Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-beta1.
Paracrine effect of transforming growth factor-beta1 (TGF-beta1) on autoimmune insulitis and diabetes was studied by transgenic production of the active form of porcine TGF-beta1 (pTGF-beta1) in pancreatic islet (islet) alpha cells in nonobese diabetic (NOD) mice under the control of rat glucagon promoter (RGP) (NOD-RGP-TGF-beta1). None of 27 NOD-RGP-TGF- beta1 mice developed diabetes by 45 wk of age, in contrast to 40 and 71% in male and female nontransgenic mice, respectively. None of the NOD-RGP-TGF-beta1 mice developed diabetes after cyclophosphamide (CY) administration. Adoptive transfer of splenocytes of NOD-RGP-TGF-beta1 mice to neonatal NOD mice did not transfer diabetes after CY administration. Adoptive transfer of three types of diabetogenic lymphocytes to NOD-RGP-TGF-beta1 and nontransgenic mice after CY administration led to the lower incidence of diabetes in NOD-RGP-TGF-beta1 mice versus that in nontransgenic mice: 29 vs. 77% for diabetogenic splenocytes, 25 vs. 75% for islet beta cell-specific Th1 clone cells, and 0 vs. 50% for islet beta cell-specific CD8(+) clone cells, respectively. Based on these, it is concluded that autoimmune diabetes in NOD mice is not a systemic disease and it can be completely prevented by the paracrine TGF-beta1 in the islet compartment through protection against CD4(+) and CD8(+) effector lymphocytes.
Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima, Tokushima, Japan.
M
M
Moritani
K
K
Yoshimoto
S F
SF
Wong
C
C
Tanaka
T
T
Yamaoka
T
T
Sano
Y
Y
Komagata
J
J
Miyazaki
H
H
Kikutani
M
M
Itakura
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D002999:Clone Cells / Q000276:immunology / Q000637:transplantation; D003520:Cyclophosphamide / Q000633:toxicity; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005813:Genes, Synthetic; D005934:Glucagon / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013552:Swine / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D003520:Cyclophosphamide; D005934:Glucagon