The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection?

Abstract

Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell "cross-dressing" by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).

Keywords: IL-6; allograft; endothelial cells; exosomes; inflammation; rejection; tolerance.

Figure 1

(A) Structure of HLA-E illustrating HLA-E specific epitopes on α1 and α2 helices. The interaction between the HLA-E amino acid sequences on α1 and α2 helices (boxes) and NKG2a and CD94 inhibitory receptors (arrows) involves H-bonding (H), van der Waal forces (vf), and salt linkages (salt) of the amino acids of HLA-E and the inhibitory receptors. (B) Proinflammatory cytokines upregulate not only HLA-E but also HLA-G. When HLA-E and HLA-G present non-allogenic peptides, they bind to the respective inhibitory receptors on the NK cells, leading to inhibition of cytotoxic capabilities of NK cells, promoting tolerance and graft survival.

Figure 2

Impact of pro-inflammatory cytokines on HLA-I molecules. On the cell surface, HLA class-I occur as dimers for HLA-I (α-chain and β2-microglobulin (β2m) complexed with a short peptide, designated as Closed Conformers (CCs). Upon activation by pro-inflammatory factors, many ICs express monomeric variant of the HLA, called “Open Conformers (OCs). Commercial microbeads coated with HLA CCs admixed with OCs will not provide accurate assessment of serum antibodies against intact cell surface HLA.

Figure 3

The dynamic role of proinflammatory mediators generated following transplant surgery and the role of one of the cytokines (IL-6) in generating biomarkers post-Tx. Other cytokines and chemokines also generate such biomarkers. There is an imminent need to identify time-based production of these inflammation biomarkers post-Tx to prevent allograft rejection, to promote tolerance of allografts and to develop appropriate personalized, dynamic, chemo-immunotherapeutic strategies.