Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model.
Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing beta cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model in NOD-scid IL2rgamma(null) mice. The selective destruction of pancreatic islet beta cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total beta-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the beta cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet beta cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4(+) T cell infiltration and clonal expansion, and the mouse islet beta-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet beta cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.
Zhao
Yong
Y
Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. yongzhao@uic.edu
Guo
Chengshan
C
Hwang
David
D
Lin
Brian
B
Dingeldein
Michael
M
Mihailescu
Dan
D
Sam
Susan
S
Sidhwani
Seema
S
Zhang
Yongkang
Y
Jain
Sumit
S
Skidgel
Randal A
RA
Prabhakar
Bellur S
BS
Mazzone
Theodore
T
Holterman
Mark J
MJ
D000818:Animals; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000528:radiation effects / Q000637:transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000528:radiation effects; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D057170:Translational Research, Biomedical
D054377:Chemokine CXCL12