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Findings in transplant medicine provide new insights
(Science Letter Via Thomson Dialog NewsEdge)
Reports from New Zealand and United States highlight recent research on transplant medicine.
Study 1: Transplantation of intraperitoneal alginate-encapsulated neonatal porcine islets proved safe in diabetic primate model.
According to recent research from New Zealand, "A nonhuman primate model of diabetes is valuable for assessing porcine pancreatic islet transplants that might have clinical benefits in humans. Neonatal porcine islets, microencapsulated in alginate-polyornithine-alginate, were injected intraperitoneally (10,000 IEQs/kg islets) into eight adult male cynomolgus monkeys rendered diabetic with streptozotocin."
R.B. Elliott and colleagues at the Living Cell Technology New Zealand explained, "Eight diabetic controls were given an equivalent dose of empty placebo capsules. All subjects received a repeat transplant 3 months after the first. The transplant was well tolerated and no adverse or hypoglycemic events occurred.
"There were two deaths from nontransplant treatment or diabetic complications unrelated to the transplants. After transplantation, the average insulin dose was reduced in the islet-treated group and increased in the control group."
The investigators determined, "At 12 weeks after the first transplant there was a mean 36% (95% CI: 6 to 65%, p=0.02) drop in daily insulin dose compared with the control group. After 24 weeks the difference increased to a mean of 43% (95% CI: 12 to 75%, p=0.01) without significant differences in blood glucose values between the two groups. Individual responses after islet transplant varied and one monkey was weaned off insulin by 36 weeks."
The data showed, "At terminal autopsy, organs appeared normal and there was no visible peritoneal reaction. No animal had polymerase chain reaction (PCR)-amplified signals of porcine endogenous retrovirus or exogenous virus infections in blood or tissues."
"Repeated intraperitoneal transplantation of microencapsulated neonatal porcine islets is a safe procedure in diabetic primates. It was shown to result in a significant reduction in insulin dose requirement in the majority of animals studied, whereas insulin requirement increased in controls," concluded the authors.
Elliott and colleagues published their study in Transplantation Proceedings (Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant Proc, 2005;37(8):3505-3508).
For additional information, contact R.B. Elliott, Living Cell Technology New Zealand Ltd, POB 23-566 Hunters Corner, Auckland, New Zealand.
Study 2: Akt, an intracellular mediator of beta-cell growth, shows promise as a target for use in islet transplantation strategies in diabetic patients.
According to recent research published in the journal Diabetes, "Akt is an important intracellular mediator of beta-cell growth and survival in rodents. However, whether constitutive activation of Akt in human beta-cells enhances the survival and function of transplanted islets is unknown."
P. Rao and associates at the University of Pittsburgh explained, "In the current study, we examined the efficacy of constitutive activation of Akt in improving human islet transplant outcomes using a marginal mass model in diabetic severe combined immunodeficient (SCID) mice."
The researchers reported, "Human islets transduced with adenoviruses encoding constitutively active Akt1 (Adv-CA-Akt) displayed increased total and phosphorylated Akt and Akt kinase activity compared with control islets. Expression of CA-Akt in human islets induced a significant increase in beta-cell replication and a significant decrease in beta-cell death induced by serum and glucose deprivation or chronic hyperglycemia."
"Two control groups of islets (1,500 uninfected or adenovirus LacZ [Adv-LacZ]-transduced human islet equivalents [IEQs]) transplanted under the kidney capsule of streptozotocin-induced diabetic SCID mice were insufficient to correct hyperglycemia. Importantly and in marked contrast to these controls, 1,500 Adv-CA-Akt-transduced IEQs were capable of restoring euglycemia in diabetic SCID mice. Moreover, blood glucose normalization persisted for at least 6 months," the scientists wrote.
They noted, too, that "Human plasma insulin at day 54 after transplant was 10-fold higher in Adv-CA-Akt islet recipients (2.40.4 ng/ml) compared with those receiving Adv-LacZ islets (0.250.08 ng/ml) (p<0.05)."
"In summary," Rao's team wrote, "expression of CA-Akt in human islets improves islet transplant outcomes in a subcapsular renal graft model in SCID mice. Akt is an attractive target for future strategies aimed at reducing the number of islets required for successful islet transplantation in humans."
Rao and colleagues published their study in Diabetes (Gene transfer of constitutively active akt markedly improves human islet transplant outcomes in diabetic severe combined immunodeficient mice. Diabetes, 2005;54(6):1664-75).
For additional information, contact P. Rao, University of Pittsburgh, Division of Endocrinology, BST-E-1140, 200 Lothrop St., Pittsburgh, PA 15261, USA.
Study 3: Researchers from the United States have documented the role of donor-derived monocyte chemoattractant protein-1 (CCL2/MCP-1) in murine islet transplantation.
"CCL2/MCP-1 is a proinflammatory chemokine produced by several cell types, including pancreatic islets. High levels of donor-derived CCL2 have been associated with poor islet allograft outcome in patients with type 1 diabetes; however, the causal relationship is unknown.
"The constitutive and inducible expression of chemokines and their receptors by pancreatic islets in vitro were investigated, specifically the role of donor-derived CCL2 in marginal mass murine islet transplantation," wrote B. Schroppel and colleagues, Mount Sinai School of Medicine.
"The results showed that inflammatory cytokine stimulation of islets induced de novo expression of CCL2, CCL5/RANTES, CXCL9/MIG, and CXCL10/IP-10 and increased expression of CXCL2/macrophage-inflammatory protein-2. CCL2 mRNA and protein were highly expressed within 2 d in cultures.
"Transplantation of islets with high levels of CCL2 into syngeneic recipients led to a significantly greater influx of CCR2+ cells and higher expression of monocyte/macrophage-associated inflammatory cytokines compared with low CCL2-donor islets. The level of pretransplantation CCL2 inversely correlated (p<.0001) with isograft function," reported the authors.
"In contrast," they added, "in CCR2(-/-) recipients, this correlation was not present. A direct toxic effect of CCL2 on islets was excluded by assessing cell viability and insulin release in vitro."
"CCL2 secreted by islets plays an important role in the immediate islet graft function. Strategies to decrease islet-derived CCL2 release may increase the success of islet transplantation," concluded the investigators.
Schroppel and colleagues published their study in the Journal of the American Society of Nephrology (Role of donor-derived monocyte chemoattractant protein-1 in murine islet transplantation. J Am Soc Nephrol, 2005;16(2):444-451).
Additional information can be obtained by contacting B. Schroppel, Mount Sinai School of Medicine, Division of Nephrology, 1 Gustave L Levy Pl, Box 1243, New York, NY 10029, USA.
Keywords: New York, New York, United States, Biotechnology, Diabetes, Gastroenterology, Murine Islet Transplantation and Pancreatic Islets.
This article was prepared by Science Letter editors from staff and other reports. Copyright 2006, Science Letter via NewsRx.com.
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