE, Shearon CC, Yang T, Langnas AN, Thompson SC, Zhao Y, Franco KL, Radio SJ, Sudan DL. Pre-transplant analysis of accommodation in donor pigs. Xenotransplantation 2003; 10: 66–71. Ó Blackwell Munksgaard, 2003 Abstract: Accommodation could lead to xenograft acceptance without the need for severe immune suppression. Generally graft accommodation is appreciated in the sensitized recipient, after transplantation. By inducing accommodation in chimeric donors, however, the risk and cost of inducing accommodation in the recipient would be reduced. An indirect assay of accommodation in the donor pig is needed for screening donors prior to procurement of the xenograft. The resistance of peripheral blood lymphocytes to cytolysis by antibody and complement was assessed in chimeric pigs and compared with control pigs. Peripheral blood lymphocytes (PBL) from chimeric pigs demonstrated a wide range of cytolysis (0 to 85%, median 13%) whereas PBL from control pigs were consistently lysed with these conditions (86 to 99%, median 96.5%, P < 0.0001). Accommodation or reduction in cytolysis did not correlate with the amount of chimerism. A longitudinal study demonstrated persistent accommodation of the PBL for as long as 15 weeks, when the donors averaged 68 kg in weight. Accommodation has been induced by low levels of antibodies interacting with the target tissue. An ELISA for sheep IgG was developed and the serum from newborn pigs assessed. Sheep IgG (up to 4.6 lg/ml) was detected in four of seven piglets with chimerism detectable by flow cytometry and in one of four piglets with minimal chimerism, detectable only by PCR. Lymphocyte accommodation was observed in all pigs with detectable sheep IgG. Of four pigs without accommodation, none had sheep IgG. Three pigs without detectable sheep IgG also had accommodation, suggesting that factors other than sheep IgG may induce accommodation. Acute vascular rejection was not observed in the heterotopic heart transplants from six donors with PBL accommodation. Only one incident of moderate diffuse cellular rejection (grade 3) was observed. William E. Beschorner, 1 C. Carson Shearon, 1 Tianyu Yang, 2 Alan N. Langnas, 2 Scott C. Thompson, 1 Yong Zhao, 2 Kenneth L. Franco, 3 Stanley J. Radio 4 and Debra L. Sudan 2 1 Ximerex, Inc., Omaha, NE, USA, 2 Transplantation Section, Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA, 3 Cardiovascular Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA, 4 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA Key words: xenotransplantation – accommodation – porcine – heart transplant – rejection – acute vascular rejection – fetal – intrauterine – immunoglobulin – lymphocyte – immunology Address reprint requests to William E. Beschorner, M.D., Ximerex, Inc., 2614 N 161 Ave., Omaha, NB 68116–2461, USA (E-mail: beschorner@ximerex.com) Received 16 October 2001; Accepted 12 March 2002 Xenotransplantation 2003: 10: 66–71 Printed in UK. All rights reserved Copyright Ó Blackwell Munksgaard 2003 XENOTRANSPLANTATION ISSN 0908-665X 66