The mechanism behind allograft (Tx) acceptance may include a process termed """"""""infectious tolerance""""""""(IT). IT propagates itself into new sets of recipients by transferred mononuclear cells (MNC). Lew rats sensitized with BN skin Tx reject donor-specific cardiac Tx in <36 hr, yet maintain them for >200 days after treatment with CD4 mAb (RIB-5/2). This effect is accompanied by features characteristic for the IT pathway. The PI will use this rat Tx model to define key mechanisms contributing to IT. He hypothesizes that acquisition of IT to MHC-incompatible organ Tx results from host mechanisms controlled by regulatory CD4+ T cells. Once established, the Th2-type response becomes dominant and instrumental to the maintenance of well-functioning Tx in tolerant recipients. The PI plans to address the following questions: (1) What are the identity and functional characteristics of regulatory T cells mediating IT? He will fractionate MNC from RIB-5/2 mAb-treated cardiac Tx recipients into phenotypically distinct subsets and evaluate their efficacy to confer tolerance into new cohorts of test cardiac Tx recipients. These tolerance-conferring cells will be also studied for their ability to overcome allorecognition properties in """"""""mixing"""""""" experiments, following re-transplant of """"""""parked hearts"""""""" into new sets of test recipients, and in thymectomized hosts. The recirculatory routes of transferred cells will be identified. He will also analyze the functional profile of tolerant cells in vitro (MLR, CTL, cytokine elaboration). (2) What is the role of intra-Tx cytokine network in IT? First, the PI will test whether infusion of anti-IL-4 mAb of rIFN-g/rIL-2 may prevent tolerance induction, and recreate cardiac Tx rejection in test recipients. He also proposes to use in vivo gene transfers utilizing IL-4 and IFN-g encoding replication-deficient adenoviral vectors. He will determine whether intra-Tx overexpression of IL-4 may boost the Th2-type milieu, and amplify the IT pathway. He will assess how cytokine gene transfer affects intra-Tx cellular infiltrate/activation and Th1/Th2 cytokine expression profile. This approach will be then employed in an attempt to counteract the IL-4-mediated effects by intra-Tx overexpression of the IFN-g gene. (3) How does local expression of cytokine-controlled allo-Abs and """"""""protective"""""""" molecules affect Tx injury in tolerant hosts? Th2-mediated depression of certain IgG isotypes in parallel with upregulation of protective molecules (Bcl-2, Ccl-xL, A-20, HO) may contribute to the avoidance of chronic Tx rejection in tolerant hosts. The PI will test whether manipulations within the Th1/Th2 cytokine network, as proposed in Aim 2, will modify intra-Tx deposition of IgG isotypes and expression of protective proteins, with resultant avoidance of Tx arteriosclerosis and chronic rejection in the IT pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042223-03
Application #
6170715
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kehn, Patricia J
Project Start
1998-07-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$245,231
Indirect Cost
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Shen, Xiu-Da; Ke, Bibo; Uchida, Yoichiro et al. (2011) Native macrophages genetically modified to express heme oxygenase 1 protect rat liver transplants from ischemia/reperfusion injury. Liver Transpl 17:201-10
Uchida, Yoichiro; Freitas, Maria Cecilia S; Zhao, Danyun et al. (2010) The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury. Transplantation 89:1050-6
Yamaura, K; Boenisch, O; Watanabe, T et al. (2010) Differential requirement of CD27 costimulatory signaling for naïve versus alloantigen-primed effector/memory CD8+ T cells. Am J Transplant 10:1210-20
Ke, Bibo; Shen, Xiu-Da; Gao, Feng et al. (2010) Adoptive transfer of ex vivo HO-1 modified bone marrow-derived macrophages prevents liver ischemia and reperfusion injury. Mol Ther 18:1019-25
Uchida, Yoichiro; Ke, Bibo; Freitas, Maria Cecilia S et al. (2010) The emerging role of T cell immunoglobulin mucin-1 in the mechanism of liver ischemia and reperfusion injury in the mouse. Hepatology 51:1363-72
Liu, Dahai; Shen, Xiu-Da; Zhai, Yuan et al. (2009) Intragraft selection of the T cell receptor repertoire by class I MHC sequences in tolerant recipients. PLoS One 4:e6076
Uchida, Yoichiro; Freitas, Maria Cecilia S; Zhao, Danyun et al. (2009) The inhibition of neutrophil elastase ameliorates mouse liver damage due to ischemia and reperfusion. Liver Transpl 15:939-47
Ke, Bibo; Shen, Xiu-Da; Gao, Feng et al. (2009) Small interfering RNA targeting heme oxygenase-1 (HO-1) reinforces liver apoptosis induced by ischemia-reperfusion injury in mice: HO-1 is necessary for cytoprotection. Hum Gene Ther 20:1133-42
Shen, Xiuda; Wang, Yue; Gao, Feng et al. (2009) CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury. Hepatology 50:1537-46
Wu, Zheng; Wang, Yue; Gao, Feng et al. (2008) Critical role of CD4 help in CD154 blockade-resistant memory CD8 T cell activation and allograft rejection in sensitized recipients. J Immunol 181:1096-102

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