Highlights in Basic Sciences

Attending the sunrise symposia at the World Transplant Congress, I asked myself “why am I sitting in this room at 7 AM and enjoying myself with coffee and muffins?” Is it to gain new insights, to get new ideas or to hear the latest discoveries through basic scientific research? I believe it was all three. The large attendance at these sunrise symposia reflected the quality of presentations and the interest of the audience at the WTC in basic and translational sciences from which we build solutions to the current problems in organ transplantation. It is clear that finding solutions for the inevitable graft failure and lifelong dependence on toxic immunosuppressive drugs is the main driver of our research. Finding answers and moving forward with small and hopefully some big steps with the support of outstanding basic and translational research presentations seems critical. In San Francisco, it was clear that this is now more than ever recognized by the transplantation community. Lively discussions about biomarkers, experimental protocols, novel diagnostics, mechanistic insights, and translational explorations of immunosuppression and potential alternatives stand for an integrated approach of basic and translational research. The consensus on working with standardized laboratory protocols was reassuring and seemed to be a breakthrough, reflecting the new mindset that the joined and collaborative effort has the potential for big strides.1 Highlights in innate immunity were the diversity and significance of natural killer (NK) cells. Addressed by Alexander Kroemer (University Hospital, Regensburg, Germany) in this issue of Transplantation, mature CD27low NK cells seem to promote allograft survival under costimulation blockade conditions by regulating memory CD8+ T cell responses.2 This finding demonstrates the critical role of this cell population in linking innate and adaptive immunity. A recurring theme at the meeting had been the role of immunologic memory and the impact on alloreactivity. For decades, we have learned that immunological memory is a feature exclusive of the adaptive immune system. Indeed, players of innate immunity seem to have recall capacities as well. Lewis Lanier from the University of California demonstrated that NK cells can become long-lived memory cells that recall previous antigen contacts and contribute with recall immune responses.3 Whether these newly identified features of NK cells are involved in alloimmune responses toward the transplanted organ is unclear and will provide a novel and exciting field of interest. Immunological memory may also be exchanged between specialized T cells that express surface antigens associated with NK cells. Those so-called natural killer T cells (NKT) cells express an invariant T cell receptor and have been coined type I NKT cells. For the first time, it has been shown in a mouse allogeneic hepatocyte transplant model that the cognate interaction between these type I NKT cells and B cells enhanced the in vivo production of antibodies.4 Stressing the interest in B cells, an overwhelming amount of presentations provided novel aspects of antibody-mediated immune responses after transplantation. Presentations ranged from novel assays that quantified the number of alloantigen-specific B cells,5 explicit discussions on the importance of (non)complement fixing donor-specific antibodies in rejection, to agents that are involved in T follicular helper cell-B cell interactions6 in addition to specific target B-functions.7,8 Of note, CTLA-Ig seemed to interfere with ongoing B-cell responses.6 Moreover, agents blocking interleukin-6 pathways, such as tocilizumab, modulated B-cell activation in HLA–sensitized patients.9 This interplay provides novel and intriguing opportunities in targeting T follicular helper cells and by doing so, interfering with subsequent B-cell activation, novel approaches that target antibody-mediated allogeneic responses. Indeed, new biologicals like the humanized interleukin-21 receptor antibodies are on the way that interfere with those pathways. Shifting gears: cell therapies are receiving increasing attention. Although having been around for many years, optimized in vitro expansion protocols with an emphasis on moving administrative hurdles out of the way, cell therapy has made its way to the therapeutic forefront in transplantation. GMP expansion (good manufacturing protocols) has been approved for regulatory T cell therapy and the ONE Study is spearheading novel therapeutic applications.10 Clear goals lead the way: (i) minimization of immunosuppression; (ii) individualized immunosuppression, and (iii) tolerance induction. Additional studies applying expanded bone marrow–derived mesenchymal stem cells are enrolling kidney and liver transplant patients. We are looking forward to the first results of those exciting trials at the next transplant congresses. On a mechanistic basis, intriguing data have been presented which explored processes of cellular death: apoptosis and necroptosis. Tony Jevnikar (London Health Sciences Centre, Ontario, Canada) and Andreas Linkermann (Christian-Albrechts University, Kiel, Germany) provided impressive insights on why those processes are so relevant. The newly identified receptor interacting protein 1 and 3 kinase–mediated necroptotic pathways and determine allograft survival. For example, receptor interacting protein 1 and 3 kinase–deficient heart has long-term graft survival with only minimal immunosuppression.11 The scientific organizing team of the congress put together a list of outstanding presentations on breakthroughs and discoveries in transplantation immunology, such as biomarkers, immunologic memory and cell therapy, and this commentary only touches on a few of the highlights presented. The scientific quality was overall superb. The wide range of topics presented provided many novel ideas with direct translational potential that may help to improve transplant outcomes while opening avenues for developing less toxic immunosuppressive drugs. Already looking forward to the next meeting! Carla C. Baan Erasmus Medical Center Rotterdam, The Netherlands

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