Insulin2 gene (Ins2) transcription by NOD bone marrow-derived cells does not influence autoimmune diabetes development in NOD-Ins2 knockout mice.
Insulin is a critical autoantigen for the development of autoimmune diabetes in non-obese diabetic (NOD) mice. About 80% of NOD females and 30-40% of NOD males develop diabetes. However, Insulin2 (Ins2) knockout NOD mice develop autoimmune diabetes with complete penetrance in both sexes, at an earlier age, and have stronger autoimmune responses to insulin. The severe diabetes phenotype observed in NOD-Ins2-/- mice suggests that lack of Ins2 expression in the thymus may compromise immunological tolerance to insulin. Insulin is a prototypical tissue specific antigen (TSA) for which tolerance is dependent on expression in thymus and peripheral lymphoid tissues. TSA are naturally expressed by medullary thymic epithelial cells (mTEC), stromal cells in peripheral lymphoid tissues and bone marrow (BM)-derived cells, mainly CD11c(+) dendritic cells. The natural expression of TSA by mTEC and stromal cells has been shown to contribute to self-tolerance. However, it is unclear whether this also applies to BM-derived cells naturally expressing TSA. To address this question, we created BM chimeras and investigated whether reintroducing Ins2 expression solely by NOD BM-derived cells delays diabetes development in NOD-Ins2-/- mice. On follow-up, NOD-Ins2-/- mice receiving Ins2-expressing NOD BM cells developed diabetes at similar rates of those receiving NOD-Ins2-/- BM cells. Diabetes developed in 64% of NOD recipients transplanted with NOD BM and in 47% of NOD mice transplanted with NOD-Ins2-/- BM (P = ns). Thus, NOD-Ins2-/- BM did not worsen diabetes in NOD recipients and Ins2 expression by NOD BM-derived cells did not delay diabetes development in NOD-Ins2-/- mice.
Martin-Pagola
A
A
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Pileggi
A
A
Zahr
E
E
Vendrame
F
F
Damaris Molano
R
R
Snowhite
I
I
Ricordi
C
C
Eisenbarth
G S
GS
Nakayama
M
M
Pugliese
A
A
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D007328:Insulin / Q000235:genetics* / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D007328:Insulin