Positron Emission Tomography in Clinical Islet Transplantation

Eriksson, Olof; Eich, Torsten; Sundín, Anders; Tibell, Annika; Tufveson, Gunnar; Andersson, Helene H.; Felldin, Marie; Foss, Aksel; Kyllönen, L.; Långström, Bengt; Nilsson, Bo; Korsgren, Olle; Lundgren, Torbjörn

doi:10.1111/j.1600-6143.2009.02844.x

Cited by 144 publications

(99 citation statements)

References 39 publications

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“…Our in vivo and in vitro analyses showed rapid increases of TAT and C-peptide concentrations after mixing islets and autologous blood as well. Kinetics of the TAT and C-peptide increase observed in the present study matched the observations reported for clinical allogenic islet transplants (24). Therefore, coagulation activation is clearly evidenced after islet infusion in AIT, despite the presence of heparin in the islet preparation at 70 U/kg recipient body weight.…”

Section: Discussionsupporting

confidence: 89%

“…Coagulation factors, platelet count and C-peptide levels in AIT patients Previous reports in allogenic islet transplantation (24,25) have shown that major characteristics of IBMIR include activation coagulation, complement cascade and infiltration of inflammatory cells. We measured markers for these major events in plasma collected during the peritransplant period after AIT.…”

Section: Patient Characteristicsmentioning

confidence: 99%

See 1 more Smart Citation

Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

Naziruddin

Iwahashi

Kanak

et al. 2014

American Journal of Transplantation

167

149

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y These authors contributed equally.A nonspecific inflammatory and thrombotic reaction termed instant blood-mediated inflammatory reaction (IBMIR) has been reported when allogenic or xenogenic islets come into contact with blood. This reaction is known to cause significant loss of transplanted islets. We hypothesized that IBMIR occurs in patients undergoing total pancreatectomy followed by autologous islet transplantation (TP-AIT) and tested this hypothesis in 24 patients and in an in vitro model. Blood samples drawn during the peritransplant period showed a significant and rapid increase of thrombinanti-thrombin III complex (TAT) and C-peptide during islet infusion, which persisted for up to 3 h, along with a decreased platelet count. A concomitant increase in levels of inflammatory proteins IL-6, IL-8 and interferoninducible protein-10 was observed. An in vitro model composed of pure islets plus autologous blood also demonstrated significantly increased levels of TAT (p < 0.05), C-peptide (p < 0.05), tumor necrosis factoralpha (p < 0.05) and MCP-1 (p < 0.05), as well as strong tissue factor expression in islets. Islet viability decreased significantly but was rescued by the presence of low-molecular-weight dextran sulfate. In conclusion, AIT-induced elevation of TAT and destruction of islets suggests that IBMIR might occur during AIT. Modulating this process may help improve islet engraftment and the insulin independence rate in TP-AIT patients.

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Section: Discussionsupporting

confidence: 89%

Section: Patient Characteristicsmentioning

confidence: 99%

Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

Naziruddin

Iwahashi

Kanak

et al. 2014

American Journal of Transplantation

167

149

View full text Add to dashboard Cite

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“…3 However, it is unclear which mechanisms are involved and whether they are primarily immunologic or nonimmunologic. Many investigators agree that the liver may not be the optimal site for islet survival or function and that inadequate oxygen supply may be an issue.…”

Section: Review Articlementioning

confidence: 99%

Intraportal Islet Oxygenation

Suszynski

Avgoustiniatos

Papas

2014

J Diabetes Sci Technol

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Islet transplantation (IT) is a promising therapy for the treatment of diabetes. The large number of islets required to achieve insulin independence limit its cost-effectiveness and the number of patients who can be treated. It is believed that >50% of islets are lost in the immediate post-IT period. Poor oxygenation in the early post-IT period is recognized as a possible reason for islet loss and dysfunction but has not been extensively studied. Several key variables affect oxygenation in this setting, including (1) local oxygen partial pressure (pO 2 ), (2) islet oxygen consumption, (3) islet size (diameter, D), and (4) presence or absence of thrombosis on the islet surface. We discuss implications of oxygen-limiting conditions on intraportal islet viability and function. Of the 4 key variables, the islet size appears to be the most important determinant of the anoxic and nonfunctional islet volume fractions. Similarly, the effect of thrombus formation on the islet surface may be substantial. At the University of Minnesota, average size distribution data from clinical alloislet preparations (n = 10) indicate that >150-µm D islets account for only ~30% of the total islet number, but >85% of the total islet volume. This suggests that improved oxygen supply to the islets may have a profound impact on islet survivability and function since most of the β-cell volume is within large islets which are most susceptible to oxygen-limiting conditions. The assumption that the liver is a suitable islet transplant site from the standpoint of oxygenation should be reconsidered.

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“…As evidenced by positron emission tomography scan imaging and acute C-peptide release, it has been estimated that up to 50% of the infused islets are lost within minutes of being transplanted, largely as a result of the IBMIR. [16][17][18] Unfortunately, we did not find evidence of prolonged graft survival in the intraportal allotransplant model tested when used in combination with CTLA-4 Ig; although, a study transplanting syngeneic islets into the liver via the portal vein has been conducted by Piemonti et. al.…”

Section: Discussionmentioning

confidence: 68%

Reparixin, a CXCR1/2 inhibitor in islet allotransplantation

Pawlick

Wink

Pepper

et al. 2016

Islets

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Quality of life in Type 1 diabetic patients may be improved with islet transplantation, but lifelong immunosuppression is required to prevent rejection. Allo-immune response is a key player in graft dysfunction and although the adaptive immune response is well characterized, the effect of the innate immune reaction after transplantation is only recently becoming appreciated. In this study, we address how the innate response affects long-term outcomes in a murine islet allotransplant model. CTLA-4 Ig treatment is known to significantly prolong kidney subcapsular islet allograft survival and enhance glucose tolerance. The combination of CTLA-4 Ig with reparixin, which blocks against inflammatory neutrophil infiltration, yielded no long-term graft survival in an intrahepatic allotransplant model but had similar long-term graft survival in the kidney subcapsular model. Seven days after transplant, serum blood IFN-g levels were significantly lower in the CTLA-4 Ig with reparixin treatment group compared to controls. IL-12p70 cytokine levels were increased with combination treatment, a positive modulation of the inflammatory response to the allograft. Furthermore, KC GRO, also known as CXCL1, was decreased in serum 7 d after transplant. Histologically, we found that immune cell infiltrate, CD4C and CD8C T cell populations along with both CXCR1C and CXCR2C cell populations were decreased within the CTLA-4 Ig and reparixin islet transplant graft. Overall these data provide insight into the down regulation of T-cell recruitment by CTLA-4 Ig and decreased neutrophil activation and recruitment with reparixin after long-term islet graft survival.

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Positron Emission Tomography in Clinical Islet Transplantation

Cited by 144 publications

References 39 publications

Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

Intraportal Islet Oxygenation

Reparixin, a CXCR1/2 inhibitor in islet allotransplantation

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