Tissue Factor Produced by the Endocrine Cells of the Islets of Langerhans Is Associated With a Negative Outcome of Clinical Islet Transplantation

Abstract

There are strong indications that only a small fraction of grafts successfully engraft in clinical islet transplantation. One explanation may be the instant blood-mediated inflammatory reaction (IBMIR) elicited by tissue factor, which is produced by the endocrine cells. In the present study, we show that islets intended for islet transplantation produce tissue factor in both the transmembrane and the alternatively spliced form and that the membrane-bound form is released as microparticles often associated with both insulin and glucagon granules. A low-molecular mass factor VIIa (FVIIa) inhibitor that indirectly blocks both forms of tissue factor was shown in vitro to be a promising drug to eliminate the IBMIR. Thrombin-antithrombin complex (TAT) and FVIIa-antithrombin complex (FVIIa-AT) were measured in nine patients who together received 20 infusions of isolated human islets. Both the TAT and FVIIa-AT complexes increased rapidly within 15-60 min after infusion. When the initial TAT and FVIIa-AT levels were plotted against the increase in C-peptide concentration after 7 days, patients with an initially strong IBMIR showed no significant increase in insulin synthesis after 7 days. In conclusion, tissue factor present in both the islets and the culture medium and elicits IBMIR, which affects the function of the transplanted islets. Diabetes 54: [1755][1756][1757][1758][1759][1760][1761][1762] 2005

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“…However, the clinical application of islet transplantation has been slowed by the inability to use islets from a single donor to restore euglycemia, even short term, in most islet allograft recipients and by the unacceptably high 5 y failure rate even for islet transplants that function at 1 y posttransplantation (1). As a result of nonimmunologic processes, many islets perish during harvest, purification, and shortly following transplantation (2,3). Moreover, the marked nonimmunologic loss of islets may render the recipient prone to β-cell exhaustion long term (4).…”

The synthetic liver X receptor agonist GW3965 reduces tissue factor production and inflammatory responses in human islets in vitro

“…Tissue factor produced by islets is considered to activate this process and the clinical outcome of islet transplantation is directly related to the extent of TF production [16].…”

The role of macrophage migration inhibitory factor on glucose metabolism and diabetes

“…Furthermore, islet transplantation involves the early loss of many islet cells (50% or more), owing to poor engraftment. Several factors may induce these events, including the activation of the coagulation cascade, which is responsible for non-specific inflammatory reactions [92]. Several mediators, including MCP-1, IFN-γ and IL-1β, have been associated with lower islet isolation yields and impaired post-transplantation islet function [82,93].…”