A new T-cell receptor transgenic model of the CD4+ direct pathway: level of priming determines acute versus chronic rejection

TV Brennan, V Hoang, KR Garrod, FC Liu… - …, 2008 - journals.lww.com
TV Brennan, V Hoang, KR Garrod, FC Liu, T Hayden, J Kim, SM Kang
Transplantation, 2008journals.lww.com
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 …
Abstract
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 IA d 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.
Lippincott Williams & Wilkins