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* Institut d’Investigacions Biomèdiques August Pi i Sunyer and University of Barcelona, Barcelona, Spain;
National Center for Oncology Research, Madrid, Spain; and
Department of Physiology,
Department of Biostatistics (Faculty of Biology), and
¶ Unit of Animal Experimentation (Faculty of Medicine), University of Barcelona, Barcelona, Spain
Cyclin-dependent kinase 4 (Cdk4) plays a central role in perinatal pancreatic β cell replication, thus becoming a potential target for therapeutics in autoimmune diabetes. Its hyperactive form, Cdk4R24C, causes β cell hyperplasia without promoting hypoglycemia in a nonautoimmune-prone mouse strain. In this study, we explore whether β cell hyperproliferation induced by the Cdk4R24C mutation balances the autoimmune attack against β cells inherent to the NOD genetic background. To this end, we backcrossed the Cdk4R24C knockin mice, which have the Cdk4 gene replaced by the Cdk4R24C mutated form, onto the NOD genetic background. In this study, we show that NOD/Cdk4R24C knockin mice exhibit exacerbated diabetes and insulitis, and that this exacerbated diabetic phenotype is solely due to the hyperactivity of the NOD/Cdk4R24C immune repertoire. Thus, NOD/Cdk4R24C splenocytes confer exacerbated diabetes when adoptively transferred into NOD/SCID recipients, compared with NOD/wild-type (WT) donor splenocytes. Accordingly, NOD/Cdk4R24C splenocytes show increased basal proliferation and higher activation markers expression compared with NOD/WT splenocytes. However, to eliminate the effect of the Cdk4R24C mutation specifically in the lymphocyte compartment, we introduced this mutation into NOD/SCID mice. NOD/SCID/Cdk4R24C knockin mice develop β cell hyperplasia spontaneously. Furthermore, NOD/SCID/Cdk4R24C knockin females that have been adoptively transferred with NOD/WT splenocytes are more resistant to autoimmunity than NOD/SCID WT female. Thus, the Cdk4R24C mutation opens two avenues in the NOD model: when expressed specifically in β cells, it provides a new potential strategy for β cell regeneration in autoimmune diabetes, but its expression in the immune repertoire exacerbates autoimmunity.
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1 This work was supported by an Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) predoctoral fellowship (to N.M.); the European Foundation for the Study of Diabetes (EFSD)/Paul Langerhans/Amylin Pharmaceuticals Award 2004 (to C.M.); an EFSD/Lilly Research Fund grant (to C.M.); the Ministerio de Ciencia y Tecnología (Ramon y Cajal Program (to C.M.) and SAF 2003-06139 to A.G.)); Ministerio de Educacion y Ciencia Grant BMC2000-0130 (to S.O.); Ministerio de Educacion y Ciencia Grant SAF2004-02666 (to T.S.); Ministerio de Sanidad y Consumo PI040587 (to T.S.); the European Commission (MIRG-CT-2004-012692) (to T.S.); and RCMN 03/08 and RGDM 03/212, FISPI 051264, FISPI 051241 by the Instituto de Salud Carlos III, Madrid (to R.G.). C.M. is an investigator at the IDIBAPS.
2 Address correspondence and reprint requests to Dr. Conchi Mora, Clinic Hospital of Barcelona, Experimental Diabetes Research Group (GIDEHC), Metabolic Diseases Research Area, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, C/. Villarroel 170, 08036 Barcelona, Spain. E-mail address: cmora{at}clinic.ub.es
3 Abbreviations used in this paper: Cdk4, cyclin-dependent kinase 4; T1D, type 1 diabetes; WT, wild type; DC, dendritic cell; AICD, apoptosis-induced cell death; PLN, pancreatic lymph node; HMZ, homozygous; HTZ, heterozygous.
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