The Role of the Fc Region in CD70-specific Antibody Effects on Cardiac Transplant Survival

Background: The role of the CD70-specific antibody and the mechanisms by which it extends transplant survival are not known. Methods: Fully major histocompatibility complex-mismatched heterotopic heart transplantation (BALB/c to C57BL/6) was performed. Treated mice received intraperitoneal injections of wild-type (WT) CD70-specific antibody (FR70) or IgG1 or IgG2a chimeric antibodies on days 0, 2, 4, and 6 posttransplantation. Results: WT FR70 antibody significantly extended heart transplant survival to 19 days compared with untreated mice (median survival time [MST]=10 days). Graft survival using the nondepleting IgG1 antibody was significantly shorter (MST=14 days), whereas the survival using depleting IgG2a antibody (MST=18) was similar to that using WT FR70. The FR70 and IgG2a antibodies demonstrated a greater efficiency of fixing mouse complement over the IgG1 variant in vitro. CD4 and CD8 T-cell graft infiltration was reduced with treatment; however, this was most pronounced with WT FR70 and IgG2a antibody therapy compared with the IgG1 chimeric variant. Circulating donor-specific IgG alloantibodies were initially reduced with WT FR70 treatment (day 8 posttransplantation) but increased at days 15 and 20 posttransplantation to the level detected in untreated controls. Conclusion: We conclude that WT (FR70) and the IgG2a depleting variant of CD70-specific antibody reduce graft infiltrating CD4 and CD8 T cells, transiently reduce serum alloantibody levels, and extend graft survival. In contrast, the nondepleting IgG1 variant of this antibody showed lower efficacy. These data suggest that a depleting mechanism of action and not merely costimulation blockade plays a substantial role in the therapeutic effects of CD70-specific antibody

Desensitization protocol enabling pediatric crossmatch-positive renal transplantation: successful HLA-antibody-incompatible renal transplantation of two highly sensitized children

BACKGROUND: Renal transplantation improves quality of life (QoL) and survival in children requiring renal replacement therapy (RRT). Sensitization with development of a broad-spectrum of anti-HLA antibodies as a result of previous transplantation or after receiving blood products is an increasing problem. There are no published reports of desensitization protocols in children allowing renal transplantation from HLA-antibody-incompatible living donors. METHODS: We adopted our well-established adult desensitization protocol for this purpose and undertook HLA antibody-incompatible living donor renal transplants in two children: a 14-year-old girl and a 13-year-old boy. RESULTS: After 2 and 1.5 years of follow-up, respectively, both patients have stable renal allograft function despite a rise in donor-specific antibodies in one case. CONCLUSIONS: HLA-incompatible transplantation should be considered in selected cases for sensitized children

Improved Diagnosis and Management of Paediatric Renal Transplant Recipients Using the Banff 2013 Histopathological Classification

Introduction: Since the publication of the 2013 Banff classification, adult studies have shown evidence of improved prognosis using the new histopathological criteria. Our study assesses for the first time the impact of the new classification on the diagnosis of acute antibody-mediated rejection (AMR) in paediatric renal transplant recipients (pRTR). / Methods: This single-centre study is a retrospective evaluation of 56 paediatric post-transplant de novo DSA-positive patients who had a percutaneous renal transplant biopsy due to renal allograft dysfunction from January 2006 to March 2012. Their biopsies were re-scored by a solitary specialist trained in 2013 Banff classification. The results were compared with previous classification as per 2003/2007 Banff criteria with results presented as range (median). / Results: At the time of biopsy, pRTR were aged 1.6 - 17.5 (median 14.9) years old with 412 - 2735 mean fluorescence intensity (MFI; maximal at 713 - 31,625; median 3466 and 4809). Following the 2013 Banff classification, there was a total of 5 cases of acute AMR compared to one confirmed and one suspicious AMR with the 2003/2007 Banff classification (with no change in the remaining 51 patients’ classification). Consequently, 5.3% (3 of 56) patients would have been diagnosed with T-cell mediated rejection with suboptimal treatment. There was an overall 70% (48 - 112%) decrease in the renal allograft function in the 6 months follow-up period after aggressive treatment for acute AMR and 2 of 3 patients had further rejection episodes in the following year. / Conclusion: This research supports the new Banff 2013 classification as a more precise classification in pRTR in the diagnosis of AMR with 5% of patients being correctly diagnosed and managed with improvement in renal allograft function

Inference for bivariate integer-valued moving average models based on binomial thinning operation

Time series of (small) counts are common in practice and appear in a wide variety of fields. In the last three decades, several models that explicitly account for the discreteness of the data have been proposed in the literature. However, for multivariate time series of counts several difficulties arise and the literature is not so detailed. This work considers Bivariate INteger-valued Moving Average, BINMA, models based on the binomial thinning operation. The main probabilistic and statistical properties of BINMA models are studied. Two parametric cases are analysed, one with the cross-correlation generated through a Bivariate Poisson innovation process and another with a Bivariate Negative Binomial innovation process. Moreover, parameter estimation is carried out by the Generalized Method of Moments. The performance of the model is illustrated with synthetic data as well as with real datasets.publishe

Understanding barriers and outcomes of unspecified (non-directed altruistic) kidney donation from both professional's and patient's perspectives: research protocol for a national multicentre mixed-methods prospective cohort study.

INTRODUCTION: Living donation accounts for over one-third of all kidney transplants taking place in the UK. 1 The concept of anonymously donating a kidney to a stranger (non-directed altruistic or unspecified kidney donation (UKD)) remains uncomfortable for some clinicians, principally due to concerns about the motivations and long-term physical and psychological outcomes in this donor group. AIMS: The research programme aims to provide a comprehensive assessment of the unspecified donor programme in the UK. It aims to identify reasons for variations in practice across centres, explore outcomes for donors and ascertain barriers and facilitators to UKD, as well as assess the economic implications of unspecified donation. METHODS: The research programme will adopt a mixed-methods approach to assessing UKD nationally using focus groups, interviews and questionnaires. Two study populations will be investigated. The first will include transplant professionals involved in unspecified kidney donation. The second will include a 5-year prospective cohort of individuals who present to any of the 23 UK transplant centres as a potential unspecified living kidney donor. Physical and psychological outcomes will be followed up to 1 year following donation or withdrawal from the donation process. A matched sample of specified donors (those donating to someone they know) will be recruited as a control group. Further qualitative work consisting of interviews will be performed on a purposive sample of unspecified donors from both groups (those who do and do not donate). DISSEMINATION: The findings will be reported to NHS Blood and Transplant and the British Transplant Society with a view to developing national guidelines and a protocol for the management of those presenting for unspecified donation. TRIAL REGISTRATION NUMBER: ISRCTN23895878, Pre-results