Impact of everolimus plus calcineurin inhibitor on formation of non-HLA antibodies and graft outcomes in kidney transplant recipients: 12-month results from the ATHENA substudy.

Background: Non-human leukocyte antigen (non-HLA) antibodies including antibodies targeting Angiotensin II type 1 (AT1R) and Endothelin-1 type A (ETAR) receptors represent a topic of interest in kidney transplantation (KTx). This exploratory substudy evaluated the impact of everolimus (EVR) or mycophenolic acid (MPA) in combination with tacrolimus (TAC) or cyclosporine A (CsA) in patients with preformed non-HLA antibodies, potentially associated rejections and/or their impact on renal function over 1 year. Methods: All eligible patients were randomized (1:1:1) before transplantation to receive either EVR/TAC, EVR/CsA, or MPA/TAC regimen. The effect of these regimens on the formation of non-HLA antibodies within one year post de novo KTx and the association with clinical events was evaluated descriptively in randomized (n = 268) population. Results: At Month 12, in EVR/TAC group, higher incidence of patients negative for AT1R- and ETAR-antibodies (82.2% and 76.7%, respectively) was noted, whereas the incidence of AT1R- and ETAR-antibodies positivity (28.1% and 34.7%, respectively) was higher in the MPA/TAC group. Non-HLA antibodies had no influence on clinical outcomes in any treatment group and no graft loss or death was reported. Conclusions: The studied combinations of immunosuppressants were safe with no influence on clinical outcomes and suggested minimal exposure of calcineurin inhibitors for better patient management. Clinical Trial Registration: https://clinicaltrials.gov/ (NCT01843348; EudraCT number: 2011-005238-21).

The emerging field of non-human leukocyte antigen antibodies in transplant medicine and beyond.

The major medical advances in our knowledge of the human leukocyte antigen (HLA) system have allowed us to uncover several gaps in our understanding of alloimmunity. Although the non-HLA system has long sparked the interest of the transplant community, recognition of the role of immunity to non-HLA antigenic targets has only emerged recently. In this review, we will provide a comprehensive summary of the paradigm-changing concept of immunity to the non-HLA angiotensin II type 1 receptor (AT1R), discovered by Duska Dragun et al., that began from careful bedside clinical observations, to validated detection of anti-AT1R antibodies and lead to clinical intervention. This scientific approach has also allowed the recognition of broader pathogenicity of anti-AT1R antibodies across multiple organ transplants and in other human diseases, the integration of both non-HLA and HLA systems to understand their immunologic effects on organ allografts, and the identification of future directions for therapeutic intervention to modulate immunity to AT1R. Rationally designed successful interventions to target AT1R system provide an exemplar for other non-HLA antibodies to cross borders between medical specialties, will generate new avenues in translational research beyond transplantation, and will foster the development of new and reliable tools to improve our understanding of non-HLA immunity and ultimately allow us to improve patient care.

Genetics of systemic sclerosis.

Systemic sclerosis is an autoimmune disease characterized by generalized fibrosis in connective tissues and internal organs as consequences of microvascular dysfunction and immune dysfunctions, which leads to premature death in affected individuals. The etiology of systemic sclerosis is complex and poorly understood, but as with most autoimmune diseases, it is widely accepted that both environmental and genetic factors contribute to disease risk. During the last decade, the number of genetic markers convincingly associated with systemic sclerosis has exponentially increased. In this article, we briefly mention the genetic components of systemic sclerosis. Then, we review the classical and novel genetic associations with systemic sclerosis, analyzing the firmest and replicated signals within non-human leukocyte antigen genes, identified by both candidate gene approach and genome-wide association studies. We also provide an insight into the future perspectives that will shed more light into the complex genetic background of the disease. Despite the remarkable advance of systemic sclerosis genetics during the last decade, the use of the new genetic technologies such as next-generation sequencing, as well as the deep phenotyping of the study cohorts, to fully characterize the genetic component of this disease is imperative to identify causal variants, which leads to more targeted and effective treatment of systemic sclerosis.

Angiotensin II type I receptor antibodies in pediatric solid organ transplant.

Minimizing immunologic complications is critical for long-term patient survival in pediatric solid organ transplant recipients. Multiple factors distinguish pediatric from adult organ transplant recipients which may influence the risk and manifestations of immunologic responses. Angiotensin II type 1 receptor antibody (AT1R-Ab) is a non-HLA antibody that has been has been associated with poor clinical outcomes in adult kidney transplant recipients. There is now limited evidence available to suggest that AT1R-Ab may be an important part of the immunologic milieu impacting pediatric organ transplant outcomes and that differences in this phenomenon may exist between pediatric and adult patients. The mechanisms by which autoimmunity is provoked and mediates organ dysfunction in childhood and effective treatment options require further research.

Cardiac Non-Human Leukocyte Antigen Identification: Techniques and Troubles.

Historically efforts have focused on the human leukocyte antigen (HLA) as the major cause for acute and chronic rejection following cardiac transplantation. However, rising evidence indicates that non-HLA antibodies can be both primary initiators and modifiers of antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV). The purpose of this review is to assess currently available technologies for non-HLA identification and leveraging such responses toward antibody quantification. Several techniques have been used to identify antigenic determinants of recipient graft-specific non-HLA humoral immune responses, but each comes with its own set of benefits and caveats. Improving our ability to detect non-HLA humoral immune response will aid in our understanding of the underlying antigenic determinants of AMR and CAV, as well as improve patient outcomes.

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes.

The outcome of hematopoietic stem cell transplantation (HSCT) is controlled by genetic factors among which the leukocyte antigen human leukocyte antigen (HLA) matching is most important. In addition, minor histocompatibility antigens and non-HLA gene polymorphisms in genes controlling immune responses are known to contribute to the risks associated with HSCT. Besides single-nucleotide polymorphisms (SNPs) in protein coding genes, SNPs in regulatory elements such as microRNAs (miRNAs) contribute to these genetic risks. However, genetic risks require for their realization the expression of the respective gene or miRNA. Thus, gene and miRNA expression studies may help to identify genes and SNPs that indeed affect the outcome of HSCT. In this review, we summarize gene expression profiling studies that were performed in recent years in both patients and animal models to identify genes regulated during HSCT. We discuss SNP-mRNA-miRNA regulatory networks and their contribution to the risks associated with HSCT in specific examples, including forkheadbox protein 3 and regulatory T cells, the role of the miR-155 and miR-146a regulatory network for graft-versus-host disease, and the function of MICA and its receptor NKG2D for the outcome of HSCT. These examples demonstrate how SNPs affect expression or function of proteins that modulate the alloimmune response and influence the outcome of HSCT. Specific miRNAs targeting these genes and directly affecting expression of mRNAs are identified. It might be valuable in the future to determine SNPs and to analyze miRNA and mRNA expression in parallel in cohorts of HSCT patients to further elucidate genetic risks of HSCT.

Impact of Non-Human Leukocyte Antigen-Specific Antibodies in Kidney and Heart Transplantation.

The presence of donor human leukocyte antigen (HLA)-specific antibodies has been shown to be associated with graft loss and decreased patient survival, but it is not uncommon that donor-specific HLA antibodies are absent in patients with biopsy-proven antibody-mediated rejection. In this review, we focus on the latest findings on antibodies against non-HLA antigens in kidney and heart transplantation. These non-HLA antigens include myosin, vimentin, Kα1 tubulin, collagen, and angiotensin II type 1 receptor. It is suggested that the detrimental effects of HLA antibodies and non-HLA antibodies synergize together to impact graft outcome. Injury of graft by HLA antibodies can cause the exposure of neo-antigens which in turn stimulate the production of antibodies against non-HLA antigens. On the other hand, the presence of non-HLA antibodies may increase the risk for a patient to develop HLA-specific antibodies. These findings indicate it is imperative to stratify the patient's immunologic risk by assessing both HLA and non-HLA antibodies.

Minor H antigen matches and mismatches are equally distributed among recipients with or without complications after HLA identical sibling renal transplantation.

Studies of the effect of minor H antigen mismatching on the outcome of renal transplantation are scarce and concern mainly single center studies. The International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 16 laboratories of the IHIW, the role of 15 autosomal, 10 Y-chromosome encoded minor H antigens and 3 CD31 polymorphisms, was investigated in relation to the incidence of renal graft rejection and graft loss in 444 human leukocyte antigens (HLA)-identical sibling renal transplantations. Recipient and donor DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, C19Orf48, LB-ECGF-1, CTSH, LRH-1, LB-ADIR and HY. The correlation between minor H antigen mismatch and the primary outcome graft rejection or graft loss was statistically analyzed. The incidence of rejection was very low and no correlation was observed between one or more minor H antigen mismatch(es) and a rejection episode (n = 36), of which only eight resulted in graft loss. In summary, in our study cohort of 444 renal transplants, mismatching for neither autosomal nor HY minor H antigens correlate with rejection episodes or with graft loss.