Brain Death in Combination with Warm Ischemic Stress during Isolation Procedures Induces the Expression of Crucial Inflammatory Mediators in the Isolated Islets

Abstract

Tissue factor (TF) and monocyte chemoattractant protein-1 (MCP-1) expressed on the islets have been identified as the main trigger of the instant blood-mediated inflammatory reaction (IBMIR) in islet transplantation. Because the key steps that directly induce TF and MCP-1 remain to be determined, we focused on the influence of brain death (BD) on TF and MCP-1 expression in the pancreatic tissues and isolated islets using a rodent model. TF and MCP-1 mRNA levels in the pancreatic tissues were similar between the BD and the control group. However, TF and MCP-1 mRNA in the fresh islets of the BD group were significantly higher than that of the control group (p < 0.01). BD may thus be suggested to be of great importance as an initiator of TF and MCP-1 induction in the isolated islets. Furthermore, the upregulation of crucial inflammatory mediators induced by BD could be exacerbated by warm ischemic damage during digestion procedures. In the present study, the islet yield and purity were affected by BD. However, almost no influences were observed with respect to islet viability, indicating that the expression of inflammatory mediators rather than islet viability is more susceptible to BD. According to the change in time course of TF and MCP-1 expression in the isolated islets, the selected time point for islet infusion in current clinical islet transplantation was thus shown to be at its worst level, at least with respect to the damage caused by BD and ischemic stress. In conclusion, BD in combination with warm ischemic stress during isolation procedures induces a high expression of TF and MCP-1 in the isolated islets. In order to reduce the expression of crucial inflammatory mediators in the islet grafts, the management of the pancreas from brain-dead donors with early antiinflammatory treatments is thus warranted.

Evaluation of Viable β-Cell Mass is Useful for Selecting Collagenase for Human Islet Isolation: Comparison of Collagenase NB1 and Liberase HI

“…As others reported (2), our data also showed significantly longer digestion times in the NB1 group. The longer exposure of pancreatic tissues to active enzyme at high temperature (37°C) results in the lower islet viability through the enzymatic toxicity and hypoxia (29, 40). Even though NB1 blend might be less harmful to islet cells, some of the lots tested showed less potency in terms of pancreas dissociation, which exposed the tissue to longer to a detrimental environment.…”

An Engineered Innate Repair Receptor Agonist, ARA 290, Protects Rat Islets from Cytokine-induced Apoptosis

“…This may be explained by lack of IRR expression in the setting of low temperature and will require further study. Although prolonged cold ischemia is reported to be associated with lower islet yields and viability, as well as the function of transplanted islet [31], the pancreases used in our study were obtained from non-brain dead donors and therefore were not subjected to the cytokine storm arising from brain death [16].…”

“…A strong inflammatory response induced by islet isolation manifests as upregulation of tissue factor, monocyte chemoattractant protein (MCP)-1 [13] and inflammation associated genes such as interleukin-8 (IL-8), chemokine ligand 6, and compliment factor B [7]. In addition, the brain-death status of a donor, which induces a cytokine storm, organ procurement procedures, and prolonged cold ischemia time reduces isolated pancreatic islet yields and functionality after PITx [14][15][16]. Beyond the direct toxic effect on β-cells [17], inflammatory mediators, such as tumor necrosis factor (TNF)-α [18] IL-1β [19] and MCP-1 [20], may damage the transplanted islets by enhancing inflammation and innate immune responses following PITx.…”

Taking a Lesson from the past in Organ Biology

“…by in vivo supCD28mAb-expanded antigen-specific nTreg cells (9), the induced expression of crucial inflam-JSOPMB was started in 1974 for the study of organ preservation and developed widely in 1990s with particimatory mediators in islets by brain death and warm ischemic stress (22), and human immune reactivity against pation of researchers in various fields of medicine, pharmacology, engineering, veterinary medicine, and basic liver sinusoidal endothelial cells from galTα(1,3) GalTdeficient pigs (26). science.…”

“…Excellent presentations conducted at the 35th annual ness of a self-assembling peptide (PuraMatrix) for bone repair (14) and xenogenic hepatocyte transplantation meeting of JSOPMB held November [22][23]2008 three papers looking at ways to culture iPS cells (5) …”