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

TLDR

Small fractions of grafts engraft successfully in clinical islet transplantation, likely because tissue factor produced by endocrine cells triggers an instant blood‑mediated inflammatory reaction (IBMIR). The authors measured thrombin‑antithrombin (TAT) and factor VIIa‑antithrombin (FVIIa‑AT) complexes in nine patients who received 20 islet infusions to assess the inflammatory response. They found that islets release tissue factor as membrane‑bound microparticles, that a low‑molecular‑mass FVIIa inhibitor can block this activity, and that rapid rises in TAT and FVIIa‑AT complexes after infusion are associated with impaired insulin production, indicating that tissue‑factor‑driven IBMIR compromises islet graft function.

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.