Persistence of recipient lymphocytes in NOD mice after irradiation and bone marrow transplantation Raymond J. Steptoe a *, Sanda Stankovic a , Sash Lopaticki b , Lynelle K. Jones a , Leonard C. Harrison a , Grant Morahan b a Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia b Division of Genetics and Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia Received 23 July 2003; revised 2 December 2003; accepted 15 December 2003 Abstract The non-obese diabetic (NOD) mouse is a unique and invaluable model of autoimmune disease, in particular type 1 diabetes. Bone marrow transplantation as a therapy for type 1 diabetes has been explored in NOD mice. NOD mice require higher doses of conditioning irradiation for successful allogeneic bone marrow transplantation, suggesting that NOD hematopoietic cells are radioresistant compared to those of other mouse strains. However, studies of hematopoietic reconstitution in NOD mice are hampered by the lack of mice bearing a suitable cell-surface marker that would allow transferred cells or their progeny to be distinguished. In order to monitor hematopoietic reconstitution in NOD mice we generated congenic NOD mice that carry the alternative allelic form of the pan-leukocyte alloantigen CD45. Following irradiation and congenic bone marrow transplantation, we found that the myeloid lineage was rapidly reconstituted by cells of donor origin but substantial numbers of recipient T lymphocytes persisted even after supra-lethal irradiation. This indicates that radiation resistance in the NOD hematopoietic compartment is a property primarily of mature T lymphocytes.  2004 Elsevier Ltd. All rights reserved. Keywords: Radiation resistance; CD45; Congenic; Autoimmunity; Diabetes 1. Introduction Female non-obese diabetic (NOD) mice develop spontaneous autoimmune diabetes at a high rate and are the most widely used animal model of human type 1 diabetes (T1D). Studies with MHC-congenic mice show that non-MHC genes contribute to the generalised auto- immune disease susceptibility of NOD mice, whereas the unique MHC haplotype of NOD mice determines the dominant pancreatic islet lesion [1,2]. These features make NOD mice valuable tools for defining the genetic contributions to autoimmune disease susceptibility. The ability to transfer diabetes susceptibility with bone marrow (BM) or hematopoietic progenitor cells [3,4] demonstrates that susceptibility to diabetes is deter- mined within the hematopoietic compartment. As such, BM transplantation (BMT) represents a potential thera- peutic tool for T1D [5–7]. NOD mice are reported to be radioresistant relative to other strains [8] and to require higher doses of conditioning irradiation for successful allogeneic BMT [6]. It is, however, unclear whether these findings represent radiation resistance of hematopoietic stem cells, mature hematopoietic-derived cells, non- hematopoietic cells or radiation-dependence of other processes responsible for allogeneic engraftment. Studies requiring BM or leukocyte transfers in NOD mice have been hampered by the lack of suitable con- genic mice carrying a cell-surface marker that would allow transferred donor cells or their progeny to be distinguished from those of recipient origin. The CD45 molecule (leukocyte common antigen or Ly5) is a pro- tein tyrosine phosphatase receptor type C encoded by the Ptprc gene. It is expressed on leukocytes and * Corresponding author. Tel.: +61-3-9345-2462; fax: +61-3-9347-0852 E-mail address: steptoe@wehi.edu.au (R.J. Steptoe). Journal of Autoimmunity 22 (2004) 131–138 www.elsevier.com/locate/issn/08968411 0896-8411/04/$ - see front matter  2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2003.12.003