The Impact of Donor and Recipient Genetic Variation on Outcomes After Solid Organ Transplantation:a Scoping Review and Future Perspectives

At the outset of solid organ transplantation, genetic variation between donors and recipients was recognized as a major player in mechanisms such as allograft tolerance and rejection. Genome-wide association studies have been very successful in identifying novel variant-trait associations, but have been difficult to perform in the field of solid organ transplantation due to complex covariates, era effects, and poor statistical power for detecting donor-recipient interactions. To overcome a lack of statistical power, consortia such as the International Genetics and Translational Research in Transplantation Network have been established. Studies have focused on the consequences of genetic dissimilarities between donors and recipients and have reported associations between polymorphisms in candidate genes or their regulatory regions with transplantation outcomes. However, knowledge on the exact influence of genetic variation is limited due to a lack of comprehensive characterization and harmonization of recipients' or donors' phenotypes and validation using an experimental approach. Causal research in genetics has evolved from agnostic discovery in genome-wide association studies to functional annotation and clarification of underlying molecular mechanisms in translational studies. In this overview, we summarize how the recent advances and progresses in the field of genetics and genomics have improved the understanding of outcomes after solid organ transplantation

Patterns of 1,748 Unique Human Alloimmune Responses Seen by Simple Machine Learning Algorithms

Allele specific antibody response against the polymorphic system of HLA is the allogeneic response marker determining the immunological risk for graft acceptance before and after organ transplantation and therefore routinely studied during the patient’s workup. Experimentally, bead bound antigen- antibody reactions are detected using a special multicolor flow cytometer (Luminex). Routinely for each sample, antibody responses against 96 different HLA antigen groups are measured simultaneously and a 96-dimensional immune response vector is created. Under a common experimental protocol, using unsupervised clustering algorithms, we analyzed these immune intensity vectors of anti HLA class II responses from a dataset of 1,748 patients before or after renal transplantation residing in a single country. Each patient contributes only one serum sample in the analysis. A population view of linear correlations of hierarchically ordered fluorescence intensities reveals patterns in human immune responses with striking similarities with the previously described CREGs but also brings new information on the antigenic properties of class II HLA molecules. The same analysis affirms that “public” anti-DP antigenic responses are not correlated to anti DR and anti DQ responses which tend to cluster together. Principal Component Analysis (PCA) projections also demonstrate ordering patterns clearly differentiating anti DP responses from anti DR and DQ on several orthogonal planes. We conclude that a computer vision of human alloresponse by use of several dimensionality reduction algorithms rediscovers proven patterns of immune reactivity without any a priori assumption and might prove helpful for a more accurate definition of public immunogenic antigenic structures of HLA molecules. Furthermore, the use of Eigen decomposition on the Immune Response generates new hypotheses that may guide the design of more effective patient monitoring tests

How to recognize inborn errors of immunity in a child presenting with a malignancy: guidelines for the pediatric hemato-oncologist

Inborn errors of immunity (IEI) are a group of disorders caused by genetically determined defects in the immune system, leading to infections, autoimmunity, autoinflammation and an increased risk of malignancy. In some cases, a malignancy might be the first sign of an underlying IEI. As therapeutic strategies might be different in these patients, recognition of the underlying IEI by the pediatric hemato-oncologist is important. This article, written by a group of experts in pediatric immunology, hemato-oncology, pathology and genetics, aims to provide guidelines for pediatric hemato-oncologists on how to recognize a possible underlying IEI and what diagnostic tests can be performed, and gives some consideration to treatment possibilities

Multiple Sclerosis Outcomes after Cancer Immunotherapy

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes. METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution. RESULTS: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors. CONCLUSIONS: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS

Discovering genetic drivers in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

University of Minnesota Ph.D. dissertation. May 2019. Major: Biomedical Informatics and Computational Biology. Advisors: Caleb Kennedy, Claudia Neuhauser. 1 computer file (PDF); x, 128 pages + 2 supplementary tablesAcute graft-versus-host disease (GVHD) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HCT) that cause non-relapse morbidity and mortality. Although the increasing matching rate of the human leukocyte antigen (HLA) genes between donor and recipient (DR) has significantly reduced the risk of GVHD, clinically significant GVHD remains as a transplantation challenge, even in HLA-identical transplants. Candidate gene studies and genome-wide association studies have revealed susceptible individual genes and gene pairs from DR pairs that are associated with acute GVHD; however, the roles of genetic disparities between donor and recipient remain to be understood. To identify genetic factors linked to acute GVHD, we investigated the classical HLA and non-HLA genes and conducted a genome-wide clinical outcome association study. Assessment of 4,646 antigen recognition domain (ARD)-matched unrelated donor allo-HCT cases showed that the frequency of mismatches outside the ARD in HLA genes is very low when the DR pairs are matched at ARD. Due to the low frequency of amino acid mismatches in the non-ARD region and their reportedly weak alloimmune reactions, we suggest that the non-ARD sequence mismatches within the ARD-matched DR pairs have limited influence on the development of acute GVHD, and may not be a primary factor. The genome-wide clinical outcome association study between DR pairs observed multiple autosomal minor histocompatibility antigens (MiHAs) restricted by HLA typing, though their association with acute GVHD outcome was not statistically significant. This result suggests that HLA mismatching outweighs other genetic mismatches as contributors to acute GVHD risk. In the cases of female donors to male recipients, we identified the significant association of the Y chromosome-specific peptides encoded by PCDH11Y, USP9Y, UTY, and NLGN4Y with the acute GVHD outcome. Additionally, we developed a machine learning-based genetic variant selection algorithm for ultra-high dimensional transplant genomic studies. The algorithm successfully selected a set of genes from over 1 M genetic variants, all of which have evidence to be linked to the transplant-related complications. This work offers evidence and guidance for further research in acute GVHD and allo-HCT and provides useful bioinformatics and data mining tools for transplant genomic studies

Immunodeficiency-associated viral oncogenesis

AbstractSeveral viruses with different replication mechanisms contribute to oncogenesis by both direct and indirect mechanisms in immunosuppressed subjects after solid organ transplantation, after allogeneic stem cell transplantation, or with human immunodeficiency virus (HIV) infection. Epstein–Barr virus (EBV), human papillomavirus (HPV), Kaposi sarcoma herpesvirus (KSHV), human T-cell lymphotropic virus type 1 (HTLV-1) and Merkel cell polyoma virus (MCV) are the main viruses associated with the development of cancer in immunosuppressed patients. Besides being a main cause of immunodeficiency, HIV1 has a direct pro-oncogenic effect. In this review, we provide an update on the association between the condition of acquired immunodeficiency and cancer risk, specifically addressing the contributions to oncogenesis of HPV, MCV, KSHV, HTLV-1, and EBV

In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation.

Regulatory T cells (Tregs) have been shown to be critical in the balance between autoimmunity and tolerance and have been implicated in several human autoimmune diseases. However, the small number of Tregs in peripheral blood limits their therapeutic potential. Therefore, we developed a protocol that would allow for the expansion of Tregs while retaining their suppressive activity. We isolated CD4+CD25 hi cells from human peripheral blood and expanded them in vitro in the presence of anti-CD3 and anti-CD28 magnetic Xcyte Dynabeads and high concentrations of exogenous Interleukin (IL)-2. Tregs were effectively expanded up to 200-fold while maintaining surface expression of CD25 and other markers of Tregs: CD62L, HLA-DR, CCR6, and FOXP3. The expanded Tregs suppressed proliferation and cytokine secretion of responder PBMCs in co-cultures stimulated with anti-CD3 or alloantigen. Treg expansion is a critical first step before consideration of Tregs as a therapeutic intervention in patients with autoimmune or graft-versus-host disease

Paving the way for precision medicine v2.0 in intensive care by profiling necroinflammation in biofluids

Current clinical diagnosis is typically based on a combination of approaches including clinical examination of the patient, clinical experience, physiologic and/or genetic parameters, high-tech diagnostic medical imaging, and an extended list of laboratory values mostly determined in biofluids such as blood and urine. One could consider this as precision medicine v1.0. However, recent advances in technology and better understanding of molecular mechanisms underlying disease will allow us to better characterize patients in the future. These improvements will enable us to distinguish patients who have similar clinical presentations but different cellular and molecular responses. Treatments will be able to be chosen more "precisely", resulting in more appropriate therapy, precision medicine v2.0. In this review, we will reflect on the potential added value of recent advances in technology and a better molecular understanding of necrosis and inflammation for improving diagnosis and treatment of critically ill patients. We give a brief overview on the mutual interplay between necrosis and inflammation, which are two crucial detrimental factors in organ and/or systemic dysfunction. One of the challenges for the future will thus be the cellular and molecular profiling of necroinflammation in biofluids. The huge amount of data generated by profiling biomolecules and single cells through, for example, different omic-approaches is needed for data mining methods to allow patient-clustering and identify novel biomarkers. The real-time monitoring of biomarkers will allow continuous (re)evaluation of treatment strategies using machine learning models. Ultimately, we may be able to offer precision therapies specifically designed to target the molecular set-up of an individual patient, as has begun to be done in cancer therapeutics

Assessing the human immune system through blood transcriptomics

Blood is the pipeline of the immune system. Assessing changes in transcript abundance in blood on a genome-wide scale affords a comprehensive view of the status of the immune system in health and disease. This review summarizes the work that has used this approach to identify therapeutic targets and biomarker signatures in the field of autoimmunity and infectious disease. Recent technological and methodological advances that will carry the blood transcriptome research field forward are also discussed

The Process of Organ Donation from Non-Living Donors: A Case-Based Journey from Potential Donor Identification to Organ Procurement

Each year, thousands of people worldwide succumb to end-organ failure while awaiting life-saving transplantation procedures. The shortage of organs continues with no signs of easing in the foreseeable future. The availability of organs from living donors continues to be constrained. At the same time, the cumulative knowledge of organ preservation is advancing steadily resulting in an enhanced ability to utilize a growing number of previously unsuitable tissue and organ gifts. Our ability to procure and preserve more organs is accompanied by the increasing use of so-called “expanded criteria” donors, or those whose organs may not have been suitable without modern advances in organ preservation science. Within the overall context of organ donation from non-living donors, the importance of physiologic and end-organ optimization cannot be understated. This chapter discusses our current state of understanding of optimized organ procurement approaches derived from practical experiences and “lessons learned” at a high-performing, community-based tertiary referral hospital