Enhanced cardiac allograft survival by Vav1-Rac signaling blockade in a mouse model.
BACKGROUND
Vav1-Rac signaling plays a pivotal role in TCR/antigen and CD28 signals for T cell activation. However, pharmacological interference of this signaling has not been tested in the prevention of alloimmune-mediated allograft rejection. It has been demonstrated that 6-thio-GTP, a metabolite of azathioprine, specifically inhibits Vav1-Rac activity in T lymphocytes. Here we show the immunosuppressive efficacy of 6-thio-GTP in the prevention of cardiac allograft rejection.


METHODS
T cell proliferations were measured by (3)H-thymidine uptake. The immunosuppressive activities of 6-thio-GTP were tested in the cardiac allograft model of C57BL/6 (H-2(b)) to Balb/c (H-2(d)) mice.


RESULTS
6-Thio-GTP inhibited TCR/alloantigen stimulated T cell proliferation and CD28-dependent T cell survival. Administration of 6-thio-GTP (0.5 mg/kg) prolonged graft survival to 13.8+/-2.39 days compared to 8.3+/-0.48 days in PBS controls (p<0.0001). Combination of 6-thio-GTP (0.5 mg/kg) with CsA (15 mg/kg) enhanced graft survival from 15.0+/-1.61 days in CsA treated recipients to 36.8+/-2.17 days in those received 20 days of combination therapy of CsA and 6-thio-GTP (p<0.0001), or to 42.7+/-16.63 days in the group treated with 20 days of CsA and 60 days of 6-thio-GTP (p<0.0001). Lymphocytes from 6-thio-GTP treated recipients with long-term surviving grafts (>60 days) displayed reduced proliferative response to alloantigen and higher frequencies of regulatory T cells (Treg).


CONCLUSIONS
Vav1-Rac inhibitor 6-thio-GTP prolongs allograft survival alone or in combination with CsA by suppression of alloreactive T cell activation. Our findings suggest the therapeutic potential of pharmacological interference of Vav1-Rac signaling for transplantation.
Wang
Shuang
S
Department of Medicine, The University of Western Ontario, London, Ontario, Canada.
Diao
Hong
H
Guan
Qiunong
Q
Jevnikar
Anthony M
AM
Du
Caigan
C
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects*; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D016027:Heart Transplantation / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D051567:Proto-Oncogene Proteins c-vav / Q000037:antagonists & inhibitors* / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology*; D014184:Transplantation, Homologous; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
D018106:CD28 Antigens; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D013873:Thionucleotides; C496619:Vav1 protein, mouse; C032827:6-thioguanosine 5'-triphosphate; D016572:Cyclosporine; D006160:Guanosine Triphosphate; D020744:rac GTP-Binding Proteins