Organ transplantation is first choice therapy for end stage organ failure. Advances in clinical transplantation have resulted in improved short term transplant survival for most solid organ allografts, yet long term graft survival with preserved organ function is still elusive. Current therapies effectively control conventional immune pathways contributing to transplant rejection, however unconventional rejection pathways have emerged, including CD4-independent, CD8 +T cell mediated rejection, antibody-mediated acute rejection, and memory T cell-mediated rejection. These immune pathways have all been described as significant barriers to establishing long term survival of transplanted organs.
A murine model of hepatocellular transplantation activates conventional as well as unconventional T cell-dependent rejection pathways. This prompted studies to investigate the activation, effector mechanisms, and peripheral phenotypes of responding rejection pathways, with emphasis on unconventional rejection. The hypothesis was that allogeneic hepatocytes promote activation of recipient CD8 +T cells through exclusive expression of MHC class I (independent of recipient immune factors) which is manifest by a dominant CD8 +T cell-mediated cytotoxic phenotype of rejection; only in the absence of recipient CD8 +T cells, rejection deviates to a CD4 +T cell-mediated immune pathway and a distinct effector mechanism.
The studies showed, in contrast to the hypothesis, recipient immune factors, such as the location of hepatocyte engraftment or the presence of CD4 +T helper cells, significantly influenced CD8 +T cell activation, effector function and mechanism, memory responses, and susceptibility to immune therapy. The data support the modified hypothesis that CD8 +T cells mature along distinct effector pathways depending on the presence of CD4 +T cell help during priming with alloantigen. In the absence of recipient CD8 +T cells, hepatocellular allografts initiate CD4-mediated rejection, which occurs through recipient production of cytotoxic antibody and specific destruction of engrafted parenchymal cells in cooperation with recipient macrophages.
These results characterize the T cell dependent immune mechanisms of rejection and the conditions that elicit or suppress them. These studies have productively contributed to the present understanding of the effector phenotype and mechanisms of both conventional and unconventional allograft rejection pathways and highlight some possible new targets for therapy to combat rejection occurring through unconventional immune pathways.