BACKGROUND: T-cell receptor transgenic (TCR-tg) mouse models with direct CD4 alloreactivity will help elucidate mechanisms of transplant rejection and tolerance in vivo. Although such models exist, they are limited by unusual strain combinations or are based on model antigens. METHODS: A TCR-tg mouse with direct CD4 specificity in the widely used BALB/c donor --> C57BL/6 host strain combination was created. This TCR-tg mouse, named 4C, was selected for reactivity against BALB/c dendritic cells in order to model early priming events after transplantation. The response of 4C T cells to skin and heart transplants were characterized. RESULTS: The alloantigen is restricted by I-A and appears to be widely distributed in mouse tissues. 4C T cells are able to acutely reject skin but not heart allografts. Paradoxically, heart grafts elicited a stronger proliferation and effector function of TCR-tg T cells than skin grafts. 4C T cells caused cardiac allograft vasculopathy in the absence of other T cells and alloantibodies, suggesting a role for the direct pathway in chronic rejection. Augmentation of priming with an infusion of donor-derived dendritic cells resulted in acute heart allograft rejection by 4C T cells, demonstrating that the level of priming can play a role in determining acute versus chronic rejection by the CD4 direct pathway. CONCLUSIONS: Rejection of a graft by the direct CD4 pathway is determined by graft susceptibility to rejection, as well as the degree of T-cell priming caused by the graft. Grafts that are not acutely rejected can develop transplant vasculopathy mediated by the direct CD4 T cells.
BACKGROUND: T-cell receptor transgenic (TCR-tg) mouse models with direct CD4 alloreactivity will help elucidate mechanisms of transplant rejection and tolerance in vivo. Although such models exist, they are limited by unusual strain combinations or are based on model antigens. METHODS: A TCR-tg mouse with direct CD4 specificity in the widely used BALB/c donor --> C57BL/6 host strain combination was created. This TCR-tg mouse, named 4C, was selected for reactivity against BALB/c dendritic cells in order to model early priming events after transplantation. The response of 4C T cells to skin and heart transplants were characterized. RESULTS: The alloantigen is restricted by I-A and appears to be widely distributed in mouse tissues. 4C T cells are able to acutely reject skin but not heart allografts. Paradoxically, heart grafts elicited a stronger proliferation and effector function of TCR-tg T cells than skin grafts. 4C T cells caused cardiac allograft vasculopathy in the absence of other T cells and alloantibodies, suggesting a role for the direct pathway in chronic rejection. Augmentation of priming with an infusion of donor-derived dendritic cells resulted in acute heart allograft rejection by 4C T cells, demonstrating that the level of priming can play a role in determining acute versus chronic rejection by the CD4 direct pathway. CONCLUSIONS: Rejection of a graft by the direct CD4 pathway is determined by graft susceptibility to rejection, as well as the degree of T-cell priming caused by the graft. Grafts that are not acutely rejected can develop transplant vasculopathy mediated by the direct CD4 T cells.
Authors: Jooho Chung; Christen L Ebens; Eric Perkey; Vedran Radojcic; Ute Koch; Leonardo Scarpellino; Alexander Tong; Frederick Allen; Sherri Wood; Jiane Feng; Ann Friedman; David Granadier; Ivy T Tran; Qian Chai; Lucas Onder; Minhong Yan; Pavan Reddy; Bruce R Blazar; Alex Y Huang; Todd V Brennan; D Keith Bishop; Burkhard Ludewig; Christian W Siebel; Freddy Radtke; Sanjiv A Luther; Ivan Maillard Journal: J Clin Invest Date: 2017-03-20 Impact factor: 14.808
Authors: Liwen Lin; He Xu; Muath Bishawi; FeiFei Feng; Kannan Samy; George Truskey; Andrew S Barbas; Allan D Kirk; Todd V Brennan Journal: Am J Transplant Date: 2019-03-13 Impact factor: 8.086
Authors: William Bracamonte-Baran; Jonathan Florentin; Ying Zhou; Ewa Jankowska-Gan; W John Haynes; Weixiong Zhong; Todd V Brennan; Partha Dutta; Frans H J Claas; Jon J van Rood; William J Burlingham Journal: Proc Natl Acad Sci U S A Date: 2017-01-17 Impact factor: 11.205
Authors: Eric Perkey; Dave Maurice De Sousa; Léolène Carrington; Jooho Chung; Alexander Dils; David Granadier; Ute Koch; Freddy Radtke; Burkhard Ludewig; Bruce R Blazar; Christian W Siebel; Todd V Brennan; Jeffrey Nolz; Nathalie Labrecque; Ivan Maillard Journal: J Immunol Date: 2020-02-14 Impact factor: 5.422