title: Abrogation of chronic rejection in rat model system involves modulation of the mTORC1 and mTORC2 pathways.
abstract: BACKGROUND
  Current immunosuppressive regimens fail to avert chronic rejection (CR) of transplanted organs; however, selective targeting of actin-cytoskeletal regulators decreases T-cell motility and abrogates CR in rat model system. Administration of mutated class I major histocompatibility complex molecules or selective targeting of the RhoA pathway, which controls T-cell cytoskeletal activity, using Y27632 (a selective Rock1 inhibitor) resulted in reduced T-cell infiltration and abrogation of CR as judged from the neointimal index (13.9±19.7 vs. 45±37.5; P<0.001) and the number of affected vessels (30% vs. 60%; P<0.01). Here, we examined the role of mammalian target of rapamycin (mTOR) pathway in inhibition of CR.
  
  
  METHODS
  A mutated class I major histocompatibility complex molecule that eliminates CR was delivered into ACI recipients of Wistar-Furth hearts at the time of transplantation with subtherapeutic cyclosporine (10 mg/kg on days 0-2). Controls included untreated and cyclosporine A-treated (10 mg/kg on days 0-2) heart allograft recipients.
  
  
  RESULTS
  Western blotting and immunostaining showed that rat heart allografts with abolished CR exhibited down-regulation of the RAPA-sensitive mTORC1 components such as mTOR and Raptor and down-regulation of the RAPA-insensitive mTORC2 elements Rictor and Sin1. The mTOR regulator Deptor and its downstream target Rac1 were also inhibited.
  
  
  CONCLUSIONS
  Abrogation of CR in rat model system involves modulation of two mTOR pathways: a RAPA-sensitive mTORC1 pathway regulating cellular proliferation and a RAPA-insensitive mTORC2 pathway regulating T-cell motility. Selective targeting of T-cell actin cytoskeletal pathways shows potential for pathway-targeted immunosuppression therapies.
authors.affiliation: 1 Department of Transplantation, The First Central Clinical College of Tianjin Medical University, Tianjin, China. 2 Department of Surgery, The Methodist Hospital, Houston, TX. 3 Methodist Hospital Research Institute, Houston, TX. 4 Address correspondence to: Rafik M. Ghobrial or Malgorzata Kloc, Department of Surgery, The Methodist Hospital, 6550 Fannin Street, Houston, TX 77030.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Junping
authors.initials: J
authors.lastname: You
authors.forename: Jitinderpal
authors.initials: J
authors.lastname: Sidhu
authors.forename: Neelam
authors.initials: N
authors.lastname: Tejpal
authors.forename: Malathesha
authors.initials: M
authors.lastname: Ganachari
authors.forename: T Spencer
authors.initials: TS
authors.lastname: Skelton
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kloc
authors.forename: Xian C
authors.initials: XC
authors.lastname: Li
authors.forename: Rafik M
authors.initials: RM
authors.lastname: Ghobrial
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D016027:Heart Transplantation / Q000009:adverse effects*; D006649:Histocompatibility Antigens / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051381:Rats; D011912:Rats, Inbred ACI; D017208:Rats, Wistar; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C516104:Akt1s1 protein, rat; D002352:Carrier Proteins; D006649:Histocompatibility Antigens; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C572458:Rptor protein, rat; C038353:histocompatibility antigens RT, rat; C550254:rictor protein, rat; D016572:Cyclosporine; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D020123:Sirolimus