The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy ...determines durability of insulin independence. We analyzed the proportion of insulin‐independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti‐CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF‐α inhibition (TNF‐α‐i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF‐α‐i (group 2; n = 20); CITR recipients given TCDAb without TNF‐α‐i (group 3; n = 43); and CITR recipients given IL‐2 receptor antibodies (IL‐2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5‐year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5‐year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long‐term insulin independence after ITA using potent induction therapy, with anti‐CD3 Ab or TCDAb+TNF‐α‐i.
Islet transplant recipients who receive induction immunosuppression with one of several depletional antibody preparations are more likely to exhibit long‐term insulin independence at 3 and 5 years posttransplant than patients who do not receive depletional induction therapy based on data from the Collaborative Islet Transplant Registry.
The simple question of how much tissue volume (TV) is really safe to infuse in total pancreatectomy–islet autotransplantation (TP–IAT) for chronic pancreatitis (CP) precipitated this analysis. We ...examined a large cohort of CP patients (n = 233) to determine major risk factors for elevated portal pressure (PP) during islet infusion, using bivariate and multivariate regression modeling. Rates of bleeding requiring operative intervention and portal venous thrombosis (PVT) were evaluated. The total TV per kilogram body weight infused intraportally was the best independent predictor of change in PP (ΔPP) (p < 0.0001; R2 = 0.566). Rates of bleeding and PVT were 7.73% and 3.43%, respectively. Both TV/kg and ΔPP are associated with increased complication rates, although ΔPP appears to be more directly relevant. Receiver operating characteristic analysis identified an increased risk of PVT above a suggested cut‐point of 26 cmH2O (area under the curve = 0.759), which was also dependent on age. This ΔPP threshold was more likely to be exceeded in cases where the total TV was >0.25 cm3/kg. Based on this analysis, we have recommended targeting a TV of <0.25 cm3/kg during islet manufacturing and to halt intraportal infusion, at least temporarily, if the ΔPP exceeds 25 cmH2O. These models can be used to guide islet manufacturing and clinical decision making to minimize risks in TP–IAT recipients.
This study describes an analysis of major risk factors that influence complications due to islet autotransplantation following total pancreatectomy and recommends thresholds for tissue volume infusion and changes in portal pressure.
The Collaborative Islet Transplant Registry (CITR) collects data on clinical islet isolations and transplants. This retrospective report analyzed 1017 islet isolation procedures performed for 537 ...recipients of allogeneic clinical islet transplantation in 1999–2010. This study describes changes in donor and islet isolation variables by era and factors associated with quantity and quality of final islet products. Donor body weight and BMI increased significantly over the period (p < 0.001). Islet yield measures have improved with time including islet equivalent (IEQ)/particle ratio and IEQs infused. The average dose of islets infused significantly increased in the era of 2007–2010 when compared to 1999–2002 (445.4 ± 156.8 vs. 421.3 ± 155.4 ×103 IEQ; p < 0.05). Islet purity and total number of β cells significantly improved over the study period (p < 0.01 and <0.05, respectively). Otherwise, the quality of clinical islets has remained consistently very high through this period, and differs substantially from nonclinical islets. In multivariate analysis of all recipient, donor and islet factors, and medical management factors, the only islet product characteristic that correlated with clinical outcomes was total IEQs infused. This analysis shows improvements in both quantity and some quality criteria of clinical islets produced over 1999–2010, and these parallel improvements in clinical outcomes over the same period.
Product criteria from clinical grade allogeneic human islets exhibit consistently superior‐quality characteristics and significantly increasing islet equivalent yield, paralleling improving success rates of islet transplantation for type I diabetes.
The promise and progress of islet transplantation for treating type 1 diabetes has been challenged by obstacles to patient accessibility and long-term graft function that may be overcome by ...integrating emerging technologies in biomaterials, drug delivery and immunomodulation. The hepatic microenvironment and traditional systemic immunosuppression stress the vulnerable islets and contribute to the limited success of transplantation. Locally delivering extracellular matrix proteins and trophic factors can enhance transplantation at extrahepatic sites by promoting islet engraftment, revascularisation and long-term function while avoiding unintended systemic effects. Cell- and cytokine-based therapies for immune cell recruitment and reprogramming can inhibit local and systemic immune system activation that normally attacks transplanted islets. Combined with antigen-specific immunotherapies, states of operational tolerance may be achievable, reducing or eliminating the long-term pharmaceutical burden. Integration of these technologies to enhance engraftment and combat rejection may help to advance the therapeutic efficacy and availability of islet transplantation.
We sought to determine the long‐term outcomes in type 1 diabetic recipients of intraportal alloislet transplants on a modified immunosuppressive protocol. Six recipients with hypoglycemia unawareness ...received one to two islet infusions. Induction therapy was with antithymocyte globulin (ATG) plus etanercept for tumor necrosis factor‐α blockade. Recipients received cyclosporine and everolimus for maintenance immunosuppression for the first year posttransplant, with mycophenolic acid or mycophenolate mofetil subsequently substituted for everolimus. Recipients have been followed for 1173 ± 270 days since their last infusion for islet graft function (insulin independence, hemoglobin A1c levels and C‐peptide production) and for adverse events associated with the study protocol. Of the six recipients, five were insulin‐independent at 1 year, and four continue to be insulin‐independent at a mean of 3.4 ± 0.4 years posttransplant. None of the six recipients experienced recurrence of severe hypoglycemia. Measured glomerular filtration rate decreased from 110.5 ± 21.2 mL/min/1.73 m2 pretransplant to 82.6 ±19.1 mL/min/1.73 m2 at 1 year posttransplant. In conclusion, islet transplants restored insulin independence for a mean of >3 years in four of six recipients treated with ATG and etanercept induction therapy and with cyclosporine and, initially, everolimus for maintenance. Our results suggest this immunosuppressive protocol may allow long‐term graft survival.
In 4 of 6 type 1 diabetic islet allotransplant recipients treated with ATG and etanercept induction therapy and with cyclosporine and, initially, everolimus for maintenance, insulin independence was maintained for a mean of >3 years.
The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive ...regimen using the antileukocyte functional antigen‐1 antibody efalizumab which permits long‐term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single‐islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long‐term follow‐up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid‐free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long‐term islet allograft survival.
An immunosuppressive regimen based on the anti‐LFA‐1 antibody efalizumab showed some promising results in eight islet transplant recipients. See Editorial by Oberholzer et al 1725.
In this paper we report chemically resolved measurements of organic aerosol (OA) and related tracers during the Biosphere Effects on Aerosols and Photochemistry Experiment (BEARPEX) at the Blodgett ...Forest Research Station, California from 15 August–10 October 2007. OA contributed the majority of the mass to the fine atmospheric particles and was predominately oxygenated (OOA). The highest concentrations of OA were during sporadic wildfire influence when aged plumes were impacting the site. In situ measurements of particle phase molecular markers were dominated by secondary compounds and along with gas phase compounds could be categorized into six factors or sources: (1) aged biomass burning emissions and oxidized urban emissions, (2) oxidized urban emissions (3) oxidation products of monoterpene emissions, (4) monoterpene emissions, (5) anthropogenic emissions and (6) local methyl chavicol emissions and oxidation products. There were multiple biogenic components that contributed to OA at this site whose contributions varied diurnally, seasonally and in response to changing meteorological conditions, e.g. temperature and precipitation events. Concentrations of isoprene oxidation products were larger when temperatures were higher during the first half of the campaign (15 August–12 September) due to more substantial emissions of isoprene and enhanced photochemistry. The oxidation of methyl chavicol, an oxygenated terpene emitted by ponderosa pine trees, contributed similarly to OA throughout the campaign. In contrast, the abundances of monoterpene oxidation products in the particle phase were greater during the cooler conditions in the latter half of the campaign (13 September–10 October), even though emissions of the precursors were lower, although the mechanism is not known. OA was correlated with the anthropogenic tracers 2-propyl nitrate and carbon monoxide (CO), consistent with previous observations, while being comprised of mostly non-fossil carbon (>75%). The correlation between OA and an anthropogenic tracer does not necessarily identify the source of the carbon as being anthropogenic but instead suggests a coupling between the anthropogenic and biogenic components in the air mass that might be related to the source of the oxidant and/or the aerosol sulfate. Observations of organosulfates of isoprene and α-pinene provided evidence for the likely importance of aerosol sulfate in spite of neutralized aerosol although acidic plumes might have played a role upwind of the site. This is in contrast to laboratory studies where strongly acidic seed aerosols were needed in order to form these compounds. These compounds together represented only a minor fraction (<1%) of the total OA mass, which may be the result of the neutralized aerosol at the site or because only a small number of organosulfates were quantified. The low contribution of organosulfates to total OA suggests that other mechanisms, e.g. NOx enhancement of oxidant levels, are likely responsible for the majority of the anthropogenic enhancement of biogenic secondary organic aerosol observed at this site.
There is a need for simple, quantitative and prospective assays for islet quality assessment that are predictive of islet transplantation outcome. The current state‐of‐the‐art athymic nude mouse ...bioassay is costly, technically challenging and retrospective. In this study, we report on the ability of 2 parameters characterizing human islet quality: (1) oxygen consumption rate (OCR), a measure of viable volume; and (2) OCR/DNA, a measure of fractional viability, to predict diabetes reversal in nude mice. Results demonstrate that the probability for diabetes reversal increases as the graft's OCR/DNA and total OCR increase. For a given transplanted OCR dose, diabetes reversal is strongly dependent on OCR/DNA. The OCR and OCR/DNA (the ‘OCR test’) data exhibit 89% sensitivity and 77% specificity in predicting diabetes reversal in nude mice (n = 86). We conclude that the prospective OCR test can effectively replace the retrospective athymic nude mouse bioassay in assessing human islet quality prior to islet transplantation.
When combined, the total viable amount and the fractional viability of transplanted human islet tissue, estimated based on Oxygen Consumption Rate and DNA measurements, predict diabetes reversal in diabetic nude mice and thus can be used as a real‐time predictor islet potency assay.
Islet autotransplant (IAT) may ameliorate postsurgical diabetes following total pancreatectomy (TP), but outcomes are dependent upon islet mass, which is unknown prior to pancreatectomy. We evaluated ...whether preoperative metabolic testing could predict islet isolation outcomes and thus improve assessment of TPIAT candidates. We examined the relationship between measures from frequent sample IV glucose tolerance tests (FSIVGTT) and mixed meal tolerance tests (MMTT) and islet mass in 60 adult patients, with multivariate logistic regression modeling to identify predictors of islet mass ≥2500 IEQ/kg. The acute C‐peptide response to glucose (ACRglu) and disposition index from FSIVGTT correlated modestly with the islet equivalents per kilogram body weight (IEQ/kg). Fasting and MMTT glucose levels and HbA1c correlated inversely with IEQ/kg (r values −0.33 to −0.40, p ≤ 0.05). In multivariate logistic regression modeling, normal fasting glucose (<100 mg/dL) and stimulated C‐peptide on MMTT ≥4 ng/mL were associated with greater odds of receiving an islet mass ≥2500 IEQ/kg (OR 0.93 for fasting glucose, CI 0.87–1.0; OR 7.9 for C‐peptide, CI 1.75–35.6). In conclusion, parameters obtained from FSIVGTT correlate modestly with islet isolation outcomes. Stimulated C‐peptide ≥4 ng/mL on MMTT conveyed eight times the odds of receiving ≥2500 IEQ/kg, a threshold associated with reasonable metabolic control postoperatively.
In adult patients with chronic pancreatitis undergoing total pancreatectomy and islet autotransplant, the authors show that metabolic testing performed prior to transplant is modestly helpful in predicting which patients are likely to have at least a moderate islet mass isolated for transplant.
Animal donors such as pigs could provide an alternative source of organs
for transplantation. However, the promise of xenotransplantation is offset
by the possible public health risk of a ...cross-species infection.
All pigs contain several copies of porcine endogenous retroviruses (PERV), and at least three variants of PERV can infect human cell lines
in vitro in co-culture, infectivity and pseudotyping experiments. Thus, if xenotransplantation of pig tissues results in
PERV viral replication, there is a risk of spreading and adaptation of
this retrovirus to the human host. C-type retroviruses related to PERV are
associated with malignancies of haematopoietic lineage cells in their natural
hosts. Here we show that pig pancreatic islets produce PERV
and can infect human cells in culture. After transplantation into NOD/SCID
(non-obese diabetic, severe combined immunodeficiency) mice, we detect ongoing
viral expression and several tissue compartments become infected. This is
the first evidence that PERV is transcriptionally active and infectious cross-species
in vivo after transplantation of pig tissues. These results show that
a concern for PERV infection risk associated with pig islet xenotransplantation
in immunosuppressed human patients may be justified.
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