Elevated CXCL12 expression in the bone marrow of NOD mice is associated with altered T cell and stem cell trafficking and diabetes development.
BACKGROUND
Type I diabetes (TID) is an autoimmune disease resulting from destruction of the insulin-producing beta-cells by autoreactive T cells. Studies have shown that polymorphisms of chemokine CXCL12 gene are linked to TID in humans. In non-obese diabetic (NOD) mice, which are predisposed to develop the disease, reduction of CXCL12 level leads to significant delays in the onset of diabetes. Despite these initial observations, however, how CXCL12 affects development of TID has not been fully investigated.


RESULTS
We found that the level of CXCL12 transcript is significantly elevated in the bone marrow of NOD mice as compared to Balb/c and C57BL/6 mice. Correspondingly, naïve T cells, regulatory T cells and hematopoietic stem cells (HSC) accumulate in the bone marrow of NOD mice. Treatment of NOD mice with AMD3100, an antagonist for CXCL12's receptor CXCR4, mobilizes T cells and HSC from the bone marrow to the periphery, concomitantly inhibits insulitis and delays the onset of diabetes.


CONCLUSIONS
These results suggest that the elevated CXCL12 expression promotes TID in NOD mice by altering T cell and hematopoietic stem cell trafficking. The findings highlight the potential usefulness of AMD3100 to treat or prevent TID in humans.
Leng
Qibin
Q
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. qbleng@sibs.ac.cn
Nie
Yuchun
Y
Zou
Yongrui
Y
Chen
Jianzhu
J
D000818:Animals; D001596:Benzylamines; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D000080027:Cyclams; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors
D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor
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