Evidence generation throughout paediatric medicines life cycle: findings from collaborative work between European Medicines Agency (EMA) and EUnetHTA on use of extrapolation.

Drug development for children presents unique challenges and is highly regulated. Novel approaches, such as the use of extrapolation to address, for example, the need to avoid unethical studies, whilst supporting robust evidence generation have been developed in support of benefit/risk considerations by regulatory authorities. This is only one step in the decision-making process towards access, which in Europe also includes health technology assessment (HTA) bodies.

Risk Stratification Before Living Donor Kidney Transplantation in Patients With Preformed Donor-specific Antibodies by Different Crossmatch Methods.

Background: Preformed donor-specific HLA antibodies (DSA) are a well-known risk factor in kidney transplantation. There is still considerable debate, however, about the optimal risk stratification among patients with preformed DSA. Additionally, data on the prognostic value of different crossmatch assays in DSA-positive patients are scarce.

Five-year follow-up of a phase I trial of donor-derived modified immune cell infusion in kidney transplantation.

Background: The administration of modified immune cells (MIC) before kidney transplantation led to specific immunosuppression against the allogeneic donor and a significant increase in regulatory B lymphocytes. We wondered how this approach affected the continued clinical course of these patients.

Methods: Ten patients from a phase I clinical trial who had received MIC infusions prior to kidney transplantation were retrospectively compared to 15 matched standard-risk recipients.

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients.

Background: We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls.

Methods: Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080.

Human Leucocyte Antigens as Prognostic Markers in Head and Neck Squamous Cell Carcinoma.

Background: The induction and regulation of immune responses depend on human leucocyte antigen (HLA) molecules that present peptides derived from mutated neoantigens or tumor-associated antigens to cytotoxic T cells. The natural variation of HLA molecules might differ between tumor patients and the normal population. Thus, there might be associations between the frequencies of HLA alleles and the survival of tumor patients.

Functional Fc Gamma Receptor Gene Polymorphisms and Long-Term Kidney Allograft Survival.

The functional Fc gamma receptor (FcγR) IIIA polymorphism -V/F158 was earlier suggested to determine the potential of donor-specific HLA antibodies to trigger microcirculation inflammation, a key lesion of antibody-mediated renal allograft rejection. Associations with long-term transplant outcomes, however, have not been evaluated to date. To clarify the impact of -V/F158 polymorphism on kidney transplant survival, we genotyped a cohort of 1,940 recipient/donor pairs.

Analysis of de novo donor-specific HLA-DPB1 antibodies in kidney transplantation.

HLA matching and avoidance of unacceptable mismatches are important aspects in the selection of donors for solid organ transplantation. The impact of HLA-DPB1 incompatibility on the outcomes of kidney transplantation is not fully understood. We investigated a potential effect of mismatching for HLA-DPB1 at allele, eplet, or Terasaki epitope (TerEp) level on the formation of de novo donor-specific antibodies (dnDSA) and also asked whether polymorphisms associated with HLA-DPB1 expression level may influence dnDSA induction.

Pre-transplant HLA Antibodies and Delayed Graft Function in the Current Era of Kidney Transplantation.

Delayed graft function (DGF) occurs in a significant proportion of deceased donor kidney transplant recipients and was associated with graft injury and inferior clinical outcome. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of human leukocyte antigen (HLA) antibodies. 1,724 patients who received a deceased donor kidney transplant during 2008-2017 and on whom a pre-transplant serum sample was available were studied.

Relevance of donor-specific antibody monitoring after kidney transplantation: Findings from the Collaborative Transplant Study and the Heidelberg Transplant Center.

Monitoring of donor-specific HLA antibodies (DSA) has become part of the clinical routine in kidney transplantation. This paper gives a brief overview on data from the Collaborative Transplant Study (CTS) and the Heidelberg Transplant Center on the clinical relevance of post-transplant DSA monitoring in patients undergoing renal transplantation. The obtained findings underline the importance of DSA monitoring in the post-operative course in immunologically high-risk patients and patients with deterioration of graft function.

Endothelial precursor cell cross-match using Tie-2-enriched spleen cells.

Background: Non-HLA antibodies against human endothelial progenitor cells (EPC) in pre-transplant recipient serum can have a deleterious influence on the graft. EPC enriched from peripheral blood have been commonly used for EPC cross-matching. In the present study, we describe cross-matches using EPC enriched from fresh or frozen-thawed spleen cell preparations, thereby widening the sample source for deceased-donor cross-matching and retrospective studies.

Donor-specific antibodies require preactivated immune system to harm renal transplant.

Background: It is an unresolved issue why some kidney transplant recipients with pretransplant donor-specific HLA antibodies (DSA) show a high transplant failure rate, whereas in other patients DSA do not harm the graft. We investigated whether help from preactivated T-cells might be necessary for DSA to exert a deleterious effect.

Methods: The impact of pretransplant DSA and immune activation marker soluble CD30 (sCD30) on 3-year graft survival was analyzed in 385 presensitized kidney transplant recipients.

Clinical relevance of preformed IgG and IgM antibodies against donor endothelial progenitor cells in recipients of living donor kidney grafts.

Background: Literature reports suggest that non-HLA-antibodies against human endothelial progenitor cells (EPC) can be detected in pre-transplant recipient serum and that EPC antibodies can have a deleterious influence on the graft.

Methods: We investigated 71 renal transplant recipients from living donors for a possible influence of pre-transplant donor-specific IgG and/or IgM recipient antibodies against EPC of the donor using the flow cytometric XM-ONE cross-match.

Results: Eight of the 71 patients developed acute biopsy-proven rejection.

Association of Kidney Graft Loss With De Novo Produced Donor-Specific and Non-Donor-Specific HLA Antibodies Detected by Single Antigen Testing.

Background: The association of donor-specific HLA antibodies (DSA) with kidney graft failure has been addressed previously; however, the majority of studies were based on small numbers of patients with graft failure.

Methods: We investigated 83 patients with failed kidney transplants for a possible association of de novo development and persistence or loss of pre-existing DSA with graft failure. Single Antigen Bead assay-detected DSA and non-DSA antibodies were compared between patients with graft loss and matched controls with functioning grafts.

Seven novel HLA alleles reflect different mechanisms involved in the evolution of HLA diversity: description of the new alleles and review of the literature.

The human leukocyte antigen (HLA) loci are among the most polymorphic genes in the human genome. The diversity of these genes is thought to be generated by different mechanisms including point mutation, gene conversion and crossing-over. During routine HLA typing, we discovered seven novel HLA alleles which were probably generated by different evolutionary mechanisms.

HIV-Specific CD8(+) T Lymphocytes in Blood of Long-Term HIV-Infected Hemophilia Patients.

Hemophilia patients infected with human immunodeficiency virus (HIV) 30 years ago show increased proportions of activated CD8(+)DR(+) blood lymphocytes. We hypothesized that this might indicate a cellular immune response directed against HIV and might be the reason for long-term clinical stability of these patients. CD8(+) peripheral blood lymphocytes (PBL) reactive with six HIV and two cytomegalovirus (CMV) pentamers were determined in heparinized whole blood.

The collaborative transplant study registry.

The Collaborative Transplant Study (CTS) was initiated in 1982. Over the last 30 years, it has collected information on over half a million kidney, liver, heart, lung, and pancreas transplant procedures. Participation is voluntary and the study has strictly scientific objectives.

Association of single nucleotide polymorphisms on chromosome 9p21.3 with cardiovascular death in kidney transplant recipients.

Background: Recipient death is a leading cause for renal allograft loss. Cardiovascular mortality is the most important cause of death among this patient group. Single nucleotide polymorphisms (SNPs) in a noncoding region close to the CDKN2a/b senescence genes have been associated with higher cardiovascular morbidity and mortality in nontransplant populations.

Living donor kidney transplantation in patients with donor-specific HLA antibodies enabled by anti-CD20 therapy and peritransplant apheresis.

Objective: Due to increasing waiting times for deceased donor kidneys, living donor kidney transplantation is increasingly performed in the presence of donor-specific antibodies (DSA).

Methods: Twenty-three patients with Luminex-detected DSA were successfully desensitized by anti-CD20 therapy and immunoadsorption (N = 19) or plasmapheresis (N = 4) and received a kidney transplant from a living donor. Twelve of the 23 patients (52%) had a positive CDC and/or ELISA crossmatch result before desensitization.

Deleterious impact of HLA-DRB1 allele mismatch in sensitized recipients of kidney retransplants.

Background: Whether mismatches between donor and recipient of a kidney transplant at the HLA allele level can elicit an immune response strong enough to impact graft survival is not known.

Methods: We examined the influence of HLA-DRB1 allele level mismatch on graft survival based on high-resolution typing, utilizing blood samples and clinical data provided by the Collaborative Transplant Study. HLA-DRB1*04 was selected as a model for this investigation because it is the most common HLA-DRB1 allele group and consists of several alleles with relatively high frequencies, allowing for analysis of transplants matched at the antigen level but mismatched at the allele level.

Living donor kidney transplantation in crossmatch-positive patients enabled by peritransplant immunoadsorption and anti-CD20 therapy.

Living donor kidney transplantation in crossmatch-positive patients is a challenge that requires specific measures. Ten patients with positive crossmatch results (n = 9) or negative crossmatch results but strong donor-specific antibodies (DSA; n = 1) were desensitized using immunoadsorption (IA) and anti-CD20 antibody induction. IA was continued after transplantation and accompanied by HLA antibody monitoring and protocol biopsies.

Deleterious impact of mismatching for human leukocyte antigen-C in presensitized recipients of kidney transplants.

Background: Allocation of deceased donor kidneys is commonly based on matching for human leukocyte antigen (HLA)-A, -B, and -DR, whereas HLA-C is currently disregarded. We investigated the influence of HLA-C compatibility on renal allograft survival. In addition, we tested an approach of matching for HLA-C epitopes.

No association of kidney graft loss with human leukocyte antigen antibodies detected exclusively by sensitive Luminex single-antigen testing: a Collaborative Transplant Study report.

Background: It is unclear whether kidney transplant recipients with preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) detectable only in the highly sensitive Luminex single-antigen (LSA) assay are at an increased risk of graft failure.

Methods: We studied 3148 patients who received a deceased donor kidney graft between 1996 and 2008 and were enrolled in the prospective serum project of the Collaborative Transplant Study. There were 118 patients with graft loss during the first 3 years after transplantation on whom recipient and donor DNA was available for complete HLA typing.

An integrative approach for the transplantation of high-risk sensitized patients.

Background: Sensitized patients have a lower chance of receiving a crossmatch-negative kidney and, if transplanted, are at risk of antibody-mediated allograft rejection.

Methods: For safe and timely transplantation of sensitized patients at our center, we developed an integrative algorithm that includes identification of high-risk patients, good human leukocyte antigen match, inclusion in the Eurotransplant Acceptable Mismatch Program when applicable, apheresis, anti-CD20 therapy, posttransplant antibody monitoring, and protocol biopsies. Thirty-four high-risk recipients of a deceased donor kidney (DDK: n=28) or living donor kidney (LDK: n=6) were transplanted using this algorithm.

Genetic polymorphisms of adhesion molecules and kidney transplant survival.

BACKGROUND.: Adhesion molecules play a key role in the recruitment of leukocytes to sites of inflammation. Genetic polymorphisms of adhesion molecules may alter their expression or function and may thereby influence the process of leukocyte infiltration in the transplanted organ.