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| Status |
Public on Oct 31, 2008 |
| Title |
Interferon-γ-dependent regulatory circuits in immune inflammation highlighted in diabetes |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
We demonstrate diverse roles of interferon–gamma (IFN-γ) in the induction and regulation of immune-mediated inflammation using a transfer model of autoimmune diabetes. The diabetogenic CD4+BDC2.5 (BDC) T cell clone upon transfer into NOD.scid mice induced destruction of islets of Langerhans leading to diabetes. Administration of a neutralizing antibody to IFN-γ (H22) resulted in long term protection (LTP) from diabetes, with inflammation but persistence of a significant, albeit decreased numbers of β-cells. BDC T cells were a mixture of cells expressing high, intermediate and low levels of the T cell receptor. Clonotype-low BDC T cells were required for LTP. Furthermore, islet infiltrating leukocytes in the LTP mice contained Foxp3+CD4 T cells. Islet inflammation in both diabetic and LTP mice was characterized by heavy infiltration of macrophages. Gene expression profiles indicated that macrophages in diabetic mice were M1-type, while LTP mice contained M2-differentiated. The LTP was abolished if mice were treated with either an antibody depleting CD4 T cells, or a neutralizing antibody to CTLA-4, in this case, only at a late stage. Neutralization of IL-10, TGF-β, GITR or CD25 had no effect. Transfer of only clonotype-high expressing BDC T cells induced diabetes but in contrast, H22 antibodies did not inhibit diabetes. While clonotype high T cells induced diabetes even when IFN-γ was neutralized, paradoxically, there was reduced inflammation and no diabetes if host myeloid cells lacked IFN-γ receptor. Hence, using monoclonal CD4 T cells, IFN-γ can have a wide diversity of roles, depending on the setting of the immune process.
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| Overall design |
Pancreatic islets were laser-capture microdissected from mice injected with diabetogenic T cells. One cohort of mice also received injections with anti-interfereon gamma monoclonal antibody, which protected those mice from developing diabetes. RNA prepared from islets was amplified and analyzed by Affymetrix GeneChips. Each GeneChip was prepared from RNA pooled from 5 mice at each timepoint. GeneChips were prepared from RNA extracted at different days following injection of T cells. The following days were assayed day 0 (i.e., untreated), day 3 (for diabetic and protected islets), day 4 (diabetic and protected), day 5 (only for protected, as diabetic islets were too edematous to dissect), day 8 (diabetic and protected).
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| Contributor(s) |
Mills JC, Unanue ER, Calderon B |
| Citation(s) |
18981116 |
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| Submission date |
Aug 08, 2008 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Jason C Mills |
| E-mail(s) |
jason.mills@bcm.edu
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| Phone |
7137984607
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| Organization name |
Baylor College of Medicine
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| Department |
Gastroenterology, Medicine
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| Street address |
One Baylor Plaza
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| City |
Houston. |
| State/province |
T |
| ZIP/Postal code |
77401 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA113141 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE12389_RAW.tar |
20.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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