Thymectomy and Radiation-Induced Type 1 Diabetes in Nonlymphopenic BB Rats

Thymectomy and Radiation-Induced Type 1 Diabetes in Nonlymphopenic BB Rats Sheela Ramanathan 1 2 3 , Marie-Therese Bihoreau 4 , Andrew D. Paterson 5 , Leili Marandi 1 2 3 , Dominique Gauguier 4 and Philippe Poussier 1 2 3 1 Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada 2 Department of Medicine, University of Toronto, Toronto, Ontario, Canada 3 Department of Immunology, University of Toronto, Toronto, Ontario, Canada 4 the Welcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. 5 Program in Genetics and Genomics Biology, Hospital for Sick Children, Toronto, Ontario, Canada Abstract Spontaneous type 1 diabetes in BB rats is dependent on the RT1 u MHC haplotype and homozygosity for an allele at the Lyp locus, which is responsible for a peripheral T-lymphopenia. Genetic studies have shown that there are other, as yet unidentified, genetic loci contributing to diabetes susceptibility in this strain. BB rats carrying wild-type Lyp alleles are not lymphopenic and are resistant to spontaneous diabetes (DR). Here we show that thymectomy and exposure to one sublethal dose of γ-irradiation (TX-R) at 4 weeks of age result in the rapid development of insulitis followed by diabetes in 100% of DR rats. Administration of CD4 + 45RC − T-cells from unmanipulated, syngeneic donors immediately after irradiation prevents the disease. Splenic T-cells from TX-R-induced diabetic animals adoptively transfer type 1 diabetes to T-deficient recipients. ACI, WF, WAG, BN, LEW, PVG, and PVG.RT1 u strains are resistant to TX-R-induced insulitis/diabetes. Genetic analyses revealed linkage between regions on chromosomes 1, 3, 4, 6, 9, and 16, and TX-R-induced type 1 diabetes in a cohort of nonlymphopenic F 2 (Wistar Furth × BBDP ) animals. This novel model of TX-R-induced diabetes in nonlymphopenic BB rats can be used to identify environmental and cellular factors that are responsible for the initiation of antipancreatic autoimmunity. Footnotes Address correspondence and reprint requests to Philippe Poussier, Sunnybrook and Women’s Health Sciences Centre, 2075 Bayview Ave., Room A3 38, Toronto, Ontario, Canada M4N 3M5. E-mail: ppoussie{at}sten.sunnybrook.utoronto.ca . Received for publication 1 April 2002 and accepted in revised form 26 June 2002. FACS, fluorescence-activated cell sorting; KRV, Kilham’s rat virus; mAb, monoclonal antibody; MNC, mononuclear cell; PE, phycoethrin; SPF, specific pathogen free; TX-R,