Intraportal Infusion Research Articles

Rescue of a Pancreatic Islet Graft After Steroid Therapy

Rescue of a Pancreatic Islet Graft After Steroid Therapy

Blood Flow in Endogenous and Transplanted Pancreatic Islets in Anesthetized Rats

The objective of this study was to evaluate the effects of exogenously administered lactate and pyruvate on blood perfusion in endogenous and transplanted islets. Anesthetized Wistar-Furth rats were given lactate or pyruvate intravenously, and regional blood perfusion was studied 3 or 30 minutes later with a microsphere technique. Separate rats received a 30-minute infusion of pyruvate or lactate into the portal vein before blood flow measurements. We also administered these substances to islet-implanted rats 4 weeks after transplantation and measured graft blood flow with laser Doppler flowmetry. The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was analyzed. The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was markedly up-regulated in transplanted as compared with endogenous islets. Administration of pyruvate, but not lactate, increased mesenteric blood flow after 3 minutes. Pyruvate decreased mesenteric blood flow after 30 minutes, whereas lactate decreased only islet blood flow. These responses were absent in transplanted animals. A continuous intraportal infusion of lactate or pyruvate increased selectively islet blood flow but did not affect blood perfusion of transplanted islets. Lactate and pyruvate affect islet blood flow through effects mediated by interactions between the liver and the nervous system. Such a response can help adjust the release of islet hormones during excess substrate concentrations.

Donor Dendritic Cell Proliferation and Migration in Hepatic Allografts by Pretransplant Intraportal Infusion of Recipient Blood into Donor Rats

Introduction We have reported that recipient blood transfusion pretransplant prolongs hepatic allograft survival in rats. This study further investigated the mechanisms of the phenomenon. Materials and methods Male LEW and ACI rats were used as liver transplant recipients and donors, respectively. Experimental animals were divided into control; treatment experimental; and intraportally transfused (1 mL recipient blood) at 7 days before transplantation. Results Rat survival time was significantly longer among the experiment versus the control group. A large number of donor-source dendritic cells were detected among infiltrating cells in the liver and spleen in the experimental group. Conclusion We concluded that the prolonged survival of hepatic allograft in these rats was associated with donor dendritic cell proliferation and migration.

Preclinical evaluation of a 68Ga-labeled biotin analogue for applications in islet transplantation

Islet transplantation is a promising treatment for type 1 diabetes mellitus, but the fate of the cells after intraportal infusion is unclear. It is therefore imperative to develop novel techniques for noninvasive imaging and quantification of events following islet transplantation. Small islet-like microbeads, avidin-covered agarose resins (AARs), were used as a model system for islet transplantation. Capability for specific [(68)Ga]Ga-DOTA-(PEG)(2)-biotin uptake and retention for either AARs or human islets conjugated with avidin by means of a heparin scaffold was studied in vitro. Biodistribution of the novel positron emission tomography (PET) tracer [(68)Ga]Ga-DOTA-(PEG)(2)-biotin was evaluated in mice treated by intraportal transplantation of AARs by μPET/computed tomography and ex vivo organ distribution and compared with control mice. AARs had high capability to bind [(68)Ga]Ga-DOTA-(PEG)(2)-biotin, close to 50% of administrated tracer/μl in vitro (>0.25 MBq/μl). Avidin-tagged human islets could bind on average 2.2% of administered tracer/μl. Specificity (>90%) and retention (>90% after 1 h) were high for both AARs and avidin-tagged islets. Hepatic tracer uptake and retention were increased in mice transplanted with AARs [standardized uptake value (SUV)=2.6] compared to the untreated group (SUV=1.4). In vivo uptake of tracer to AARs was blocked by preadministration of unlabeled biotin. Avidin-tagged islet-like objects can be tracked in hepatic volume after intraportal transplantation by using [(68)Ga]Ga-DOTA-(PEG)(2)-biotin and PET.

α‐Lipoic acid prevents mild portal endotoxaemia‐induced hepatic inflammation and β cell dysfunction

This study was undertaken to evaluate the preventive effect of α-lipoic acid (LA) on chronic mild portal endotoxaemia-mediated subacute hepatic inflammation and pancreatic β cell dysfunction in rats. Male Sprague-Dawley rats were randomly assigned into four groups: those with intraportal vehicle (saline) or low-dose lipopolysaccharide (LPS) (0·42 ng/kg/min) infusion, combined with oral administration of vehicle or LA, a potent antioxidant (60 mg/kg/day) for 4 weeks. The hyperglycaemic clamp and euglycaemic clamp techniques were used to access the glucose-stimulated insulin secretion and systemic insulin sensitivity in vivo. Body weight, fasting plasma glucose and insulin were not different among groups. In rats with chronic intraportal LPS infusion, plasma C-reactive protein, amylase, superoxide levels, the contents of thiobarbituric acid-reactive substance, tumour necrosis factor α and interleukin 6 in liver and pancreas and also the gene expression of Toll-like receptor 4 in liver were significantly increased as compared with those with LA cotreatment. The histopathological examination showed that inflammatory changes were clearly visible in liver and pancreatic islets of LPS-infused rats and rarely observed in those cotreated with LA. In addition, low-dose intraportal LPS infusion also significantly impaired glucose-stimulated insulin secretion but not affect the systemic insulin sensitivity and metabolic clearance rate of insulin. LA administration markedly reversed LPS-induced β cell dysfunction. α-Lipoic acid cotreatment could significantly prevent mild portal endotoxaemia-induced chronic hepatic inflammation and impaired pancreatic insulin secretion in absence of changing systemic insulin resistance.

Block by Nitrate Tolerance of Meal-Induced Insulin Sensitization in Conscious Rabbits

Hemodynamic nitrate tolerance has been shown to result in an insulin-resistant state. We studied whether nitrate tolerance induced by a 7-day continuous exposure to transdermal nitroglycerin influenced the meal-induced insulin sensitization phenomenon in rabbits. Changes in insulin sensitivity in response to feeding in conscious rabbits were determined by rapid insulin sensitivity test, in both nitrate-tolerant and nitrate-intolerant animals. In a separate series of experiments with anesthetized rabbits with or without nitrate tolerance, the hyperinsulinemic euglycemic glucose clamping methods was used to study the effect of intraportal infusion of cholecystokinin (CCK) on whole-body insulin sensitivity. Rabbits with normal feeding exhibited a 46 ± 6% increase in insulin sensitivity as compared with their matching fasting controls. A 7-day period of treatment with patches releasing 0.07 mg of nitroglycerin per hour yielded nitrate tolerance and a state of insulin resistance and no increase in insulin sensitivity in response to food. Intraportal infusion of CCK8 (0.3-3.0 μg/kg over 20 minutes) resulted in a dose-dependent increase in insulin sensitivity in normal but not in nitrate-tolerant, fasted anesthetized animals. Nitrate tolerance blocks both the meal-induced insulin sensitization phenomenon and the insulin-sensitizing effect of intraportal CCK.

Imaging the islet graft by positron emission tomography

Clinical islet transplantation is being investigated as a permanent cure for type 1 diabetes mellitus (T1DM). Currently, intraportal infusion of islets is the favoured procedure, but several novel implantation sites have been suggested. Noninvasive longitudinal methodologies are an increasingly important tool for assessing the fate of transplanted islets, their mass, function and early signs of rejection. This article reviews the approaches available for islet graft imaging by positron emission tomography and progress in the field, as well as future challenges and opportunities.

A comparison of islet autotransplantation with allotransplantation and factors elevating acute portal pressure in clinical islet transplantation

Acute portal pressure rise is occasionally observed during intraportal islet infusion, especially in islet autotransplantation (IAT) where tissue purification is rarely applied. In this paper we investigate factors associated with acute portal pressure rise, a known risk factor for portal vein thrombosis. Retrospective data was collected on 15 islet autotransplant and 122 allogeneic islet transplant subjects. Non-purified pancreatic cells were transplanted in islet autotransplants, and purified islet cells were transplanted in allogeneic transplants. Portal pressure was documented throughout the islet infusion. The total numbers of transplanted islets were significantly smaller in autotransplants than allografts, although the packed cell volume in autotransplants was larger. Autoislet infusion, with a larger packed cell volume, caused higher transient portal venous pressures than allogeneic islet transplant. Univariate analysis and multivariate linear regression revealed that packed cell volume and the number of transplanted cells were significant risk factors for acute portal pressure rise in both autotransplants and allogeneic transplants. Non-purified IAT has a higher risk for acute portal pressure rise than allogeneic islet transplantation, and the rise is associated with the packed cell volume and the number of transplanted cells. Minimization of packed cell volume and cautious monitoring of portal pressure are important to avoid potential complications of portal hypertension.

Increased numbers of low-oxygenated pancreatic islets after intraportal islet transplantation.

OBJECTIVENo previous study has measured the oxygenation of intraportally transplanted islets, although recent data suggest that insufficient engraftment may result in hypoxia and loss of islet cells.RESEARCH DESIGN AND METHODSAfter intraportal infusion into syngeneic mice, islet oxygenation was investigated in 1-day-old, 1-month-old, or 3-month-old grafts and compared with renal subcapsular grafts and native islets. Animals received an intravenous injection of pimonidazole for immunohistochemical detection of low-oxygenated islet cells (pO2 <10 mmHg), and caspase-3 immunostaining was performed to assess apoptosis rates in adjacent tissue sections.RESULTSIn the native pancreas of nontransplanted animals, ∼30% of the islets stained positive for pimonidazole. In 1-day-old and 1-month-old grafts, the percentage of pimonidazole-positive islets in the liver was twice that of native islets, whereas this increase was abolished in 3-month-old grafts. Beneath the renal capsule, pimonidazole accumulation was, however, similar to native islets at all time points. Apoptosis rates were markedly increased in 1-day-old intrahepatic grafts compared with corresponding renal islet grafts, which were slightly increased compared with native islets. One month posttransplantation renal subcapsular grafts had similar frequencies of apoptosis as native islets, whereas apoptosis in intraportally implanted islets was still high. In the liver, islet graft vascular density increased between 1 and 3 months posttransplantation, and apoptosis rates simultaneously dropped to values similar to those observed in native islets.CONCLUSIONSThe vascular engraftment of intraportally transplanted islets is markedly delayed compared with renal islet grafts. The prolonged ischemia of intraportally transplanted islets may favor an alternative implantation site.

Alternative Transplantation Sites for Pancreatic Islet Grafts

The liver is the current site of choice for pancreatic islet transplantation, even though it is far from being an ideal site because of immunologic, anatomic, and physiologic factors leading to a significant early graft loss. A huge amount of alternative sites have been used for islet transplantation in experimental animal models to provide improved engraftment and long-term survival minimizing surgical complications. The pancreas, gastric submucosa, genitourinary tract, muscle, omentum, bone marrow, kidney capsule, peritoneum, anterior eye chamber, testis, and thymus have been explored. Site-specific differences exist in term of islet engraftment, but few alternative sites have potential clinical translation and generally the evidence of a post-transplant islet function better than that reached after intraportal infusion is still lacking. This review discusses site-specific benefits and drawbacks taking into account immunologic, metabolic, and technical aspects to identify the ideal microenvironment for islet function and survival.

Effect of intraportal infusion of tacrolimus on ischaemic reperfusion injury in orthotopic liver transplantation: a randomized controlled trial

The increased use of older and/or marginal donor organs in liver transplantation over the last decade calls for strategies to minimize ischaemic reperfusion (I/R) injury to prevent early graft failure. Tacrolimus, a very potent and effective calcineurin inhibitor, was selected because of its ability to ameliorate I/R injury. A randomized, blinded, controlled single-centre trial of 26 liver transplant recipients was performed between February 2008 and December 2009. Donor organs were randomized to be perfused intraportally during liver transplantation with 1.5 l 5% albumin infusion containing either 20 ng/ml tacrolimus or placebo. The primary end point was liver function as assessed by aspartate transaminase (AST) or alanine transaminase (ALT) levels 6 days after transplantation. Treatment effectiveness was tested by transcriptome-wide analysis of biopsies. There was no difference in the primary end point, i.e. AST (IU/l) and ALT (IU/l) at day 6 after transplantation between groups. Furthermore, choleastatic parameters as well as parameters of liver synthesis were not different between groups. However, tacrolimus treatment suppressed inflammation and immune response in the transplanted liver on a genome-wide basis. Intrahepatic administration of tacrolimus did not result in a reduction of AST and ALT within the first week after transplantation.

Effect of the regulation of retinoid X receptor‐α gene expression on rat hepatic fibrosis

To study the effect of retinoid X receptor-α (RXR-α) expression on rat hepatic fibrosis. Rat hepatic fibrosis was induced by CCl(4) , and the rats were randomly divided into an early-phase hepatic fibrosis group (2 weeks) and a sustained hepatic fibrosis group (8 weeks). They were then divided into four groups (normal control, hepatic fibrosis, negative control and RXR-α groups). A recombinant lentiviral expression vector carrying the rat RXR-α gene was injected into the rats to induce RXR-α expression by intraportal infusion, hepatic tissue pathological examination was performed, and hydroxyproline content was detected. Hepatic stellate cells (HSC) were cultured in vitro, an RXR-α lentivirus vector was used to activate HSC, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) activation was assayed to detect HSC proliferation. In vivo experiments indicated that in the sustained hepatic fibrosis group, there were significant differences in the hydroxyproline content, and expression of RXR-α, α-smooth muscle actin (α-SMA) and type I collagen (P < 0.01). However, in the early-phase hepatic fibrosis group, hydroxyproline content and the protein level of RXR-α showed no significant difference compared with the normal control group (P > 0.05). In vitro studies revealed that expression of RXR-α significantly inhibited expression of α-SMA and type I collagen in activated HSC (P < 0.01), as well as HSC proliferation (P < 0.01). The increased RXR-α gene expression inhibited HSC activation and proliferation and the degree of hepatic fibrosis.

Pharmacokinetic assessment of the sites of first-pass metabolism of BMS-181101, an antidepressant agent, in rats.

The relative contribution of the gut and the liver to the first-pass metabolism of BMS-181101 (3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-5-fluoro-1H-ind ole dihydrochloride), a potential antidepressant agent, has been evaluated in rats. Nine male Sprague-Dawley rats were divided into three groups of three and each rat received a single 20 mg kg(-1) dose of [14C]BMS-181101 via a 30 min constant-rate intravenous infusion, a 30-min constant-rate intraportal infusion or oral gavage. Serial blood samples were collected for 8 h after dosing and plasma was analysed for unchanged BMS-181101 and total radioactivity. Extraction ratios for BMS-181101 by the gut and liver were calculated on the basis of ratios of the area under the plasma BMS-181101 concentration-time curve. The gut had a high intrinsic capacity for metabolizing BMS-181101-extraction ratios were 93% and 10% for the gut and liver, respectively. After oral administration BMS-181101 is sequentially exposed to the gut then the liver. As a result, the contribution of the gut to the overall first-pass effect (ca. 93%) was significantly greater than that of the liver (ca. 0.7%). The estimated total first-pass effect of 94% for BMS-181101 in rats is in excellent agreement with the observed absolute oral bioavailability of 6%. These results clearly illustrate the importance of metabolic activity in the gut for orally administered BMS-181101.

Permanent protection of PLG scaffold transplanted allogeneic islet grafts in diabetic mice treated with ECDI-fixed donor splenocyte infusions

Allogeneic islet cell transplantation is a promising treatment for human type 1 diabetes. Currently, human islets are transplanted via intra-portal infusions. While successful, it leads to significant early islet attrition from instant blood-mediated inflammatory reaction. An extra-hepatic site was established by transplanting islet-loaded microporous poly(lactide-co-glycolide) (PLG) scaffolds into the epididymal fat pad in syngeneic islet transplant models. This study examined this technology in allogeneic islet transplantation and determined whether transplant tolerance could be effectively induced to protect PLG scaffold transplanted allogeneic islets. The efficacy of an established tolerance induction strategy using donor splenocytes treated with ethylcarbodiimide(ECDI) was tested. ECDI-fixed donor splenocytes were infused 7 days before and 1 day after islet transplantation. Immediate normoglycemia was restored, and treated mice maintained indefinite normoglycemia whereas untreated mice rejected islet grafts within 20 days of transplantation. Interestingly, efficacy of tolerance induction was superior in PLG scaffold compared with intra-portal transplanted islets. Protection of PLG scaffold islet allografts was associated with several mechanisms of immune regulation. In summary, PLG scaffolds can serve as an alternative delivery system for islet transplantation that does not impair tolerance induction. This approach of combining tolerance induction with scaffold islet transplantation has potential therapeutic implications for human islet transplantation.

Elucidating the mechanism of glucagon‐like peptide‐1 for glucose utilization during periods of fasting

Glucagon-like peptide-1 (GLP-1), an insulinotropic hormone, is a target for novel therapies for the treatment of type 2 diabetes mellitus (T2DM). Insulin resistance is a characteristic of T2DM and is evident, to a lesser extent, under fasted conditions. We have previously shown that intraportal infusion of GLP-1, in combination with intraportal glucose infusion, increases whole body glucose uptake without changing pancreatic hormone levels in 42-hour fasted dogs. To evaluate GLP-1's effect under various conditions of insulin sensitivity, we infused GLP-1 and glucose intraportally into 18-hour fasted dogs. Under these conditions, there was no change in glucose uptake in the presence of GLP-1, compared to glucose infusion alone. Receptor expression could be a contributing factor to the increase in glucose utilization after longer periods of fasting. To evaluate this mechanism, GLP-1 receptor expression was examined in murine pancreatic, liver, heart, small intestine, and skeletal muscle tissue using a Western blot to quantify the differences in GLP-1 receptor expression in these tissues under fasted conditions. Preliminary results indicate that GLP-1 receptor expression changes over the course of a prolonged fast (24 hours), suggesting a possible mechanism for our in vivo findings. This study was supported by the NIH, Grant R01 DK-43706, and the Beloit College Biomedical Research Fellows Program.

Hepatic Glycogen Supercompensation Activates AMP-Activated Protein Kinase, Impairs Insulin Signaling, and Reduces Glycogen Deposition in the Liver

OBJECTIVEThe objective of this study was to determine how increasing the hepatic glycogen content would affect the liver’s ability to take up and metabolize glucose.RESEARCH DESIGN AND METHODSDuring the first 4 h of the study, liver glycogen deposition was stimulated by intraportal fructose infusion in the presence of hyperglycemic-normoinsulinemia. This was followed by a 2-h hyperglycemic-normoinsulinemic control period, during which the fructose infusion was stopped, and a 2-h experimental period in which net hepatic glucose uptake (NHGU) and disposition (glycogen, lactate, and CO2) were measured in the absence of fructose but in the presence of a hyperglycemic-hyperinsulinemic challenge including portal vein glucose infusion.RESULTSFructose infusion increased net hepatic glycogen synthesis (0.7 ± 0.5 vs. 6.4 ± 0.4 mg/kg/min; P < 0.001), causing a large difference in hepatic glycogen content (62 ± 9 vs. 100 ± 3 mg/g; P < 0.001). Hepatic glycogen supercompensation (fructose infusion group) did not alter NHGU, but it reduced the percent of NHGU directed to glycogen (79 ± 4 vs. 55 ± 6; P < 0.01) and increased the percent directed to lactate (12 ± 3 vs. 29 ± 5; P = 0.01) and oxidation (9 ± 3 vs. 16 ± 3; P = NS). This change was associated with increased AMP-activated protein kinase phosphorylation, diminished insulin signaling, and a shift in glycogenic enzyme activity toward a state discouraging glycogen accumulation.CONCLUSIONSThese data indicate that increases in hepatic glycogen can generate a state of hepatic insulin resistance, which is characterized by impaired glycogen synthesis despite preserved NHGU.

本邦における膵臓外科の歴史と私の経験

The first case of pancreatoduodenectomy(PD) in Japan was done by Kuru in 1946, then Yoshioka in 1947, and then Honjyo performed a total pancreatectomy in 1949. Portal vein resection combined with PD was reported by Kikuchi in 1956 and by Asada in 1963. They used 70% alcohol-preserved homograft of the vein. Fortner's report of regional pancreatectomy in 1973 greatly impressed Japanese pancreatic surgeons. Then in 1981, I developed my own catheter-bypass method of the portal vein using antithrombogenic material. The isolated pancreatoduodenectomy combined with portal vein resection was completed. This bypass method made it possible to prevent portal congestion or hepatic ischemia during portal vein resection or simultaneous resection of the hepatic artery. Thus, vascular resection has become safer and easier during pancreatic surgery. Extended radical pancreatic resection was developed during the 1970s and 1980s. The high mortality rate of PD in the 1950s and 1960s decreased gradually to within 10% in the 1980s and 5% in the 1990s. Hanyu had performed a landmark 1000 PDs in 1997, and the mortality rate has been 1% since 1989. We have performed 825 pancreatic resections, for various diseases since 1981 and mortality was observed in 14 cases (1.7%). Moreover 441 pancreatic resections for pancreatic cancer along with combined resection of the portal vein were performed in 282 cases during 1981-2009. The mortality rate of PD for pancreatic cancer was 2.7% in my series, but no mortality has been experienced in the last 11 years. However, the prognosis for pancreatic cancer is still poor and adjuvant therapy has been combined with radical surgery such as intraoperative radiotherapy using linac, and intraportal continuous infusion of 5-FU. Adjuvant chemotherapy using gemcitabine or TS-1 and clinical trial of oncolytic virus therapy using herpes simplex virus (HF10) have been performed, yet numerous problems remained to be solved. I have devised techniques such as isolated pancreatoduodenectomy combined with portal vein resection using catheter-bypass method for the portal vein and a mesenteric approach and pancreatic head resection with segmental duodenectomy(PHRSD) for IPMN. Every day I still feel great pleasure and a sense of fulfillment in performing surgery. Surgeons are able to care for patients all the way from diagnosis and surgery through postoperative management and follow-up after the patient leaves the hospital. This sense of accomplishment is truly great, and it is a specialty that I believe we should be sure to pass down to younger people. Let me say that I am filled with gratitude to my colleagues and the younger doctors I have worked with in medical practice and research.

Hepatic flow optimization in full right split liver transplantation

Split liver transplantation for two adults offers a valuable opportunity to expand the donor pool for adult recipients. However, its application is mainly hampered by the physiological limits of these partial grafts. Small for size syndrome is a major concern during transplantation with partial graft and different techniques have been developed in living donor liver transplantation to prevent the graft dysfunction. Herein, we report the first application of synergic approaches to optimise the hepatic hemodynamic in a split liver graft for two adults. A Caucasian woman underwent liver transplantation for alcoholic cirrhosis (MELD 21) with a full right liver graft (S5-S8) without middle hepatic vein. Minor and accessory inferior hepatic veins were preserved by splitting the vena cava; V5 and V8 were anastomosed with a donor venous iliac patch. After implantation, a 16G catheter was advanced in the main portal trunk. Inflow modulation was achieved by splenic artery ligation. Intraportal infusion of PGE1 was started intraoperatively and discontinued after 5 d. Graft function was immediate with normalization of liver test after 7 d. Nineteen months after transplantation, liver function is normal and graft volume is 110% of the recipient standard liver volume. Optimisation of the venous outflow, inflow modulation and intraportal infusion of PGE1 may represent a valuable synergic strategy to prevent the graft dysfunction and it may increase the safety of split liver graft for two adults.

Combined Pancreatic Islets–Lung Transplantation in Cystic Fibrosis-Related Diabetes: Case Reports

We report two cases of percutaneous portal embolization of pancreatic islets performed after double lung transplantation in cystic fibrosis (CF) patients using the pancreas of the same donor. Case 1 A 19-year-old man with CF had insulin-dependent diabetes, which was poorly controlled despite an external insulin pump (96 IU/d): HbA 1c = 9.8% and 1 to 3 hypoglycemic events per day. On October 29, 2007, he received a double lung graft because of chronic respiratory failure. For days after lung transplantation, 149,000 cultured IEQ (Islet EQuivalent) were injected by percutaneous intraportal infusion under local anesthesia. Immunosuppression consisted of steroids, cyclosporine, and azathioprine. Two years later, the forced expiratory volume (FEV) was 83%; C peptide level reached 1.4 μg/L, and the diabetes was satisfactorily controlled with an HbA 1c of 7.5% and a decrease in insulin requirements to 30 U/d in the absence of hypoglycemic events. Case 2 On July 10, 2006, a 32-year-old man with CF-related diabetes received a double lung graft because of chronic respiratory failure. Under multiple insulin injections, the HbA 1c was 9.6% with numerous hypoglycemic events. On March 11, 2008, he again received a double lung graft because of persistent humoral rejection. Despite severe bleeding during the postoperative course, 234,000 IEQ were injected via the portal vein one week after lung transplantation. Immunosuppression consisted of steroids, tacrolimus, and mycophenolate mofetil. Eighteen months after the combined graft, the FEV was 52%; the plasma C-peptide reached 0.79 μg/L, the HbA 1c, 6% and the insulin requirements decreased to 55 U/d in the absence of hypoglycemic events. Conclusion Combined lung–islet transplantation for patients with CF-related diabetes improved pulmonary and metabolic function.

Monitoring of Liver Cell Transplantation in a Preclinical Swine Model Using Magnetic Resonance Imaging.

Liver cell transplantation (LCT) is a promising treatment approach for certain liver diseases, but clinical implementation requires methods for noninvasive follow-up. Labeling with superparamagnetic iron oxide particles can enable the detection of cells with magnetic resonance imaging (MRI). We investigated the feasibility of monitoring transplanted liver cells by MRI in a preclinical swine model and used this approach to evaluate different routes for cell application. Liver cells were isolated from landrace piglets and labeled with micron-sized iron oxide particles (MPIO) in adhesion. Labeled cells (n = 10), native cells (n = 3), or pure particles (n = 4) were transplanted to minipigs via intraportal infusion into the liver, direct injection into the splenic parenchyma, or intra-arterial infusion to the spleen. Recipients were investigated by repeated 3.0 Tesla MRI and computed tomography angiography up to 8 weeks after transplantation. Labeling with MPIO, which are known to have a strong effect on the magnetic field, enabled noninvasive detection of cell aggregates by MRI. Following intraportal application, which is commonly applied for clinical LCT, MRI was able to visualize the microembolization of transplanted cells in the liver that were not detected by conventional imaging modalities. Cells directly injected into the spleen were retained, whereas cell infusions intra-arterially into the spleen led to translocation and engraftment of transplanted cells in the liver, with significantly fewer microembolisms compared to intraportal application. These findings demonstrate that MRI can be a valuable tool for noninvasive elucidation of cellular processes of LCT and-if clinically applicable MPIO are available-for monitoring of LCT under clinical conditions. Moreover, the results clarify mechanisms relevant for clinical practice of LCT, suggesting that the intra-arterial route to the spleen deserves further evaluation.