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Elevated neutrophil counts in broncho-alveolar lavage (BAL) fluids of lung transplant (LTx) patients with chronic lung allograft dysfunction (CLAD) are associated with disease pathology. However, phenotypical characteristics of these cells remained largely unknown. Moreover, despite enhanced levels of the most potent human neutrophil-attracting chemokine CXCL8 in BAL fluid, no discrimination had been made between natural NH2-terminally truncated CXCL8 proteoforms, which exhibit up to 30-fold differences in biological activity. Therefore, we aimed to characterize the neutrophil maturation and activation state, as well as proteolytic activation of CXCL8, in BAL fluids and peripheral blood of LTx patients with CLAD or infection and stable LTx recipients. Flow cytometry and microscopy revealed a high diversity in neutrophil maturity in blood and BAL fluid, ranging from immature band to hypersegmented aged cells. In contrast, the activation phenotype of neutrophils in BAL fluid was remarkably homogeneous. The highly potentiated NH2-terminally truncated proteoforms CXCL8(6–77), CXCL8(8–77) and CXCL8(9–77), but also the partially inactivated CXCL8(10–77), were detected in BAL fluids of CLAD and infected LTx patients, as well as in COVID-19 and influenza patient cohorts by tandem mass spectrometry. Moreover, the most potent proteoform CXCL8(9–77) specifically correlated with the neutrophil counts in the LTx BAL fluids. Finally, rapid proteolysis of CXCL8 in BAL fluids could be inhibited by a combination of serine and metalloprotease inhibitors. In conclusion, proteolytic activation of CXCL8 promotes neutrophilic inflammation in LTx patients. Therefore, application of protease inhibitors may hold pharmacological promise for reducing excessive neutrophil-mediated inflammation and collateral tissue damage in the lungs. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the effects of clotrimazole troche on the risk of transplant rejection and the pharmacokinetics of tacrolimus. Methods: The data mining approach was used to investigate whether the use of clotrimazole increased the risk of transplant rejection in patients receiving tacrolimus therapy. Patient data were acquired from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the end of 2017. Next, we retrospectively investigated the effect of clotrimazole troche on tacrolimus pharmacokinetics in seven patients who underwent heart transplantation between March and December 2017. Results: The FAERS subset data indicated a significant association between transplant rejection and tacrolimus with clotrimazole [reporting odds ratio 1.92, 95% two-sided confidence interval (95% CI) 1.43–2.58, information component 0.81, 95% CI 0.40–1.23]. The pharmacokinetic study demonstrated a significant correlation between trough concentration (C0) and area under the concentration-time curve of tacrolimus after discontinuation of clotrimazole (R2 = 0.60, P < 0.05) but not before its discontinuation. Furthermore, the median clearance/bioavailability of tacrolimus after discontinuation of clotrimazole was 2.2-fold greater than that before its discontinuation (0.27 vs. 0.59 L/h/kg, P < 0.05). The median C0 decreased from 10.7 ng/mL on the day after discontinuation of clotrimazole to 6.5 ng/mL at 1 day and 5.3 ng/mL at 2 days after its discontinuation. Conclusion: Immediate dose adjustments of tacrolimus may be beneficial to avoid transplant rejection when clotrimazole troche is added or discontinued. [ABSTRACT FROM AUTHOR]

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Cardiovascular magnetic resonance (CMR) is a versatile imaging modality that enables aetiological assessment and provides additional information to that of standard echocardiography in a significant proportion of patients with heart failure. In addition to highly accurate and reproducible assessment of ventricular volumes and replacement fibrosis, multiparametric mapping techniques have rapidly evolved to further expand the diagnostic and prognostic applications in various conditions ranging from acute inflammatory and ischaemic cardiomyopathy, to cardiac involvement in systemic diseases such as sarcoidosis and iron overload cardiomyopathy. In this review, we discuss the established role of T2* imaging and rapidly evolving clinical applications of myocardial T2 mapping as quantitative adjuncts to established qualitative imaging techniques. [ABSTRACT FROM AUTHOR]

Kidney allograft biopsies were analyzed for the presence of B cell clusters/aggregates using CD20 staining. Few B cells were found in the diffuse interstitial infiltrates, but clusters of B cells were found in nodular infiltrates. These nodular infiltrates were smaller shortly after transplantation, and their size increased over time. At the time of clinical rejection, the nodules often presented as tertiary lymphoid structures (TLS) with lymphoid-like follicles. The presence of small B cell clusters during the first 2 months after transplantation was not associated with early rejection. Even in animals that did not reject their allograft, TLS-like structures were present and could disappear over time. Although TLS were more often found in samples with interstitial fibrosis and tubular atrophy (IFTA), TLS were also present in samples without IFTA. The presence and density of clusters resembling tertiary lymphoid structures most likely reflect an ongoing immune response inside the graft and do not necessarily signify a poor graft outcome or IFTA. [ABSTRACT FROM AUTHOR]

Bone grafting is a very useful approach to reconstruction of skeletal defects. However, the clinical use of autografts, allografts, and synthetic products is associated with a number of problems. The use of bone xenotransplantation, on the other hand, is associated with strong immune response, and therefore clear understanding of the mechanisms of immune rejection is essential. In this study, we used rabbit-to-rat xenotransplantation model to investigate the role of IL-17, and the relationship between IL-17, IL-23 and RANKL in inflammatory response during the bone grafting. Rabbit hindlimb bone was transplanted to rats, and half of the xenograft recipient animals received injection of IL-17 neutralizing antibodies before xenotransplantation. Sham control rats did not receive bone transplants. In the xenotransplant group, significant mononuclear cell infiltration and erosion/resorption of graft bone were observed. Administration of IL-17 neutralizing antibodies decreased mononuclear cell infiltration and inhibited bone resorption. The levels of IL-17+, IL-23+, and RANKL+ cells were elevated in xenotransplanted group from compared to the sham control. IL-17+ and RANKL+ cells infiltration was decreased upon administration of IL-17 neutralizing antibodies. No significant difference in the level of IL-23 in xenotransplanted groups with and without IL-17 antibodies was observed. Our results indicate that RANKL, IL-17, and IL-23 participate in the immune rejection of bone xenotransplantion. The IL-17/RANKL pathway may play a very important role in the bone resorption during rejection of fresh bone xenotransplants. [ABSTRACT FROM AUTHOR]

Previous adult heart transplantation studies have demonstrated that donor-recipient human leukocyte antigen (HLA) matching results in reduced graft failure and improved patient survival. No study has examined these effects in children. This study investigated the effect of HLA matching on outcomes in pediatric heart transplantation. All pediatric heart transplantation data for patients 0-18 years of age available from the United Network for Organ Sharing Transplant Registry from 1987 to 2009 were analyzed retrospectively. Donor-recipient HLA matching at loci A, B, and DR (0-6) was compared with graft survival and recipient survival. For this study, 3,751 pediatric cardiac transplantation events with complete HLA matching data were identified and grouped as having 0 to 2 matches (3,416 events) or 3 to 6 matches (335 events). The 3- to 6-match group had less graft failure than the 0- to 2-match group (28.7 % vs 34.4 %; p = 0.035) and greater patient survival by 5 years (81 % vs 72 %; p = 0.045) and 10 years (66 % vs 55 %; p = 0.005) after transplantation. The HLA-DR matching alone resulted in less graft failure ( p = 0.038) and improved patient survival ( p = 0.017). A higher degree of HLA matching in pediatric heart transplantation is associated with decreased graft failure and improved patient survival. In this study, decreased graft failure rates and superior survival also were seen with DR matching alone. [ABSTRACT FROM AUTHOR]

Molecular imaging is highly advantageous as various insidious inflammatory events can be imaged in a serial and quantitative fashion. Combined with the conventional imaging modalities like computed tomography (CT), magnetic resonance (MR), and nuclear imaging, it helps us resolve the extent of ongoing pathology, quantify inflammation, and predict outcome. Macrophages are increasingly gaining importance as an imaging biomarker in inflammatory cardiovascular diseases. Macrophages, recruited to the site of injury, internalize necrotic or foreign material. Along with phagocytosis, activated macrophages release proteolytic enzymes like matrix metalloproteinases (MMPs) and cathepsins into the extracellular environment. Proinflammatory monocytes and macrophages also induce tissue oxidative damage through the inflammatory enzyme myeloperoxidase (MPO). In this review we will highlight recent advances in molecular macrophage imaging. Particular stress will be given to macrophage functional and enzymatic activity imaging, which targets phagocytosis, proteolysis, and myeloperoxidase activity imaging. [ABSTRACT FROM AUTHOR]

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Ischemic acute kidney injury (AKI) contributes to considerable morbidity and mortality in hospitalized patients and can contribute to rejection during kidney transplantation. Maladaptive immune responses can exacerbate injury, and targeting these responses holds promise as therapy for AKI. In the last decade, a number of molecules and receptors were identified in the innate immune response to ischemia-reperfusion injury. This review primarily focuses on one pathway that leads to maladaptive inflammation: toll-like receptor 4 (TLR4) and one of its ligands, high mobility group box protein 1 (HMGB1). The temporal-spatial roles and potential therapeutics targeting this particular receptor-ligand interaction are also explored. [ABSTRACT FROM AUTHOR]

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Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

During acute rejection leukocyte–endothelial cell interaction fuelled by costimulatory molecules such as the CD40/CD154 receptor/ligand dyad disrupts microcirculation of the small bowel. Downregulating endothelial CD40 expression by employing a decoy oligonucleotide (dODN) neutralizing the transcription factor signal transducer and activator of transcription-1 (STAT-1) may protect the graft. Therefore allogenic small bowel transplantation was performed in the Brown Norway to Lewis rat model. Graft vessels were pretreated with STAT-1 dODN, mutant control ODN (20 μM) or vehicle (n=8). CD40 antisense ODN and scrambled control ODN-treated transplants served as target control (n=3 each). Intravital microscopy, histology, immunohistochemistry and Western blot analyses were performed 7 days later. Functional capillary density, red blood cell velocity and perfusion index in STAT-1 dODN and CD40 antisense ODN-treated transplants were improved whereas stasis index was reduced. Leukocyte–endothelial cell interaction showed no difference. Histological parameters of rejection, infiltrating CD3-positive cells and apoptotic bodies were also reduced in STAT-1 dODN and CD40 antisense ODN-treated transplants 7 days post-transplantation. CD40 protein abundance was reduced to less than 10% of control in STAT-1 dODN-treated grafts. STAT-1 dODN blockade of CD40 expression improves mucosal perfusion, reduces graft rejection, T-cell infiltration and apoptosis in rat small bowel allografts during acute rejection.Gene Therapy (2007) 14, 883–890. doi:10.1038/sj.gt.3302931; published online 15 March 2007 [ABSTRACT FROM AUTHOR]

This review seeks to apply a decision-making algorithm to establish whether clinical pharmacokinetic monitoring (CPM) of sirolimus (rapamycin) in solid organ transplantation is indicated in specific patient populations. The need for CPM of sirolimus, although a regulatory requirement in Europe, has not yet been firmly established in North America and other parts of the world. Sirolimus has demonstrated immunosuppressive efficacy in renal, pancreatic islet cell, liver and heart transplant recipients. The pharmacological response of immunosuppressive therapy with sirolimus cannot be readily evaluated; however, a relationship between trough blood sirolimus concentrations, area under the plasma concentration-time curve (AUC) and the incidence of rejection has been proposed. Furthermore, sirolimus can be measured in whole blood by several assays – high-performance liquid chromatography with detection by tandem mass spectrometry, or with ultraviolet detection, radioreceptor assay or microparticle enzyme immunoassay. Both experimental animal and clinical data suggest that adverse events and their associated severity are correlated with blood concentrations. To prevent rejection and minimise toxicity, a therapeutic range of 4–12 μg/L (measured via chromatographic assays) is recommended when sirolimus is used in conjunction with ciclosporin. If ciclosporin therapy is discontinued, a target trough range of 12–20 μg/L is recommended. Sirolimus pharmacokinetics display large inter- and intrapatient variability, which may change in specific patient populations due to disease states or concurrent immunosuppressants or other interacting drugs. Due to the long half-life of sirolimus, dosage adjustments would ideally be based on trough levels obtained more than 5–7 days after initiation of therapy or dosage change. Once the initial dose titration is complete, monitoring sirolimus trough concentrations weekly for the first month and every 2 weeks for the second month appears to be appropriate. After the first 2 months of dose titration, routine CPM of sirolimus is not necessary in all patients, but may be warranted to achieve target concentrations in certain populations of patients, but the frequency of further monitoring remains to be determined and should be individualised. [ABSTRACT FROM AUTHOR]

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The anti-interleukin-2 receptor (anti-IL-2R) antibody therapy is an exciting approach to the prevention of acute rejection after renal allograft transplantation whereby immunosuppression is exerted by a selective and competitive inhibition of IL-2–induced T cell proliferation, a critical pathway of allorecognition. The anti-IL-2R antibodies specifically block the α-subunit of the IL-2R on activated T cells, and prevent T cell proliferation and activation of the effector arms of the immune system. The anti-IL-2R antibodies are used as induction therapy, immediately after renal transplantation, for prevention of acute cellular rejection in children and adults. During acute rejection, the IL-2Rα chain is no longer expressed on T cells; thus, the antibodies cannot be used to treat an existing acute rejection. Two anti-IL-2R monoclonal antibodies are currently in clinical use: daclizumab and basiliximab. In placebo-controlled phase III clinical trials in adults, daclizumab and basiliximab in combination with calcineurin inhibitor-based immunosuppression, significantly reduced the incidence of acute rejection and corticosteroid-resistant acute rejection without increasing the risk of infectious or malignant complications, and neither antibody was associated with the cytokine-release syndrome. Children who receive calcineurin inhibitors and corticosteroids for maintenance immunosuppression, as well as children who receive augmented immunosuppression to treat acute rejection, are at increased risk of growth impairment, hypertension, hyperlipidemia, lymphoproliferative disorders, diabetes mellitus, and cosmetic changes. In older children, the cosmetic adverse effects frequently reduce compliance with the treatment, and subsequently increase the risk of allograft loss. Being effective and well tolerated in children, the anti-IL-2R antibodies reduce the need for calcineurin inhibitors while maintaining the overall efficacy of the regimen; thus, the anti-IL-2R antibodies increase the safety margin (less toxicity, fewer adverse effects) of the baseline immunosuppression. Secondly, the anti-IL-2R antibodies decrease the need for corticosteroids and muromonab CD3 (OKT3) in children as a result of decreased incidence of acute rejection. The recommended pediatric dose of daclizumab is 1 mg/kg intravenously every 14 days for five doses, with the first dose administered within 24 hours pre-transplantation. This administration regimen maintains daclizumab levels necessary to completely saturate the IL-2Rα (5–10 µg/mL) in children for at least 12 weeks. The recommended pediatric dose of basiliximab for recipients <35kg is 10mg, and 20mg for recipients ≥35kg, intravenously on days 0 and 4 post-transplantation. This administration regimen maintains basiliximab levels necessary to completely saturate the IL-2Rα (>0.2 µg/mL) in children for at least 3 weeks. [ABSTRACT FROM AUTHOR]

Adolescence is a difficult time for transplant recipients; they must learn to take responsibility for their own behavior and medication, and to balance their developing sexuality in a body that has been transformed by the adverse effects of immunosuppression. More than 80% of children survive transplantation to adolescence and adulthood, thus long-term outcome and tailoring of immunosuppression is of great importance. To date, the most experience with long-term immunosuppression regimens is cyclosporine, which is well tolerated and effective. Long-term adverse effects include hypertension, nephrotoxicity, and post-transplant lymphoproliferative disease (PTLD). The recent development of tacrolimus has improved the cosmetic adverse effects related to cyclosporine, but has similar rates of hypertension and nephrotoxicity, and possibly a higher rate of PTLD. There has been a recent, welcome development in renal sparing drugs, such as mycophenolate mofetil, which has no cosmetic adverse effects, does not require drug level monitoring and is thus particularly attractive to teenagers. Recent surveys demonstrate recovery of renal function with mycophenolate mofetil, if started prior to irreversible renal dysfunction. There are currently little published data on the use of sirolimus (rapamycin) in the pediatric population, but preliminary studies suggest that the future use of interleukin-2 receptor antibodies may be beneficial for immediate post-transplant induction of immunosuppression. It is important when planning immunosuppression for adolescents to consider the effects of drug therapy on both males and females in order to maintain fertility and to ensure safety in pregnancy. Noncompliance is a problem in this age group, but adequate practical measures and support should reduce noncompliance, and allow good, long-term graft function. [ABSTRACT FROM AUTHOR]

The benefit of HMG-CoA reductase inhibitors (statins) to the cardiovascular system is now well established and these drugs are being used extensively to treat hypercholesterolaemia clinically. However, as clinical outcomes become available it appears that statins are proving more beneficial than expected and thus it is being proposed that the actions of statins go beyond their ability to lower serum cholesterol levels. The report that statins can interact directly with lymphocyte function-associated antigen (LFA)-1 and prevent it engaging with the intracellular adhesion molecule (ICAM)-1 receptor on T cells is a novel mechanism of statin action and provides convincing evidence that these compounds can regulate biological systems other than by the cholesterol synthesis pathway. Immunosuppression to prevent organ transplant rejection is one application for which statins are currently being assessed. The clinical evidence is conflicting and does not convincingly reflect whether statins are beneficial as immunomodulators. However, in vivo studies investigating the cellular actions of statins have identified two mechanisms by which statins can potentially modulate an in vivo immune response. Firstly, statins regulate inducible class II major histocompatibility complex (MHC) expression on macrophages and endothelial cells. Secondly, statins can inhibit LFA-1 adhesion to ICAM-1 and thus regulate T cell activation. These findings suggest that statins have the potential to regulate an immune response in vivo and that more investigation is essential in order to explain the opposing clinical data. [ABSTRACT FROM AUTHOR]

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Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Solid organ transplantation during the past 30 years has developed from an experimental procedure into routine clinical practice. The current repertoire of immunosuppressive agents has made a major contribution to transplant survival; however, problems in different areas still need to be overcome. Several gene polymorphisms are supposed to influence immunosuppressive therapy and susceptibility to rejection. Therefore, a priority of transplant biologists is to estimate individual patient risk and to characterise the genetic profile of patients in need of a transplant in order to optimise the use of a scarce resource such as organs from cadaver donors, and to avoid serious drug-induced adverse effects. Polymorphisms in genes encoding tumour necrosis factor-α (TNFα), interleukin (IL)-6, IL-10, interferon-γ (IFNγ), transforming growth factor-β (TGFβ) and thiopurine S-methyltransferase (TPMT) can have significant effects on an individual’s risk of rejection, as well as their ability to tolerate immunosuppressive therapy. Genotyping of known polymorphisms in these genes may in the future contribute to our ability to individualise immunosuppressive therapy in organ transplant recipients. [ABSTRACT FROM AUTHOR]

Recipients of organ and tissue transplants require lifelong immunosuppression to prevent rejection. Better understanding of the processes culminating in allograft rejection has led to novel approaches to modulating the immune response. Co-stimulatory signals between antigen-presenting and -responding cells are essential for a normal alloimmune response, and blockade of these pathways during initial graft-host interaction may be used to ameliorate or prevent a destructive response from proceeding. A large number of experimental studies now support this concept, and early clinical trials have been initiated. Despite some early difficulties and many unanswered questions, co-stimulatory blockade has major potential as a future immune-modulating mechanism for use in clinical transplantation. [ABSTRACT FROM AUTHOR]

The mortality rates due to cardiovascular disease (CVD) in transplant recipients are greater than in the general population. CVD is a major cause of both graft loss and patient death in renal transplant recipients, and improving cardiovascular health in transplant recipients will presumably help to extend both patient and graft survival. Further studies are needed to better evaluate the effectiveness of risk modification on subsequent CVD morbidity and mortality. There is no reason to consider risk factors for CVD such as hyperlipidaemia, hypertension and diabetes mellitus in transplant recipients differently from in the general population. In addition, there are specific transplantation risk factors such as acute rejection episodes and the use of immunosuppressive drugs. It is obvious that several of the immunosuppressive agents used today have disadvantageous influences on risk factors for CVD such as hyperlipidaemia, hypertension and post-transplantation diabetes mellitus (PTDM), but the relative importance of immunosuppressant-induced increases in these risk factors is basically unknown. This may be a strong argument for the selective use and individual tailoring of immunosuppressive agents based upon the risk factor profile of the patient, without jeopardising the function of the graft. Hyperlipidaemia is common after transplantation, and immunosuppression with corticosteroids, cyclosporin, or sirolimus (rapamycin) causes different types of post-transplantation hyperlipidaemia. However, to date, no studies have demonstrated that lipid lowering strategies significantly reduce CVD morbidity or mortality and improve allograft survival in transplant recipients. Several studies using preventive or interventional approaches are ongoing and will be reported in the near future. Post-transplantation hypertension appears to be a major risk factor determining graft and patient survival, and immunosuppressive agents have different effects on hypertension. Controlled studies support the opinion that post-transplantation hypertension must be treated as strictly as in a population with essential hypertension, diabetes mellitus, or chronic renal failure. As increasing numbers of immunosuppressive agents become available for use, we may be in a better position to tailor immunosuppressive therapy to the individual patient, avoiding the use of diabetogenic drugs, drug combinations, or inappropriate doses in patients susceptible to PTDM. Multiple acute rejection episodes have also been demonstrated to be a risk factor for CVD - a strong argument for the use of immunosuppressive drugs to reduce acute rejection. Until we have a better understanding from ongoing landmark studies on the management of CVD, presently available therapy to reduce risk factors needs to be used together with individual tailoring of immunosuppressive therapy with the aim of reducing CVD in these patients. [ABSTRACT FROM AUTHOR]

Tacrolimus is a potent immunosuppressive agent used to prevent allograft rejection. The pharmacokinetics of tacrolimus have been studied in healthy volunteers and transplant recipients, mostly by using immunoassays to measure tacrolimus in plasma or blood. However, because of the cross-reactivity for certain tacrolimus metabolites of the antibodies used, these methods often lack specificity. This should be carefully taken into account when interpreting pharmacokinetic results for tacrolimus. In adult patients, tacrolimus is generally rapidly absorbed following oral administration (the time to reach maximum concentration is 1 to 2 hours), but in some patients absorption is slow or even delayed. Because of presystemic elimination, the oral bioavailability is low (around 20%) but may vary between 4 and 89%. Tacrolimus is highly bound to erythrocytes. Its binding to plasma proteins varies between 72 and 98% depending on the methodology used. Because of the extensive partitioning of tacrolimus into erythrocytes, its apparent volume of distribution (Vd) based on blood concentrations is much lower (1.0 to 1.5 L/kg) compared with values based on plasma concentrations (about 30 L/kg). Tacrolimus is metabolised by cytochrome P450 (CYP) 3A4 to at least 10 metabolites, some of which retain significant activity. Biliary excretion is the route of elimination of the tacrolimus metabolites. Systemic plasma clearance of tacrolimus is very high (0.6 to 5.4 L/h/kg), whereas blood clearance is much lower (0.03 to 0.09 L/h/kg). The terminal elimination half-life (t1/2beta) of tacrolimus is approximately 12 hours (with a range of 3.5 to 40.5 hours). Only limited information is available on the pharmacokinetics of tacrolimus in paediatric patients. The rate and extent of tacrolimus absorption after oral administration do not seem to be altered in paediatric patients. The Vd of tacrolimus based on blood concentrations in paediatric patients (2.6 L/kg) is approximately twice the adult value. Blood clearance of tacrolimus is also approximately twice as high in paediatric (0.14 L/h/kg) compared with adult (0.06 L/h/kg) patients. Consequently, t1/2beta does not appear modified in children, but oral doses need to be generally 2-fold higher than corresponding adult doses to reach similar tacrolimus blood concentrations. More pharmacokinetic studies in paediatric patients are, however, needed to rationalise the use of therapeutic drug monitoring for optimisation of tacrolimus therapy in this patient population. [ABSTRACT FROM AUTHOR]

The field of kidney transplantation is advancing so rapidly that it is difficult to keep up with the various therapeutic protocols, let alone our current understanding of transplantation immunobiology. This basic science review summarizes our current understanding of aspects of the cellular and molecular basis of renal transplant rejection and then details studies from the author's laboratory designed to specifically interrupt transplant rejection. The interaction of HLA with T cell receptors and the cascade of events following T cell activation are highlighted. [ABSTRACT FROM AUTHOR]

Sixty-one rat renal allografts were studied by light microscopy and in 18 cases also by immunohistology. Donor and recipient differ at a major histocompatibility locus in the one group ( n=37), and by an additional weak histocompatibility antigen in the other ( n=24). The mean survival time is 10.4 days and 8.3 days, respectively. A semiquantitative grading of the histologic findings shows that in both groups the rejection is predominantly manifested by lesions of extraglomerular and glomerular vessels, whereas mononuclear cell infiltration appears to be of less significance. The essential findings are necrosis of arteries and arterioles, necrosis of glomerular cells with mesangiolysis, and focal tubular necroses. This morphologic rejection type is interpreted as the result of a mixed humoral and cellular immune response, although the constant participation of circulating antibodies in the vascular damage could not be established. Since the tubular necroses correlate well with the degree of vascular alterations, but not with the mononuclear cell infiltration it would seem reasonable to conclude that these necroses are secondary to ischemia produced by vascular lesions. Finally, there is no significant difference in the degree of rejection between the two donor/recipient groups, and, therefore, there is no morphologic evidence for an increase of the rejection process by additional weak histoincompatibility in the examined strain combinations. [ABSTRACT FROM AUTHOR]

Nine patients who underwent heart transplantation (one female; average age 48 ± 11, range 19-58 years) were followed in respect to contents of right-sided heart septum, blood and plasma ubiquinone (UQ), plasma α-tocopherol (αT), and plasma free cholesterol (FC). In contrast to healthy persons, substantial inter- and intraindividual variations were observed; individually low values were seen with rejection. Heart muscle UQ in well-treated patients averaged 0.33 ± 0.08, range 0.06-0.58 μg mg (0.38 ± 0.09 μmol g dry weight) and was not different from healthy individuals. Plasma UQ, αT; and FC averaged 0.63 ± 0.33 μg ml ( P < 0.05 versus sedentary controls), 8.1 ± 4.0 μg ml ( P < 0.01), and 0.52 ± 0.23 mg ml ( P < 0.05). Corresponding molar values were 0.73 ± 0.37 (UQ), 2.0 ± 1.1 μmol l (αT), and 1.42 ± 0.54 mmol 1 (FC). Blood and plasma UQ values were identical. A saturationlike relationship was found between heart and blood UQ: blood contents below 0.7 μg ml (0.8 μmol l) corresponded to markedly lowered heart contents. In four patients in whom blood samples were taken close to a fatal complication it averaged 0.42 μg ml (0.49 μmol l, P < 0.01). When low heart muscle and blood ubiquinone were present, other variables such as left ventricle cardiac output or cycle ergometer performance was markedly impaired. Plasma UQ and off covaried with a marker of the lipoidal deposit volume, plasma FC. The ratios UQ and αT over FC (N-UQ and N-αT) are alternative means for clinical evaluation. Mean N-αT was relatively more depleted than N-UQ. On an individual basis this was more pronounced for those with low N-UQ than for those with high values. [ABSTRACT FROM AUTHOR]