Mechanisms of graft rejection after lung transplantation

Abstract

Purpose of review: To date, outcomes after lung transplantation are far worse than after transplantation of other solid organs. New insights into mechanisms that contribute to graft rejection and tolerance after lung transplantation remain of great interest. This review examines the recent literature on the role of innate and adaptive immunity in shaping the fate of lung grafts.

Recent findings: Innate and adaptive immune cells orchestrate allograft rejection after transplantation. Innate immune cells such as neutrophils are recruited to the lung graft early after reperfusion and subsequently promote allograft rejection. Although it is widely recognized that CD4 T lymphocytes in concert with CD8 T cells promote graft rejection, regulatory Foxp3 CD4 T, central memory CD8 T cells, and natural killer cells can facilitate tolerance.

Summary: This review highlights interactions between innate and adaptive immune pathways and how they contribute to lung allograft rejection. These findings lay a foundation for the design of new therapeutic strategies that target both innate and adaptive immune responses.

Fig. 1. Diagram depicting mechanisms mediating primary graft dysfunction, rejection and the induction of tolerance

In the context of ischemia-reperfusion injury (IRI), damage-associated molecular patterns (DAMPs) release contributes to the infiltration of neutrophils into the graft. Recipient-derived CCR2⁺ monocytes and donor alveolar macrophages facilitate neutrophil recruitment from blood vessels to the injured lung graft. Once activated, neutrophils in concert with mast cells can produce pro-inflammatory mediators such prostaglandins (PGs), interleukin (IL)-1β and IL-6, which can promote primary graft dysfunction. Allorecognition occurs locally within lung allografts through the engagement of antigen presenting cells (APCs) and T lymphocytes. Activated neutrophils can also express co-stimulatory molecules, which further promote the activation of naïve CD4⁺ T cells. Lymphocytes regulate outcomes after LTx. CD4⁺Th1, CD4⁺Th17, γδ IL17⁺, CD8⁺Th17 and CD8⁺ cytotoxic T cells promote graft loss, while regulatory CD4⁺Foxp3⁺ T cells (Tregs), CD8⁺CD44⁺CD62L⁺ central memory T cells and also NK cells can prevent rejection.