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Introduction Acute kidney injury (AKI) is common after liver transplantation and affects outcome after liver transplantation. Antibody induction is commonly used to reduce dose and/or to delay introduction of calcineurin inhibitor (CNI) but is very expensive. We propose a modified immunosuppressive protocol that delays administration of CNI for 48 to 72 hours without antibody induction. This study evaluates the results of our new protocol. Material and Methods A retrospective case-control study was performed. Study patients had induction with steroid and mycophenolate mofetil without antibody induction, and CNI administration was delayed for 48 to 72 hours. Control patients received CNI and steroid induction without antibody induction, and CNI was continued posttransplant. AKI was defined as an increase in serum creatinine level of at least 1.5 times the pretransplant baseline within the first postoperative week. Results Sixty liver transplant recipients from 2013 to 2015 were included in this study (30 in the delayed CNI group and 30 in the control group). The patient characteristics and intraoperative factors were comparable in both groups. AKI developed in 11 patients in the study group and in 20 patients in the control group (37% vs 66.7%; P = .02). There was no acute rejection observed in the first month in either group. Conclusion We have demonstrated that delayed CNI introduction without antibody induction is safe and helps preserve kidney function. Antibody induction can be omitted safely in a delayed CNI introduction protocol to reduce the cost of liver transplantation without increasing the risk of acute rejection.

Monoclonal antibodies are large molecules with complex structure and functions. They have a wide application for treatment of a broad range of chronic diseases and represent the largest class of biotherapeutic products. Given that biotherapeutic products may induce unwanted humoral and/or cellular immune responses in recipients, it is essential to investigate the immunogenicity of a product prior to licensure. The immune response is influenced by many factors and data generated in the pre-licensure studies are usually somewhat difficult for regulatory review. The knowledge and expertise required for this requires a thorough understanding of animal and human immunology as well as specific product characteristics, including mechanism of action, antibody assays and assessment of results in a given clinical context. The appropriate interpretation of immunogenicity data is of critical importance for defining the safety profile of a monoclonal antibody. Two case studies described in this paper were prepared to mimic a real situation in which regulators need to evaluate immunogenicity studies conducted by manufacturers of monoclonal antibody products. The specific objective of the case studies was to illustrate assessment of unwanted immunogenicity and the important factors that need to be considered in this context. Regulators and manufacturers who attended the World Health Organization (WHO) implementation workshop on Evaluation of Biotherapeutic Products, held in Seoul, Republic of Korea, in May 2014, participated in the case studies and provided valuable input. This article outlines the main aspects of immunogenicity discussed in these case studies and a summary of the lessons learned at this occasion.

Note on sources: The articles in this report are based on the reference tables in the 2009 OPTN/SRTR Annual Report, which are not included in this publication. Many relevant data appear in the figures and tables included here. All of the tables may be found online at: http://www.ustransplant.org. Improving short-term results with intestine transplantation have allowed more patients to benefit with nearly 700 patients alive in the United States with a functioning allograft at the end of 2007. This success has led to an increase in demand. Time to transplant and waiting list mortality have significantly improved over the decade, but mortality remains high, especially for infants and adults with concomitant liver failure. The approximately 200 intestines recovered annually from deceased donors represent less than 3% of donors who have at least one organ recovered. Consent practice varies widely by OPTN region. Opportunities for improving intestine recovery and utilization include improving consent rates and standardizing donor selection criteria. One-year patient and intestine graft survival is 89% and 79% for intestineonly recipients and 72% and 69% for liver-intestine recipients, respectively. By 10 years, patient and intestine survival falls to 46% and 29% for intestine-only recipients, and 42% and 39% for liver-intestine, respectively. Immunosuppression practice employs peri-operative antibody induction therapy in 60% of cases; acute rejection is reported in 30%–40% of recipients at one year. Data on long-term nutritional outcomes and morbidities are limited, while the cause and therapy for late graft loss from chronic rejection are areas of ongoing investigation.

This report reviews the immunosuppressive regimens that are used in pediatric transplantation. There are predominant themes developing in the field involving the minimization of the total exposure of immunosuppression through limiting the number of agents and newer pharmacokinetic modeling. Calcineurin inhibitors are the foundation of most immunosuppressive regimens. However, there are new pharmacologic monitoring techniques to reduce the potential for long-term side effects of this class of agents. Although tacrolimus remains one of the mainstays of current protocols, there are strides being made to reduce the patient's long-term exposure to it with transitioning to sirolimus. Corticosteroids are still used predominantly, but there is growing evidence of successful steroid-sparing protocols that are as effective and avoid the chronic morbidity of steroids. Antibody induction therapy remains a standard with clearer evidence of the efficacy of IL-2 receptor antagonists. There is preliminary clinical evidence that polyclonal antibody therapy is efficacious in pediatric transplantation. Future studies will determine the best way to assess the functional immune status of a pediatric transplant recipient to maintain the fine balance and avoid the complications of either excessive or inadequate immunosuppression.

Influenza is an important cause of morbidity and mortality in the elderly. Influenza vaccine has been shown to successfully reduce influenza- and pneumonia-associated hospitalizations and deaths, but the antibody induction by influenza vaccines is not always optimal in the elderly. The lower serological efficacy of influenza vaccines that is often observed in the elderly may be due to a multitude of factors. Here we will discuss some of these factors. These include health status and previous exposures to influenza viruses. In addition, we will discuss possibilities to improve antibody responses to influenza vaccination.

Purpose Acceptance and management of pediatric heart transplant (Tx) candidates with high pre-Tx PRA remains center dependent, largely due to lack of medium and longterm followup on outcomes. Some centers proceed only with a negative crossmatch, essentially guaranteeing no suitable donor in the worst cases. Other centers proceed across a positive crossmatch, feeling mortality is more likely waiting for a suitable donor, but with uncertain outcomes. We review outcomes after pediatric heart Tx with positive pre-Tx PRA (>10%) at a center that has not used prospective crossmatch, and more recently has chosen to transplant across a positive virtual crossmatch for those with markedly elevated PRA. Methods and Materials This is a retrospective chart review of all children undergoing heart transplantation at our center. Results We identified 19 recipients with pre-Tx PRA >10%: 11 class I, 2 class II, and 6 both class I and II. PRA class I mean was 43% (range 0-100) and class II mean was 27% (0-100). 11 of 18 tested had a positive retrospective crossmatch; 1 had no crossmatch. Only the 2 most recent recipients had specific intra-operative therapy to reduce antibody. Anti-thymocyte antibody induction is used. Post-Tx medications are often modified for better B cell coverage in this group. There were 5 deaths: rejection 2.3 y; rejection 3.2 y; PTLD 3.4 y; infection 7.0 y; and suicide 10.4 y. Both rejection deaths were linked to noncompliance. None of the high PRA recipients had documented coronary vasculopathy. Actuarial survival was 100% at 1 y; 79% at 5 y; 69% at 10y. 7 of 19 had rejection: 3 cellular, 2 AMR and 2 diagnosed clinically without biopsy. Time to first rejection was 1 y in 3. 3 recipients had >1 rejection episode. Positive crossmatch did not predict those likely to have rejection or death from rejection. Conclusions Reasonable outcomes in pediatric heart Tx recipients with high PRA, with or without a positive crossmatch, support offering Tx across a positive virtual crossmatch for those unlikely to otherwise undergo Tx.

Myosin-VI has been one of the least-understood unconventional molecular motors due to its peculiar characteristics. For instance, each myosin-VI monomer has a short lever arm (∼10nm) which contains only two Calmodulins while taking large steps (∼36nm center-of-mass movements). Recently, the Spudich group proposed, based on bacterial expressed fragments, that the medial-tail domain of myosin-VI is a single alpha helix (∼10nm), which can account for its large step sizes if dimerization occurs after the medial-tail domain. They also suggested that dimerization is formed via the cargo-binding domain. However, these results are contrary to our previous paper that showed that a myosin-VI construct without the cargo-binding domain can dimerize and walk processively. To solve this paradox, we prepared a myosin-VI construct truncated in the middle of the medial-tail domain (940-construct). A FIONA assay showed that this construct does dimerize either via antibody induction or actin-saturation method, and it walks processively with the same step size as the full-length myosin-VI construct. These results suggest that the medial-tail domain of myosin-VI is involved in dimerization and imply that the proximal-tail domain must be the major contributor to the unexpectedly large step size.View Large Image | View Hi-Res Image | Download PowerPoint Slide

The publisher regrets that during the publication of the above paper Fig.9 had the labels for the 2 antibodies reversed. The corrected figure is reproduced below. Figure 9

Conflicting results have been reported concerning the association between high age and response to influenza vaccines. Some authors have found a reduced response in aged subjects, others have found no difference or even better results as compared with younger control subjects. Seventeen papers were selected from international literature published in the period 1968-1988 for a review of the anti-haemagglutinin-IgG sero-response following vaccination: among 30 cases in which vaccine components could be studied independently, ten revealed a better immune response in young subjects than in the elderly, four found more favourable results in the elderly, and 16 could not detect any significant between-group-differences, the latter most probably because of a high type-2-error. Nine of these 16 cases tended to favour young subjects. These results were relativated by the finding that each paper had at least one of three methodological limitations: (1) the failure to exclude subjects with illnesses or using drugs influencing the immune system, (2) the failure to exclude subjects with previous vaccinations against influenza, (3) the failure to exclude subjects with high prevaccination antibody titres. The direction of these biases is such that failure to address any one issue will lead to an underestimate of the response of aged subjects. In view of the failure to control these biases, it was not surprising that the papers reviewed presented a heterogeneous picture. Thus, the association between high age per se and response to influenza vaccines, if any, has not yet been established. Suggestions are made for future studies in which admission criteria should control health state and previous exposure to influenza antigens.

Based on current concepts of the nature of specific immunocompetent cell surface receptors, hematopoietic stem cell differentiation and membrane dynamics, a simple model is proposed by which the event of immunogen binding by cell surface receptors specifically stimulates a constitutive process. The concept that enhancement of process flows in two directions with time allows for correlation of recent experimental findings into a molecular theory for antibody induction. The Model helps explain antibody specificity, heterogeneity and affinity changes and rationalizes immune memory.

A theory is presented for the induction of antibody synthesis and a functional role for antigenic determinant in this process is proposed. Basic structural and bond requirements are outlined for the antigenic determinant. A conceptual model system is developed and formulated mathematically. A set of differential equations are programmed for an analog computer, and kinetic characteristics of the system are studied. The relation between antigen concentration and antibody synthesis is determined in various experimental conditions.