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Background: A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD., Methods: Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID-based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated., Results: Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC(0-24)) and minimum concentration (C(min)) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals [CI], 86.4%-94.6%) and 87.4% (95% CI, 82.9%-92.0%), respectively (acceptance interval, 80%-125%). There was good correlation between AUC(0-24) and C(min) for tacrolimus QD (r = 0.94) and BID (r = 0.91). The relationship between these 2 parameters was also similar., Conclusions: This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) from killer immunoglobulin (Ig)-like receptors (KIR) ligand-mismatched donors. We showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer (NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and functional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1(+) NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3(+) NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen (HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3(+) (or by NKG2A(+)) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.

The regulation of the interaction between the immune system and antigens, which may lead to the induction of immune tolerance, is critical both under physiologic conditions and in different pathological settings. In the past few years, major strides have been made in our understanding of the molecular and cellular bases of this process. Novel pathways have been identified and several novel therapeutic agents are currently under clinical investigation for those diseases in which the normal balance between activation and suppression of the immune response is altered. The tryptophan catabolic enzyme, indoleamine 2,3-dioxygenase (IDO), is one of the key players involved in the inhibition of cell proliferation, including that of activated T cells. Recent works have demonstrated a crucial role for IDO in the induction of immune tolerance during infection, pregnancy, transplantation, autoimmunity, and neoplasias, including hematologic malignancies. In this review, the role of IDO in the induction of immunologic tolerance is addressed with a specific focus on its recently discovered effect on hematologic malignancies.

The effect that gonadotrophin-releasing hormone (GnRH) antagonists exert on endometrial receptivity has not yet been elucidated. GnRH antagonists might directly affect oocytes, the embryo and/or the endometrium. The aim of this study was to investigate the direct effect of GnRH antagonists on the endometrium in oocyte donation cycles. In an oocyte donation programme, oocytes from each donor (n = 49), stimulated with gonadotrophins and a GnRH antagonist, were equally shared between two different matched recipients. Recipients were randomly allocated to either receive a GnRH antagonist concomitant to donor during their endometrial priming with oestradiol (group I, n = 49) or to solely continue with their endometrial preparation (group II, n = 49). Pregnancy rate was 55.1% in group I and 59.1% in group II. Implantation rate was 26.1% in group I and 24.4% in group II. Endometrial thickness was also similar between the two groups on the day of human chorionic gonadotrophin injection to the donor. In conclusion, GnRH antagonist administration during the proliferative phase at a dose of 0.25 mg per day does not appear to adversely affect endometrial receptivity in oocyte recipients.

The feasibility, value and risk of percutaneous renal biopsy (PRB) in liver transplant candidates with renal failure are unknown. PRB was performed on 44 liver transplant candidates with renal failure of undetermined etiology and glomerular filtration rate (GFR) <40 mL/min/1.73 m(2) (n = 37) or on renal replacement therapy (RRT) (n = 7). Patients with >or=30% interstitial fibrosis (IF), >or=40% global glomerulosclerosis (gGS) and/or diffuse glomerulonephritis were approved for simultaneous-liver-kidney (SLK) transplantation. Prebiopsy GFR, urinary sodium indices, dependency on RRT and kidney size were comparable between 27 liver-transplant-alone (LTA) and 17 SLK candidates and did not relate to the biopsy diagnosis. The interobserver agreement for the degree of IF or gGS was moderate-to-excellent. After a mean of 78 +/- 67 days, 16 and 8 patients received LTA and SLK transplants. All five LTA recipients on RRT recovered kidney function after transplantation and serum creatinine was comparable between LTA and SLK recipients at last follow-up. Biopsy complications developed in 13, of these, five required intervention. PRB is feasible in liver transplant candidates with renal failure and provides reproducible histological information that does not relate to the pretransplant clinical data. Randomized studies are needed to determine if PRB can direct kidney allocation in this challenging group of liver transplant candidates.

Transplantation of pluripotent embryonic stem cells (ESC) into immune-deficient mice results in the formation of complex teratomas consisting of derivatives from all three germ layers. The highly sophisticated tissue organization found therein resembles structures normally found in the embryo and adult. Used as a functional proof of pluripotency of ESC, teratoma characterization has been restricted to identification of derivatives from all three germ layers. This paper aims to provide a thoughtful analysis of teratoma formation from a range of stem cells on the basis of published information, in an attempt to gain insight into tissue development during embryogenesis and provide a useful model for studying human development in normal as well as abnormal situations and toxicity studies. Furthermore, it is believed that studies on teratomas might lead to novel approaches in many research areas, including oncology and bioengineering.

Selection criteria for organ transplantation have evolved over time. Age has been revisited periodically. We studied the outcome of lung transplant adjusted by age in a single center transplant population. We matched the 42 lung graft recipients older than 60 years transplanted by July 1999 to younger controls by lung disease, transplant era within 2 years, type of transplant and gender. The female to male ratios were 17/25 among the older cohort (median age 61.6 years), and 15/27 (median age 51.9 years) among the matched younger. Survival analysis demonstrated a significant difference: at 1 year, 60% versus 86%, and at 5 years, 37% versus 57%, for older and younger, respectively, p=0.005. Excess annual mortality, calculated with the declining exponential approximation to life expectancy (DEALE), showed an older/younger ratio of 1.9. Eleven deaths occurred within 6 months among the older patients, 10 due to infection. After 6 months, there were 20 more deaths, 6 due to malignancy, 5 to Bronchiolitis Obliterans Syndrome (BOS), 3 to infection and 6 to other causes. Among the younger there were 6 deaths within 6 months and 12 more thereafter; among the latter, 8 were due to BOS. Despite stringent selection, lung transplant recipients older than 60 years show increased mortality even after adjusting for their expected higher age-related mortality.

The ability to generate genetically manipulated mice has revolutionized the study of development, cell biology, immunobiology and transplantation. Conventional gene targeting approaches lead to inactivation of the target gene in all tissues. This approach often has unintended consequences, such as embryonic lethality, which preclude studying the originally intended tissue. Newer approaches allowing conditional gene expression in a tissue-specific or temporally controlled fashion have the advantage of normal development with gene deletion only in the desired tissues. While nuances to these techniques continue to be developed, the underlying concepts remain consistent. This minireview focuses on the use of conditional gene targeting in mice using the Cre-loxP system and drug inducible gene expression using the tetracycline system.

Study Objective: To study the prevalence and impact of pain on the quality of life (QOL) of lung transplant recipients., Design and Patients: Prospective, observational, cross-sectional study. Ninety-six lung transplant recipients (> 3 months after transplantation) completed questionnaires measuring the severity and impact of pain (Brief Pain Inventory), anxiety (State Trait Anxiety Inventory), QOL (Short Form-36 version 2 [SF-36v2]), and depression (Beck Depression Inventory [BDI])., Setting: University medical center lung transplant outpatient clinic., Results: The prevalence of pain in lung transplant recipients was 49%. Patients with pain were older, more likely to have undergone unilateral lung transplantation (64% vs 40%, p = 0.03), and were more likely to have lung emphysema (55% vs 38%, p = 0.004). Only a pulmonary diagnosis of lung emphysema remained an independent predictor for postoperative pain in a logistic regression model. Average (+/- SD) score of the BDI was 9.6 +/- 7.8 and 5.8 +/- 5.8 (p = 0.005) for patients with and without pain, respectively. Patients with and without pain did not significantly differ in terms of anxiety. Pain-free patients had a significantly higher physical component score than patients with pain in the SF-36v2 (mean, 48.7 +/- 8.6 vs 38.6 +/- 9.8, p < 0.0001, respectively), while the mental component scores were not statistically different between the two groups., Conclusions: Lung transplant recipients have a high prevalence of pain. Patients with lung emphysema as their preoperative diagnosis are more likely to have pain. The occurrence of pain is associated with a decreased QOL in lung transplant recipients.

Cardiac transplant recipients often anticipate and suffer varying degrees of discomfort during surveillance endomyocardial biopsy (EMBx). We performed a randomized, blinded, placebo-controlled trial to determine whether topical anesthetic was associated with reduced pain and to identify factors associated with increased pain perception during EMBx. In 225 EMBxs, use of the eutectic mixture of lidocaine and prilocaine (EMLA) decreased pain score (-7.3 compared with placebo; p = 0.04); the other significant predictors of increased pain scores were time to achieve access (+2.3 per minute; p = 0.001) and female gender (+12.7 compared with males; p = 0.003). Topical anesthetic cream is associated with decreased pain during EMBx, even after adjusting for other predictors of pain, including female gender and longer time to achieve access. A better understanding of the factors affecting pain during EMBx could improve the comfort level of this procedure.

Gene targeting, the manipulation of gene in the mouse genome using homologous recombination in embryonic stem cells, is a powerful experimental tool that has been widely utilized in a number of disciplines. The ability to precisely alter genes in this way provides an avenue for investigating the role of a gene product in normal and pathological processes in the intact animal, with a precision and efficacy not possible using pharmacological agents, antibodies or engineered proteins. In transplant research, gene targeting provides a unique tool for discriminating the contributions of gene expression in donor versus recipient tissues. This review focuses on several areas in transplantation research where gene targeting has made useful contributions. These include studies of the role of donor and recipient multiple histocompatibility complex antigens in regulating rejection responses, the role of CD4+ T cell in mediating acute rejection, and the functions of cytokines during rejection and tolerance induction. These studies highlight the unique advantages of gene targeting in studies of complex processes in whole animals and illustrate the contributions of this technique to understanding the pathogenesis of allograft rejection.