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NOD marrow stem cells adoptively transfer diabetes to resistant (NOD x NON)F1 mice
D V Serreze1, E H Leiter, S M Worthen
1Jackson Laboratory, Bar Harbor, Maine 04609.
Abstract:
Autoimmune beta-cell destruction occurred in otherwise diabetes-resistant F1 mice from an outcross between the nonobese diabetic (NOD) and nonobese normal (NON) inbred strains after adoptive transfer of hematopoietic stem cells from NOD donors. F1 mice were lethally irradiated and reconstituted with either NOD, NON, or F1 bone marrow. Only F1 mice reconstituted with NOD bone marrow developed hyperglycemia. The long (greater than or equal to 16-wk) prodromal period required for expression of overt diabetes contrasted with the rapidity (4-6 days) with which kidney-grafted F1 or NON islets (but not anterior pituitary) were eliminated from diabetic F1 mice. Thus, development of beta-cell-specific immunologic effectors was a chronic process, but once sufficient levels of autoimmunity were achieved, implanted beta-cells could be eliminated in an acute fashion. Thus, expression of NOD diabetogenic alleles in hematopoietic progenitor cells is sufficient for development of anti-beta-cell immunity. The elimination of grafted NON islets shows the effectors are capable of eliminating beta-cells from mice without the diabetogenic genotype.
Insights
Hematopoietic stem cells from nonobese diabetic (NOD) mice induced autoimmune diabetes in F1 mice. This study reveals NOD diabetogenic alleles in stem cells drive anti-beta-cell immunity and rapid islet destruction.
Area of Science:
- Immunology
- Endocrinology
- Genetics
Background:
- Type 1 diabetes involves autoimmune destruction of pancreatic beta cells.
- Genetic predisposition plays a crucial role in type 1 diabetes development.
- The nonobese diabetic (NOD) mouse is a key model for studying autoimmune diabetes.
Purpose of the Study:
- To investigate the role of hematopoietic stem cells in the development of autoimmune diabetes.
- To determine if NOD diabetogenic alleles in hematopoietic progenitors are sufficient to induce anti-beta-cell immunity.
- To characterize the kinetics of beta-cell destruction in a susceptible genetic background.
Main Methods:
- Adoptive transfer of hematopoietic stem cells from NOD donors into lethally irradiated F1 mice (NOD x NON).
- Reconstitution of F1 mice with NOD, NON, or F1 bone marrow.
- Monitoring for hyperglycemia and assessing islet graft survival in recipient mice.
Main Results:
- F1 mice reconstituted with NOD bone marrow developed hyperglycemia, indicating autoimmune diabetes.
- A long prodromal period (≥16 weeks) preceded overt diabetes.
- Grafted NON islets were rapidly eliminated (4-6 days) in diabetic F1 mice, demonstrating acute autoimmune attack.
Conclusions:
- Expression of NOD diabetogenic alleles in hematopoietic progenitor cells is sufficient to induce anti-beta-cell immunity.
- The autoimmune effectors generated are capable of rapidly eliminating beta cells, even in non-diabetogenic recipients.
- This study elucidates the chronic development and acute effector phase of autoimmune diabetes driven by specific genetic factors.