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- Title
Generating Regulatory T-Cells by a JAK-STAT'5 Kinase Inhibitor.
- Authors
Davoodi-Semiromi, Abdoreza; Cheikhi, Amine; Chang-Qing Xia; Clare-Salzler, Micheal
- Abstract
AG490 is a member of tyrphostine family which blocks JAK2/3 phosphorylation and subsequently activation of Stat3 and Stats via the JAK-STAT pathway. AG490 has been broadly used to prevent rejection of allograft transplant and to prevent autoimmune diseases such as EAE with a mechanism yet to be determined. In this study we report AG490 treatment reprograms CD4[sup +]CD25[sup -] Fox3[sup -] T-cells into Foxp3 expressing T-cells which possess regulatory function both in-vitro and in-vivo. CD4[sup +]CD25[sup -] Fox3[sup -] T-cells from transgenic BALB/c DO11.10 mice became Foxp3[sup +] when treated in-vitro with AG490. These T-cells possessed regulatory function as they suppressed proliferation of syngenic responding population (CD4[sup +]CD25[sup -] T-cells) in response to OVA[sub 323-329] peptide in-vitro. Purified CD4 T-cells from BALB/c mice treated with AG490 failed to suppress proliferation of transgenic CD4[sup +]CD25[sup -] T-cells of BALB/c DO11.10 suggesting antigen-specific function of converted population. Our preliminary in-vivo studies regarding adoptive co-transfer of bulk CD4[sup +]CD25[sup -] Foxp3 T-cells treated with AG490 and diabetic splenocytes delayed onset of diabetes in 20% of treated mice for 9-weeks. Furthermore we show treatment of diabetic NOD.scid mice (recipient of diabetic splenocytes and CD4[sup +]CD25[sup -] T-cells) with AG490 increased numbers of CD4[sup +]CD25[sup +]Foxp3[sup +] T-cells when compared with the same population in B6 and NOD mice and posses regulatory function in-vitro. Splenocytes of treated mice were anergic to anti-CD3 and CD28 stimulation and purified CD4[sup +]CD25[sup +] T-cells suppressed proliferation of responding population in-vitro. In this report, we for the first time uncovered new properties of AG490 in the immune system by demonstrating upregulation of Foxp3 in CD4[sup +]CD25[sup -]T-cells and propose that this kinase inhibitor might be used to halt type 1 diabetes in NOD mice and in humans. The same mechanism described above may be responsible for AG490 to prevent rejection of allograft transplant and/or to prevent onset of EAE in mice.
- Subjects
T cells; ENZYME inhibitors; GLYCOPROTEINS; DIABETES; TRANSGENIC mice
- Publication
Diabetes, 2007, Vol 56, pA715
- ISSN
0012-1797
- Publication type
Article