Mouse Genome Informatics
cn1
    Tgfb1tm3.1Flv/Tgfb1tm3.1Flv
Tg(Cd4-cre)1Cwi/0
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0

involves: 129 * C57BL/6 * DBA/2 * NOD * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• significantly increased Th1 cell numbers in spleen and pancreatic lymph nodes
• increased frequency of T reg in the thymus and pancreatic lymph nodes
• number of T reg cells in pancreatic lymph nodes is increased as well
• rapidly develop diabetes but with a low incidence
• slow kinetics of disease progression

hematopoietic system
• significantly increased Th1 cell numbers in spleen and pancreatic lymph nodes
• increased frequency of T reg in the thymus and pancreatic lymph nodes
• number of T reg cells in pancreatic lymph nodes is increased as well


Mouse Genome Informatics
cn2
    Tgfbr2tm1.2Hlm/Tgfbr2tm1.2Hlm
Tg(Cd4-cre)1Cwi/0
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0

involves: 129 * C57BL/6 * DBA/2 * NOD * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• improved survival (J:196160)

immune system
N
• absolute numbers of Th1 cells in the spleen is unchanged from controls (J:196160)
• significant reduction in spleen and pancreas
• reduced peripheral cell numbers
• percentage in pancreatic lymph nodes is increased
• total cellularity of the spleen is reduced in 3 week old diabetic mice
• total cellularity of pancreatic lymph nodes is reduced in 3 week old diabetic mice
• massive infiltration of leukocytes into Islets before diabetes develops
• in pancreatic T cells
• decreased Il22 expression in pancreatic T cells
• decreased Il17a in pancreatic T cells
• in pancreatic T cells
• in pancreatic T cells
• in pancreatic T cells
• become diabetic between 14 and 21 days of age

endocrine/exocrine glands
• massive infiltration of leukocytes into Islets before diabetes develops

hematopoietic system
• significant reduction in spleen and pancreas
• reduced peripheral cell numbers
• percentage in pancreatic lymph nodes is increased
• total cellularity of the spleen is reduced in 3 week old diabetic mice


Mouse Genome Informatics
cn3
    Ifngtm1Ts/Ifngtm1Ts
Tgfbr2tm1.2Hlm/Tgfbr2tm1.2Hlm
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0
Tg(Cd4-cre)1Cwi/0

involves: 129 * C57BL/6 * DBA/2 * NOD * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• improved survival (J:196160)

immune system
N
• do not develop diabetes (J:196160)


Mouse Genome Informatics
cn4
    Tgfbr2tm1.2Hlm/Tgfbr2tm1.2Hlm
Tnfrsf4tm2(cre)Nik/Tnfrsf4+
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0

involves: 129 * C57BL/6 * NOD * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• absolute number of T reg cells in the spleen and the pancreatic lymph nodes are normal (J:196160)
• development of diabetes is somewhat delayed


Mouse Genome Informatics
cn5
    Tgfbr2tm1.2Hlm/Tgfbr2tm1.2Hlm
Tg(Foxp3-EGFP/cre)1cJbs/0
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0

involves: 129S6/SvEvTac * C57BL/6 * NOD * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• mice do not develop diabetes (J:196160)
• normal T reg numbers in the spleen and pancreatic lymph nodes (J:196160)

hematopoietic system


Mouse Genome Informatics
cx6
    H2g7/H2g7
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0

B6.Cg-H2g7 Tg(TcraBDC2.5,TcrbBDC2.5)1Doi
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• animals show a significant reduction in overall diabetes incidence (14.6% vs ~50% in Tnfsf4-heterozygotes and wild-type) and increase in the age of onset (9.5 weeks vs 6 weeks in controls)
• mice are considered diabetic after a blood glucose measure of >300 mg/dl and 2 positive urine glucose tests


Mouse Genome Informatics
cx7
    Ctla4tm1All/Ctla4tm1All
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * NOD * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• mice survive beyond 3 to 4 weeks of age unlike Ctla4tm1All homozygotes (J:109887)

immune system
• splenocytes transferred into Tcratm1Mjo/Tcratm1Mjo Tg(TcraBDC2.5,TcrbBDC2.5)1Doi induce diabetes at a higher rate than when Ctla4tm1All/Ctla4+ Tg(TcraBDC2.5,TcrbBDC2.5)1Doi splenocytes are used
• splenocytes transferred into Tcratm1Mjo/Tcratm1Mjo Tg(TcraBDC2.5,TcrbBDC2.5)1Doi induce diabetes at a higher rate than when Ctla4tm1All/Ctla4+ Tg(TcraBDC2.5,TcrbBDC2.5)1Doi splenocytes are used
• at 6 weeks, mice exhibit infiltration in the pancreas and spleen unlike in wild-type mice
• however, infiltration is not as severe or extensive as in Ctla4tm1All homozygotes

hematopoietic system
• splenocytes transferred into Tcratm1Mjo/Tcratm1Mjo Tg(TcraBDC2.5,TcrbBDC2.5)1Doi induce diabetes at a higher rate than when Ctla4tm1All/Ctla4+ Tg(TcraBDC2.5,TcrbBDC2.5)1Doi splenocytes are used

endocrine/exocrine glands
• splenocytes transferred into Tcratm1Mjo/Tcratm1Mjo Tg(TcraBDC2.5,TcrbBDC2.5)1Doi induce diabetes at a higher rate than when Ctla4tm1All/Ctla4+ Tg(TcraBDC2.5,TcrbBDC2.5)1Doi splenocytes are used


Mouse Genome Informatics
cx8
    H2g7/H2g7
Tg(Ins2-Vtcn1)#Xxz/0
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0

involves: C57BL/6 * NOD * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• from CD4+ pancreatic T cells
• from CD4+ pancreatic T cells
• diabetes disease progression is abrogated compared to in control mice
• however, mice develop insulitis

hematopoietic system


Mouse Genome Informatics
cx9
    Il4tm1Cgn/Il4tm1Cgn
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0

NOD.Cg-Il4tm1Cgn Tg(TcraBDC2.5,TcrbBDC2.5)1Doi
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• equal degrees of insulitis are detected at 5 weeks in transgenic IL4-deficient NOD mice and control transgenic NOD mice

immune system
• equal degrees of insulitis are detected at 5 weeks in transgenic IL4-deficient NOD mice and control transgenic NOD mice
• Il4-deficient transgenic NOD mice do not show early or frequent diabetes compared to control transgenic NOD mice

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:85924


Mouse Genome Informatics
cx10
    Mertktm1Gkm/Mertktm1Gkm
Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0

NOD.Cg-Mertktm1Gkm Tg(TcraBDC2.5,TcrbBDC2.5)1Doi
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• the frequency of double positive T cell apoptosis in thymic lobes is increased compared to in similarly treated heterozygous mice
• fetal thymic organ cultures treated with BDC2.5 produce more CD8+ single positive thymocytes than similarly treated heterozygous cells
• fetal thymic organ cultures treated with BDC2.5 produce fewer double positive thymocytes than similarly treated heterozygous cells

hematopoietic system
• the frequency of double positive T cell apoptosis in thymic lobes is increased compared to in similarly treated heterozygous mice
• fetal thymic organ cultures treated with BDC2.5 produce more CD8+ single positive thymocytes than similarly treated heterozygous cells
• fetal thymic organ cultures treated with BDC2.5 produce fewer double positive thymocytes than similarly treated heterozygous cells

cellular
• the frequency of double positive T cell apoptosis in thymic lobes is increased compared to in similarly treated heterozygous mice


Mouse Genome Informatics
tg11
    Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0
involves: C57BL/6 * NOD * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
digestive/alimentary system
N
• peri-islet Schwann cells are intact and surround remaining alpha-cells in contrast to control wild-type NOD mice (J:135214)

immune system
• treatment with anti-PDCA-1, which depleted plasmocyoid dendritic cells, or 1MT, which neutralize indoleamine 2,3 dioxygenase production, increases the severity of insulitis
• treatment with anti-PDCA-1 ablates the plasmocytoid dendritic cell population within the pancreatic lymph nodes

endocrine/exocrine glands
• treatment with anti-PDCA-1, which depleted plasmocyoid dendritic cells, or 1MT, which neutralize indoleamine 2,3 dioxygenase production, increases the severity of insulitis

hematopoietic system
• treatment with anti-PDCA-1 ablates the plasmocytoid dendritic cell population within the pancreatic lymph nodes


Mouse Genome Informatics
tg12
    Tg(TcraBDC2.5,TcrbBDC2.5)1Doi/0
NOD.Cg-Tg(TcraBDC2.5,TcrbBDC2.5)1Doi
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• insulitis begins abruptly between days 15 and 18 after birth; at 14 days after birth, few activated (CD69+) T cells are detected
• in transgenic mice, a large proportion of cells in the pancreatic lymph nodes and pancreatic islets have an activated phenotype (CD4+ Vbeta4+) compared to nontransgenic littermates
• adoptive tranfer of splenocytes from transgenic mice carrying the Tg(TcraBDC2.5)1Doi transgene into knockout recipients led to diabetes after a significant delay compared to diabetes development in wild-type recipients (100% in wild-type by 12 days versus 100% in knockouts by 20 days)

endocrine/exocrine glands
• insulitis begins abruptly between days 15 and 18 after birth; at 14 days after birth, few activated (CD69+) T cells are detected

hematopoietic system
• in transgenic mice, a large proportion of cells in the pancreatic lymph nodes and pancreatic islets have an activated phenotype (CD4+ Vbeta4+) compared to nontransgenic littermates