Factors influencing Islet of Langerhans graft function and monitoring

Pileggi, Antonello; Ricordi, Camillo; Alessiani, M.; Inverardi, Luca

doi:10.1016/s0009-8981(01)00503-4

Cited by 82 publications

(48 citation statements)

References 123 publications

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“…There were, however, islets that triggered a low level of TAT generation but still produced no C-peptide. Here, primary nonfunction due to alternative mechanisms must be operative (e.g., apotosis) (22).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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“…Within a healthy pancreas, islet function is maximized by the intimate proximity of the ␤-cells and circulating blood, and, as a result, ␤-cells require a microenvironment with highly oxygenated blood (pO 2 of 40 mmHg) and abundant nutrients (6). The current method of human islet isolation and purification destroys the capillary network in islets, causing the rapid onset of hypoxia (7). Islet hypoxia immediately after transplantation into the portal circulation further extends the postisolation hypoxic period (pO 2 of 5-10 mmHg or Ͻ1% O 2 ), and the revascularization process leads to reperfusion injury and death in islets (6).…”

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confidence: 99%

XIAP Overexpression in Human Islets Prevents Early Posttransplant Apoptosis and Reduces the Islet Mass Needed to Treat Diabetes

et al. 2005

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The Edmonton Protocol for treatment of type 1 diabetes requires islets from two or more donors to achieve euglycemia in a single recipient, primarily because soon after portal infusion, the majority of the transplanted cells undergo apoptosis due to hypoxia and hypoxia reperfusion injury. X-linked inhibitor of apoptosis protein (XIAP) is a potent endogenous inhibitor of apoptosis that is capable of blocking the activation of multiple downstream caspases, and XIAP overexpression has previously been shown to enhance engraftment of a murine ␤-cell line. In this study, human islets transduced with a XIAP-expressing recombinant adenovirus were resistant to apoptosis and functionally recovered following in vitro stresses of hypoxia and hypoxia with reoxygenation (models reperfusion injury). Furthermore Ad-XIAP transduction dramatically reduced the number of human islets required to reverse hyperglycemia in chemically diabetic immunodeficient mice. These results suggest that by transiently overexpressing XIAP in the immediate posttransplant period, human islets from a single donor might be used to effectively treat two diabetic recipients. Diabetes 54: [2541][2542][2543][2544][2545][2546][2547][2548] 2005 T he recent introduction of the Edmonton Protocol has demonstrated that islet transplantation is a viable route to achieve insulin independence in a population of patients with type 1 diabetes (1). Despite its promise, islet transplantation remains restricted to patients with severe hypoglycemia or glycemic lability and is currently unsuitable for the majority of patients with type 1 diabetes for several reasons. Most recipients require two or more islet transplant procedures (combined mass of Ͼ10,000 islet equivalents [IEQs]/kg body wt) in order to become insulin independent, which is a serious drawback given the prevalence of diabetes and the limited cadaveric organ donor pool (2,3). Also, the risks associated with islet transplantation appear to increase with the number of infusions and with the total packed cell volume of cumulative grafts (4).Expansion of clinical islet transplantation has been limited by the large requirement for donor tissue. The fact that most patients must receive Ͼ10,000 IEQs/kg to become insulin independent suggests that a large portion of the infused islets fail to engraft sufficiently. In fact, in murine models of islet transplantation, it has been determined that even under ideal circumstances, Ͼ60% of syngeneic islet graft mass is lost due to apoptosis (5). In clinical islet transplantation, it has been estimated that more than two-thirds of the implanted islets never become functional (2).This early profound loss in islet mass can be attributed to several factors. Within a healthy pancreas, islet function is maximized by the intimate proximity of the ␤-cells and circulating blood, and, as a result, ␤-cells require a microenvironment with highly oxygenated blood (pO 2 of 40 mmHg) and abundant nutrients (6). The current method of human islet isolation and purification destroys the cap...

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“…Islet transplantation offers an appealing alternative as it can be performed with high-quality islets selected and pooled from multiple donors. However, the success rate and long-term survival of islet grafts in human subjects has historically been very low (i.e., Ͻ8%) because of autoimmune/allogeneic immune rejection and cytotoxic effects of general immunosuppressants (17). Th1 cells have been shown to be correlated with the recurrence of diabetes after islet transplantation (18,19).…”

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confidence: 99%

Adeno-Associated Virus-Mediated IL-10 Gene Therapy Inhibits Diabetes Recurrence in Syngeneic Islet Cell Transplantation of NOD Mice

et al. 2003

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Factors influencing Islet of Langerhans graft function and monitoring

Cited by 82 publications

References 123 publications

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

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

XIAP Overexpression in Human Islets Prevents Early Posttransplant Apoptosis and Reduces the Islet Mass Needed to Treat Diabetes

Adeno-Associated Virus-Mediated IL-10 Gene Therapy Inhibits Diabetes Recurrence in Syngeneic Islet Cell Transplantation of NOD Mice

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