Update on islet transplantation McCall, Michael; Shapiro, A M James
Cold Spring Harbor perspectives in medicine,
07/2012, Letnik:
2, Številka:
7
Journal Article
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Clinical islet transplantation has progressed considerably over the past 12 years, and >750 patients with type 1 diabetes have received islet transplants internationally over this time. Many ...countries are beginning to accept the transition from research to accepted and funded clinical care, especially for patients with brittle control that cannot be stabilized by more conventional means. Major challenges remain, including the need for more than one donor, and the requirement for potent, chronic immunosuppression. Combining immunological tolerance both to allo- and autoantigens, and a limitless expandable source of stem cell- or xenograft-derived insulin-secreting cells represent remaining hurdles in moving this effective treatment to a potential cure for all those with type 1 or 2 diabetes.
The Clinical Impact of Islet Transplantation Fiorina, P.; Shapiro, A. M. J.; Ricordi, C. ...
American journal of transplantation,
October 2008, Letnik:
8, Številka:
10
Journal Article
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Islet cell transplantation has recently emerged as one of the most promising therapeutic approaches to improving glycometabolic control in diabetic patients and, in many cases, achieving insulin ...independence. Unfortunately, many persistent flaws still prevent islet transplantation from becoming the gold standard treatment for type 1 diabetic patients. We review the state of the art of islet transplantation, outcomes, immunosuppression and—most important—the impact on patients' survival and long‐term diabetic complications and eventual alternative options. Finally, we review the many problems in the field and the challenges to islet survival after transplantation. The rate of insulin independence 1 year after islet cell transplantation has significantly improved in recent years (60% at 1 year posttransplantation compared with 15% previously). Recent data indicate that restoration of insulin secretion after islet cell transplantation is associated with an improvement in quality of life, with a reduction in hypoglycemic episodes and potentially with a reduction in long‐term diabetic complications. Once clinical islet transplantation has been successfully established, this treatment could even be offered to diabetic patients long before the onset of diabetic complications.
The authors review islet transplant outcomes and immunosuppression, and in particular the impact on patient survival and diabetic complications, as well as alternative options.
Transplantation of human islets is an attractive alternative to daily insulin injections for patients with type 1 diabetes. However, the majority of islet recipients lose graft function within five ...years. Inflammation is a primary contributor to graft loss, and inhibiting pro-inflammatory cytokine activity can reverse inflammation mediated dysfunction of islet grafts. As mesenchymal stem cells (MSCs) possess numerous immunoregulatory properties, we hypothesized that MSCs could protect human islets from pro-inflammatory cytokines. Five hundred human islets were co-cultured with 0.5 or 1.0 × 10(6) human MSCs derived from bone marrow or pancreas for 24 hours followed by 48 hour exposure to interferon-γ, tumor necrosis factor-α and interleukin 1β. Controls include islets cultured alone (± cytokines) and with human dermal fibroblasts (± cytokines). For all conditions, glucose stimulated insulin secretion (GSIS), total islet cellular insulin content, islet β cell apoptosis, and potential cytoprotective factors secreted in the culture media were determined. Cytokine exposure disrupted human islet GSIS based on stimulation index and percentage insulin secretion. Conversely, culture with 1.0 × 10(6) bMSCs preserved GSIS from cytokine treated islets. Protective effects were not observed with fibroblasts, indicating that preservation of human islet GSIS after exposure to pro-inflammatory cytokines is MSC dependent. Islet β cell apoptosis was observed in the presence of cytokines; however, culture of bMSCs with islets prevented β cell apoptosis after cytokine treatment. Hepatocyte growth factor (HGF) as well as matrix metalloproteinases 2 and 9 were also identified as putative secreted cytoprotective factors; however, other secreted factors likely play a role in protection. This study, therefore, demonstrates that MSCs may be beneficial for islet engraftment by promoting cell survival and reduced inflammation.
Screening for tuberculosis (TB) disease aims to improve early TB case detection. The ultimate goal is to improve outcomes for people with TB and to reduce Mycobacterium tuberculosis transmission in ...the community through improved case detection, reduction in diagnostic delays and early treatment. Before screening programmes are recommended, evidence is needed of individual and/or community-level benefits.
We conducted a systematic review of the literature to assess the evidence that screening for TB disease 1) initially increases the number of TB cases initiated on anti-tuberculosis treatment, 2) identifies cases earlier in the course of disease, 3) reduces mortality and morbidity, and 4) impacts on TB epidemiology.
A total of 28 798 publications were identified by the search strategy: 27 087 were excluded on initial screening and 1749 on full text review, leaving 62 publications that addressed at least one of the study questions. Screening increases the number of cases found in the short term. In many settings, more than half of the prevalent TB cases in the community remain undiagnosed. Screening tends to find cases earlier and with less severe disease, but this may be attributed to case-finding studies using more sensitive diagnostic methods than routine programmes. Treatment outcomes among people identified through screening are similar to outcomes among those identified through passive case finding. Current studies provide insufficient evidence to show that active screening for TB disease impacts on TB epidemiology.
Individual and community-level benefits from active screening for TB disease remain uncertain. So far, the benefits of earlier diagnosis on patient outcomes and transmission have not been established.
Abstract
The delivery of encapsulated islets or stem cell-derived insulin-producing cells (i.e., bioartificial pancreas devices) may achieve a functional cure for type 1 diabetes, but their efficacy ...is limited by mass transport constraints. Modeling such constraints is thus desirable, but previous efforts invoke simplifications which limit the utility of their insights. Herein, we present a computational platform for investigating the therapeutic capacity of generic and user-programmable bioartificial pancreas devices, which accounts for highly influential stochastic properties including the size distribution and random localization of the cells. We first apply the platform in a study which finds that endogenous islet size distribution variance significantly influences device potency. Then we pursue optimizations, determining ideal device structures and estimates of the curative cell dose. Finally, we propose a new, device-specific islet equivalence conversion table, and develop a surrogate machine learning model, hosted on a web application, to rapidly produce these coefficients for user-defined devices.
Regulatory T cells (Tregs) modulate alloimmune responses and may facilitate minimization or withdrawal of immunosuppression posttransplant. Current approaches, however, rely on complex ex vivo Treg ...expansion protocols. Herein, we explore endogenous in vivo Treg expansion through antibody‐mediated agonistic stimulation of the tumor necrosis factor receptor superfamily member 25 (TNFRSF25) pathway and its potential to prolong graft survival in a mouse model of islet allotransplantation. C57BL/6 male mice were treated with a single dose of TNFRSF25 agonistic antibodies (4C12 or mPTX‐35) or IgG control. Diabetes was induced using streptozotocin. Four days later, flow cytometry was completed to corroborate Treg expansion, and 500 islets (CBA/J male mice) were transplanted. Glycemia was assessed thrice weekly until rejection/endpoint. Early intra‐graft Treg infiltration was assessed 36 h posttransplant. TNFRSF25 antibodies enabled pronounced Treg expansion and treated mice had significantly prolonged graft survival compared with controls (p < .001). Additionally, the degree of Treg expansion significantly correlated with graft survival (p < .001). Immunohistochemistry demonstrated marked Treg infiltration in long‐term surviving grafts; intra‐graft Treg infiltration occurred early posttransplant. In conclusion, a single dose of TNFRSF25 antibodies enabled in vivo Treg expansion, which promotes prolonged graft survival. TNFRSF25‐mediated in vivo Treg expansion could contribute to achieving lasting immunological tolerance in organ transplantation.
In a preclinical islet transplantation model, antibody‐mediated agonistic stimulation of the Tumor Necrosis Factor Receptor Superfamily Member 25 induces pronounced in vivo T regulatory cell expansion and promotes prolonged allograft survival.
The current model of liver graft allocation in place in the United States favors transplantation of patients with small hepatocellular carcinomas (HCCs) within the Milan criteria (a single tumor up ...to 5 cm in diameter or up to three lesions, none larger than 3 cm). Although several reports have suggested that these criteria could be extended, there is currently no agreement on new selection tools. In this study, we performed an overview of 6478 adult recipients of an isolated first liver transplant registered in the Scientific Registry of Transplant Recipients (SRTR) database. From March 2002 to January 2008, increasing numbers of patients outside Milan criteria (P ≤ 0.001) have been registered for a transplant, but they still represent less than 5% of the transplants performed for HCC. Of all the tested variables (tumor number, largest tumor size, and Milan and University of California San Francisco criteria), only total tumor volume (TTV; P ≤ 0.05) and alpha fetoprotein (AFP; P ≤ 0.001) could predict patient survival. While these two parameters demonstrated independent behaviors (no patient demonstrated an increase in both values), a composite score was defined, with patients with a TTV > 115 cm3 or an AFP > 400 ng/mL being outside criteria. The combined TTV/AFP score efficiently predicted posttransplant survival (hazard ratio = 2, 95% confidence interval = 1.7‐2.4, P ≤ 0.001); patients not meeting these criteria had a survival below 50% at 3 years. Conclusion: According to the present SRTR data, Milan criteria are too restrictive, and patients with larger TTV can enjoy satisfactory posttransplant survivals. A composite patient selection score combining TTV and AFP was the most effective of all tested staging criteria for the prediction of posttransplant patient survival for candidates with HCC. (HEPATOLOGY 2009.)
Exchange Relationships Coyle-Shapiro, Jacqueline A-M; Conway, Neil
Journal of applied psychology,
07/2005, Letnik:
90, Številka:
4
Journal Article
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The authors surveyed 347 public sector employees on 4 measurement occasions to investigate the conceptual distinctiveness of the psychological contract and perceived organizational support (POS) and ...how they are associated over time. Results support the distinctiveness of the 2 concepts. In terms of their interrelationships over time, by drawing on psychological contract theory the authors found little support for a reciprocal relationship between POS and psychological contract fulfillment. Under an alternative set of hypotheses, by drawing on organizational support theory and by separating psychological contract fulfillment into its 2 components (perceived employer obligations and inducements), the authors found that perceived employer inducements were positively related to POS, which, in turn, was negatively related to perceived employer obligations. The results suggest that POS and the components of psychological contract fulfillment are more important in predicting organizational citizenship behavior than psychological contract fulfillment.
The accurate determination of stellar rotation periods is important for estimating stellar ages and for understanding stellar activity and evolution. While rotation periods can be determined for ...about thirty thousand stars in the
Kepler
field, there are over one hundred thousand stars, especially with low photometric variability and irregular pattern of variations, for which rotational periods are unknown. Here we investigate the effect of metallicity on the detectability of rotation periods. This is done by synthesising light curves of hypothetical stars that are identical to our Sun with the exception of the metallicity. These light curves are then used as an input to the period determination algorithms. We find that the success rate for recovering the rotation signal has a minimum close to the solar metallicity value. This can be explained by the compensation effect of facular and spot contributions. In addition, selecting solar-like stars with near-solar effective temperature and photometric variability, and with metallicity between
M
/
H
= −0.35 and
M
/
H
= 0.35 from the
Kepler
sample, we analyse the fraction of stars for which rotational periods have been detected as a function of metallicity. In agreement with our theoretical estimate we find a local minimum for the detection fraction close to the solar metallicity. We further report rotation periods of 87 solar-like
Kepler
stars for the first time.
Clinical islet transplantation has transitioned from curiosity to realistic therapy over the past decade. An estimated 750 patients have undergone intraportal islet-alone transplantation over this ...period, and a smaller subset received combined islet-kidney transplants. The primary benefit of successful islet transplantation has been to eliminate severe, recurrent hypoglycemia, a problem that has been hard to eliminate by other means in 15% of those with type 1 diabetes. The secondary benefit of independence from insulin has attracted patients, but has had limited sustainability previously, especially with a single-donor graft, but recent results from four independent centers suggest marked improvement in long-term outcome, with 5-year results now approximating solitary pancreas transplantation. Emerging data confirm that islet transplantation can stabilize and reverse several secondary diabetic complications similar to whole pancreas transplantation, but larger, head-to-head trials are needed to compare islet transplantation with best medical therapies. Current goals are to extend durability, and to make islet transplantation more widely available for patients in need. Governmental and health insurance providers in several countries now reimburse islet transplantation as part of clinical care. As the safety of the procedure and of adjunctive immunosuppressive therapies improve, and benefit accrues over potential risk, islet transplantation will be offered earlier in the course of the disease, including newly diagnosed children. The role of islet transplantation in type 2 diabetes has yet to be defined. We review the current status of islet transplantation, and discuss current and future immunosuppressive protocols that will pave the way to more broad application of cellular replacement in diabetes.
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