Chronic allograft rejection

Abstract

Purpose of review New developments suggest that the graft itself, and molecules expressed within the graft microenvironment dictate the phenotype and evolution of chronic rejection. Recent findings Once ischemia-reperfusion injury, cellular and humoral immune responses target the microvasculature, the associated local tissue hypoxia results in HIF-1α-dependent expression of pro-inflammatory and pro-angiogenic growth factors including vascular endothelial growth factor (VEGF) as a physiological response to injury. However, these genes, and notably VEGF, can promote the recruitment of alloimune T effectors and T regulatory cells into the graft. Semaphorin family molecules may also bind to neuropilin-1 on T cell regulatory cell subsets to stabilize functional responses. mTOR/Akt signaling within endothelial cells regulates cytokineand alloantibody-induced activation and proliferation and their pro-inflammatory phenotype. Inhibition of mTOR and/or Akt results in an anti-inflammatory phenotype and enables the expression of coinhibitory molecules that limit local T cell reactivation and promote immunoregulation. Ligation of neuropilin-1 on T regulatory cells also inhibits Akt-induced responses suggesting common theme for enhancing local immunoregulation and long-term graft survival. Summary Events within the graft initiated by changes within the microvasculature and mTOR/Akt-induced signaling promotes the development of chronic rejection. Semaphorin-neuropilin biology represents a novel avenue for targeting this biology and warrents further investigation.

The intragraft microenvironment as a central determinant of chronic rejection or local immunoregulation/tolerance

“…Furthermore, an increasing body of evidence indicates that the response of the microvasculature to injury ( e.g. activation, protection and/or repair vs. dysfunctional angiogenesis) is critical in both the initiation as well as the progression of chronic rejection [4,5,8,10]. EC injury also results in cell death and microvascular loss, which in turn results in impaired delivery of oxygen and nutrients within the graft parenchyma/tissue.…”

“…Unexpectedly, it was reported that the leukocyte-induced angiogenesis reaction that occurs at early times in the rejection process is associated with local hypoxia [5,7,10], likely due to sluggish and chaotic blood flow patterns, as observed in tumors [4,6,12,26,27]. This is most suggestive that dynamic changes within the EC of an allograft (destruction and/or proliferation) have potential to create abnormal microvascular networks and local areas of tissue hypoxia.…”

Transplantology: Challenges for Today

“…Wedel et al (2015) presented new look on the molecular events within the intragraft microenvironment that defines the phenotype of rejection and sustains chronic rejection process. They propose that damage of endothelial cells resulting from ischemia reperfusion injury, T cell cytotoxicity, and alloantibodies.…”

“…In models of acute rejection, antibodies to VEGF prolong graft survival. The investigators indicated that new molecules regulated by HIF-1α dependent path, semaphorins, and neurophilins, as well as mTOR/Akt signaling can drive the chronic rejection process (Wedel et al 2015). …”

Macrophage-stimulated microRNA expression in mural cells promotes transplantation-induced neointima formation

“…In contrast, chronic rejection is still a clinical challenge that limits the long-term survival of transplanted organs [2]. A major pathogenic mechanism underlying chronic rejection is the development of arterial transplant vasculopathy [2–5].…”