Prostanoids modulate inflammation and alloimmune responses during graft rejection

Acute rejection of a transplanted organ is characterized by intense inflammation within the graft. Yet, for many years transplant researchers have overlooked the role of classic mediators of inflammation such as prostaglandins and thromboxane (prostanoids) in alloimmune responses. It has been demonstrated that local production of prostanoids within the allograft is increased during an episode of acute rejection and that these molecules are able to interfere with graft function by modulating vascular tone, capillary permeability, and platelet aggregation. Experimental data also suggest that prostanoids may participate in alloimmune responses by directly modulating T lymphocyte and antigen-presenting cell function. In the present paper, we provide a brief overview of the alloimmune response, of prostanoid biology, and discuss the available evidence for the role of prostaglandin E2 and thromboxane A2 in graft rejection.

Thromboxane; Prostaglandins; Transplantation; Inflammation; Rejection; Corticosteroids

Authorship

P.N. Rocha

Universidade Federal da Bahia, Faculdade de Medicina , Hospital Universitário Professor Edgard Santos, Salvador, , BrazilUniversidade Federal da BahiaBrazilSalvador, , BrazilUniversidade Federal da Bahia, Faculdade de Medicina , Hospital Universitário Professor Edgard Santos, Salvador, , Brazil

E.M. Carvalho

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (3)

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Figure 1.
Inflammatory infiltrate in acute renal allograft rejection. A and B, A hematoxylin and eosin-stained renal allograft biopsy specimen obtained from a patient without rejection during a protocol biopsy. C and D, Intense interstitial inflammatory infiltrate characteristic of acute renal allograft rejection (Banff' 97 grade IB). These inflammatory cells are the source of the inflammatory mediators (cytokines, chemokines, prostanoids) that orchestrate the alloimmune response. Top figures (A and C), 50X magnification; bottom figures (B and D) 100X magnification.

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Figure 2.
Biosynthesis of prostanoids. The biosynthesis of prostanoids begins when phospholipases break down cell membrane phospholipids into arachidonic acid, which is the substrate for the prostaglandin H (PGH) synthases (also known as cyclooxygenases). Prostanoids are synthesized by the metabolism of PGH by various isomerases such as PGE synthase and TX synthase. After synthesis, prostanoids exit the cell via prostaglandin transporters and bind to specific G protein coupled receptors present on the surface of neighboring cells. cPLA2 = cytosolic phospholipase A2; COX = cyclooxygenase; NSAIDs = non-steroidal anti-inflammatory drugs; PG = prostaglandin; TX = thromboxane; CRTH2 = chemoattractant receptor-homologous molecule expressed on Th2 cells.

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Figure 3.
Effects of prostanoids on immune cells. Schematic drawing depicting the generation of prostanoids by antigen-presenting cells (APCs), represented here by a macrophage, and the subsequent actions of these prostanoids on APCs and T cells. Inflammatory cytokines such as IL-1 and TNF-a up-regulate COX-2 in macrophages and thereby promote an increase in the output of prostanoids. The actions of PGE2 are mainly immunosuppressive. In macrophages, PGE2 causes an increase in the production of the anti-inflammatory cytokine IL-10 and a reduction in the production of pro-inflammatory cytokines and superoxide, as well as a reduction in MHC class II antigen expression. These actions are mediated by EP2 and EP4 receptors. In T cells, PGE2 binds EP2 receptors and suppresses proliferation, cytokine production and antigen-specific cytotoxicity. Conversely, TXA2 appears to stimulate both macrophage and T cell functions, effects that are mediated via a single TP receptor. In macrophages, TXA2 is known to increase the production of pro-inflammatory cytokines IL-1 and TNF-a. In T cells, TXA2 increases the proliferative responses to mitogens and alloantigens. LPS = lipopolysaccharide; IL = interleukin; TNF-a = tumor necrosis factor a; COX = cyclooxygenase; MHC = major histocompatibility complex; Th = T helper; PG = prostaglandin; TX = thromboxane.

Figure 1. Inflammatory infiltrate in acute renal allograft rejection. A and B, A hematoxylin and eosin-stained renal allograft biopsy specimen obtained from a patient without rejection during a protocol biopsy. C and D, Intense interstitial inflammatory infiltrate characteristic of acute renal allograft rejection (Banff' 97 grade IB). These inflammatory cells are the source of the inflammatory mediators (cytokines, chemokines, prostanoids) that orchestrate the alloimmune response. Top figures (A and C), 50X magnification; bottom figures (B and D) 100X magnification.

Figure 2. Biosynthesis of prostanoids. The biosynthesis of prostanoids begins when phospholipases break down cell membrane phospholipids into arachidonic acid, which is the substrate for the prostaglandin H (PGH) synthases (also known as cyclooxygenases). Prostanoids are synthesized by the metabolism of PGH by various isomerases such as PGE synthase and TX synthase. After synthesis, prostanoids exit the cell via prostaglandin transporters and bind to specific G protein coupled receptors present on the surface of neighboring cells. cPLA2 = cytosolic phospholipase A2; COX = cyclooxygenase; NSAIDs = non-steroidal anti-inflammatory drugs; PG = prostaglandin; TX = thromboxane; CRTH2 = chemoattractant receptor-homologous molecule expressed on Th2 cells.

Figure 3. Effects of prostanoids on immune cells. Schematic drawing depicting the generation of prostanoids by antigen-presenting cells (APCs), represented here by a macrophage, and the subsequent actions of these prostanoids on APCs and T cells. Inflammatory cytokines such as IL-1 and TNF-a up-regulate COX-2 in macrophages and thereby promote an increase in the output of prostanoids. The actions of PGE2 are mainly immunosuppressive. In macrophages, PGE2 causes an increase in the production of the anti-inflammatory cytokine IL-10 and a reduction in the production of pro-inflammatory cytokines and superoxide, as well as a reduction in MHC class II antigen expression. These actions are mediated by EP2 and EP4 receptors. In T cells, PGE2 binds EP2 receptors and suppresses proliferation, cytokine production and antigen-specific cytotoxicity. Conversely, TXA2 appears to stimulate both macrophage and T cell functions, effects that are mediated via a single TP receptor. In macrophages, TXA2 is known to increase the production of pro-inflammatory cytokines IL-1 and TNF-a. In T cells, TXA2 increases the proliferative responses to mitogens and alloantigens. LPS = lipopolysaccharide; IL = interleukin; TNF-a = tumor necrosis factor a; COX = cyclooxygenase; MHC = major histocompatibility complex; Th = T helper; PG = prostaglandin; TX = thromboxane.

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Prostanoids modulate inflammation and alloimmune responses during graft rejection

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