Although chronic cyclosporine or FK506-based immunosuppression has dramatically improved organ allograft survival, the vast majority of patients develop impaired graft function or even graft failure owing to chronic rejection. Therefore, the ultimate goal - to radically improve graft survival -must be achieved by induction of tolerance of organ allografts without the need for continuous drug therapy. Our results have demonstrated that designed donor/recipient histocompatibility proteins may induce tolerance. Tolerant recipients exhibited selective activation of interleukin (IL)-4-producing Th2 cells, which displayed reduced signaling through the intracellular molecules ERK2, NF-kappaB AP-1, Jak3, and Stat5. We propose that tolerance induction by tolerogenic protein depends upon the expansion of a unique regulatory Th2 with an IL-4-driven Jak3/Stat5/Stat6 feedback loop. In fact, we intend to show the existence of two types of Th2 cells: namely, regulatory Th2 with IL-4-driven Stat5 and Stat6 and classical Th2 with IL-4-driven Stat6 but not Stat5. Furthermore, we plan to demonstrate that these subsets are modulated by a family of Jak/Stat regulatory molecules, including supressors of cytokine signaling (SOCS)-1, SOCS-2, SOCS-3, cytokine inducible SH-2 containing protein (CIS)-1, and tyrosine phosphatase SH2 containing protein (Shp)-1. This study may provide evidence that tolerogenic vaccines induce potent Jak/Stat regulatory proteins, which are instrumental in tolerance induction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL069723-03
Application #
6648420
Study Section
Special Emphasis Panel (ZAI1-NN-I (M1))
Program Officer
Massicot-Fisher, Judith
Project Start
2001-09-01
Project End
2004-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$222,750
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Surgery
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Deng, Ronghai; Khattar, Mithun; Xie, Aini et al. (2014) Anti-TCR mAb induces peripheral tolerance to alloantigens and delays islet allograft rejection in autoimmune diabetic NOD mice. Transplantation 97:1216-24
Guo, Zhiyong; Khattar, Mithun; Schroder, Paul M et al. (2013) A dynamic dual role of IL-2 signaling in the two-step differentiation process of adaptive regulatory T cells. J Immunol 190:3153-62
Khattar, Mithun; Deng, Ronghai; Kahan, Barry D et al. (2013) Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts. Transplantation 95:919-27
Miyahara, Y; Khattar, M; Schroder, P M et al. (2012) Anti-TCR? mAb induces long-term allograft survival by reducing antigen-reactive T cells and sparing regulatory T cells. Am J Transplant 12:1409-18
Wang, Guohua; Miyahara, Yoshihiro; Guo, Zhiyong et al. (2010) ""Default"" generation of neonatal regulatory T cells. J Immunol 185:71-8
Wang, Guohua; Khattar, Mithun; Guo, Zhiyong et al. (2010) IL-2-deprivation and TGF-beta are two non-redundant suppressor mechanisms of CD4+CD25+ regulatory T cell which jointly restrain CD4+CD25- cell activation. Immunol Lett 132:61-8
Guo, Zhiyong; Wang, Guohua; Miyahara, Yoshihiro et al. (2010) IL-7, but not thymic stromal lymphopoietin (TSLP), during priming enhances the generation of memory CD4+ T cells. Immunol Lett 128:116-23
Fernandes, Ida; Zhang, Ye; Qi, Yuhua et al. (2009) Impact of reduced nephron mass on cyclosporine- and/or sirolimus-induced nephrotoxicity. Transplantation 88:1323-31
Stepkowski, Stanislaw M; Chen, Wenhao; Ross, Jeremy A et al. (2008) STAT3: an important regulator of multiple cytokine functions. Transplantation 85:1372-7
Ross, Jeremy A; Nagy, Zsuzsanna S; Cheng, Hanyin et al. (2007) Regulation of T cell homeostasis by JAKs and STATs. Arch Immunol Ther Exp (Warsz) 55:231-45

Showing the most recent 10 out of 24 publications