T Cell Responses in Lung Transplantion – Role of Alloantigen Priming and Regulation on Development of Transplant Arteriosclerosis in a Humanized Mouse Model

Abstract

Purpose In animal models, both naive and alloantigen-primed Treg inhibit rejection. In clinical recipients of transplants, however, not much is known with regard to the actual function of those Treg that can be found in vivo. Here, we studied the functional importance of both naive and alloantigen-primed T cell responses in a humanized mouse model, utilizing transplant arteriosclerosis as the experimental readout. Methods and Materials The pericardiophrenic artery was procured from leftover tissue of lung grafts transplanted within our clinical program and was implanted into the abdominal aorta of NRG mice. Group A received no human leukocyte and served as negative controls. Group B received 5x106 allogeneic human PBMC from the respective lung recipient harvested at the time of transplant and group C received the same naive allogeneic PBMC, depleted of CD4+CD25+ putative Treg. Group D received naive allogeneic PBMC enriched of these CD4+CD25+ cells. Group E received PBMC harvested 21 days after transplantation, containing the alloantigen-primed T cells. Human leukocyte engraftment was monitored and transplant arteriosclerosis was histologically assessed 28 days later. Results The control group A showed mild thickening of the intima. In group B intimal thickening resulting in severe obliteration of the vessel lumen was evident. In group C obliteration of the lumen was even more severe. By contrast, in group D intimal thickening was less severe. In group E, reconstituted with alloantigen-primed total PBMC, only very mild transplant arteriosclerosis developed, comparable to group D enriched of naive Treg. Conclusions We show the importance of T cell regulation for controlling alloresponses in vivo. The finding of reduced transplant arteriosclerosis elicited by alloantigen-primed PBMC is intriguing and may indicate enhanced T cell regulation in these clinical transplant recipients. Ongoing studies aim at correlating clinical transplant outcomes to T cell function assessed using humanized mouse.