Cutting edge of immune response and immunosuppressants in allogeneic and xenogeneic islet transplantation

Abstract

As an effective treatment for diabetes, islet transplantation has garnered significant attention and research in recent years. However, immune rejection and the toxicity of immunosuppressive drugs remain critical factors influencing the success of islet transplantation. While immunosuppressants are essential in reducing immune rejection reactions and can significantly improve the survival rate of islet transplants, improper use of these drugs can markedly increase mortality rates following transplantation. Additionally, the current availability of islet organ donations fails to meet the demand for organ transplants, making xenotransplantation a crucial method for addressing organ shortages. This review will cover the following three aspects: 1) the immune responses occurring during allogeneic islet transplantation, including three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence; 2) commonly used immunosuppressants in allogeneic islet transplantation, including calcineurin inhibitors (Cyclosporine A, Tacrolimus), mycophenolate mofetil, glucocorticoids, and Bortezomib; and 3) early and late immune responses in xenogeneic islet transplantation and the immune effects of triple therapy (ECDI-fixed donor spleen cells (ECDI-SP) + anti-CD20 + Sirolimus) on xenotransplantation.

Keywords: allogenic and xenogenic islet transplantation; immune response; immunosuppressants; islet transplantation; xenotransplantation.

Figure 1

Immune mechanisms at three stages of allogeneic islet transplantation. The immune responses occurring during allogeneic islet transplantation included three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence. In the early stages of transplantation, islets secrete pro-inflammatory factors and activate the complement system, promoting the recruitment of platelets, neutrophils, and monocyte macrophages to the graft. Vascular endothelial cells secrete cytokines and release P-selectin, promoting the adhesion between monocytes/neutrophils and platelets. Accumulated monocyte macrophages and neutrophils further enhance the recruitment of macrophages and the secretion of cytokines. Green arrows indicate the process by which the complement system promotes cytokine secretion by monocytes. Red arrows indicate the process by which neutrophils enhance cytokine secretion by macrophages. Purple arrows represent the process by which P-selectin promotes the adhesion of monocytes and neutrophils to platelets. Within days after transplantation, the release of inflammatory signals leads to increased cytokine production, with neutrophils signaling macrophages and dendritic cells to the site of islet phagocytosis, presenting antigens on their surface and recruiting adaptive immune cells. The infiltration of helper and cytotoxic T cells further damages the islets, recruiting B cells that produce antibodies against the allogeneic islets and differentiating T cells into memory T cells, ultimately leading to the rejection of the overall allogeneic transplant. TNFα, tumor necrosis factor alpha; MIP1α, macrophage inflammatory protein-1 alpha; IFN-γ, interferon; MCP-1, monocyte chemoattractant protein-1; GAD65, glutamic acid decarboxylase 65; IA-2, insulinoma-associated protein 2; ZnT8, transporter 8. ROS, reactive oxygen species; TH1, T helper 1 cells; TFH, follicular helper T cells; pTreg, peripheral regulatory T cells.

Figure 2

The mTOR signaling pathway in islets. Upon stimulation by insulin and other growth factors, phosphoinositide 3-kinase (PI3K) converts phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3), which localizes PKB to the membrane and activates it through PDK1 and mTORC2. Activated PKB phosphorylates and inhibits TSC1/2. Rheb, a small GTPase inhibited by TSC2, positively regulates mTORC1 activity. mTORC1 phosphorylates S6 kinase 1/2 and 4EBP1, leading to increased mRNA translation. Amino acids activate mTORC1 through Rag A/B and C/D. Under low energy conditions, the ratio of AMP to ATP increases, activating AMP-activated kinase (AMPK), which phosphorylates and activates the TSC1/2 complex, thereby inhibiting mTORC1. mTORC2 activity is primarily mediated through unknown pathways. mTORC2 phosphorylates and activates PKB, serum- and glucocorticoid-induced kinase 1 (SGK1), and PKC. Arrows indicate stimulatory effects; block ends indicate inhibitory effects; solid lines represent direct effects, and dashed lines represent indirect effects. Atg13, Autophagy-related protein 13; DAP1, Death-associated protein 1; Deptor, DEP domain-containing mTOR-interacting protein; 4EBP, eIF4E-binding protein; GbL-G, Protein Gβ-like; HIF1, Hypoxia-inducible factor 1; IMP2, Insulin-like growth factor 2 mRNA-binding protein; mLST8, Mammalian lethal with Sec13 protein 8; PDK1, Phosphoinositide-dependent protein kinase 1; Protor, Protein observed with Rictor; Raptor, Regulatory associated protein of mTOR; Rictor, Rapamycin-insensitive companion of mTOR; Sin1, Stress-activated protein kinase-interacting protein 1; TFIIIC, Transcription factor 3C; ULK1, Unc-51 like kinase 1.

Figure 3

Overview of key steps in the IBMIR process during islet xenotransplantation. The contact between xenogeneic blood and islets triggers the activation of the extrinsic coagulation pathway mediated by tissue factor (TF). Consequently, downstream effector thrombin is produced, leading to fibrin deposition and thrombosis. The attachment of platelets to the islets further supports the pro-coagulant effect. Activated complement fragments (iC3b) deposit on the islet surface, and the anaphylatoxins C3a and C5a activate and attract leukocytes. The formation of the membrane attack complex (MAC) mediates islet lysis (FVIIa, activated coagulation factor VII; MAC, membrane attack complex).