Ischemia/reperfusion injury (IRI) is a multi‐factorial antigen‐independent inflammatory condition that profoundly affects both early and long‐term function of the allograft as suggested by both ...clinical and experimental data. In recent years, the acute phase of IRI has been increasingly viewed as part of the innate immune response. Identification of novel molecular pathways and new insights into the mechanisms of known mediators of IRI have established links among innate immunity, adaptive immune responses and organ regeneration, and thus long‐term graft function. This review approaches these novel aspects of IRI in the context of solid organ transplantation, presenting data on new observations with kidney, liver and heart allografts.
Recent studies demonstrate that the human microbiota, the collection of microorganisms growing on and in individuals, have numerous bidirectional interactions with the host, influencing immunity, ...resistance to infection, inflammation and metabolism. Little has been done to study the potential associations between microbiota composition and transplant outcome. Here, we investigated the longitudinal changes in the blood, urinary, oral and rectal microbiota of renal allograft recipients before and at 1 and 6 months after transplantation. The results showed major changes in microbiota composition as a result of the transplant episode and associated medications, and these changes persisted over time. The high interindividual variation as well as differences in response to transplantation suggested that it is unlikely that the same specific microbiota members can serve as universal diagnostic markers. Rather, longitudinal changes in each individual's microbiota have the potential to be indicative of health or disease. Use of sensitive nucleic acid–based testing showed that urine, irrespective of disease states, more often harbors a diverse microbiota than appreciated by conventional culture techniques. These results lay the groundwork to construct more comprehensive future investigations to identify microbiota characteristics that can serve as diagnostic markers for transplant health and to guide intervention strategies to improve transplant outcome.
Sequencing and classification of oral, rectal, and urinary microbiota of renal allograft recipients reveal significant changes in the structure and diversity of the microbiota resulting from the transplant, with large inter‐individual variations with changes that persist over time.
Depletional induction therapies are routinely used to prevent acute rejection and improve transplant outcome. The effects of depleting agents on T‐cell subsets and subsequent T‐cell reconstitution ...are incompletely defined. We used flow cytometry to examine the effects of rabbit antithymocyte globulin (rATG) on the peripheral T‐cell repertoire of pediatric and adult renal transplant recipients. We found that while rATG effectively depleted CD45RA+CD27+ naïve and CD45RO+CD27+ central memory CD4+ T cells, it had little effect on CD45RO+CD27− CD4+ effector memory or CD45RA+CD31−, CD45RO+CD27+ and CD45RO+CD27− CD8+ T cell subsets. When we performed a kinetic analysis of CD31+ recent thymic emigrants and CD45RA+/RO+ T cells, we found evidence for both thymopoiesis and homeostatic proliferation contributing to immune reconstitution. We additionally examined the impact of rATG on peripheral CD4+Foxp3+ T cells. We found that in adults, administration of rATG‐induced peripheral expansion and new thymic emigration of T cells with a Treg phenotype, while CD4+Foxp3+ T cells of thymic origin predominated in children, providing the first evidence that rATG induces Treg in vivo. Collectively our data indicate that rATG alters the balance of regulatory to memory effector T cells posttransplant, providing an explanation for how it positively impacts transplant outcome.
This prospective study examines the contribution of thymopoiesis versus homeostatic proliferation to immune reconstitution following rATG and the influence of rATG on the emergence of Treg in renal transplant recipients.
The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite ...this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use “kidney“ rather than “renal” or “nephro-” when referring to kidney disease and kidney function; (ii) to use “kidney failure” with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than “end-stage kidney disease”; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than “abnormal” or “reduced” kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication.
Natural killer (NK) cells have been characterized classically for their cytotoxicity against pathogen infected or stressed cells as well as for their role in monitoring the expression of self MHC I. ...However, the participation of NK cells in solid organ transplantation (SOT) is poorly defined due to conflicting clinical and animal model data. Preclinical models have shown that NK cells exacerbate T‐cell allogeneic responses during rejection, but can also promote tolerance induction under immunosuppressive conditions. Further, while protocols such as costimulatory blockade effectively induce tolerance by blocking T‐cell activation and promoting Treg generation, how such regimens regulate other innate and adaptive immune cells, including NK cells, is incomplete. This review examines NK cells and the regulation of their effector functions in SOT.
Knowledge demonstrating the inflammatory as well as regulatory roles of natural killer cells in solid organ transplantation is discussed, drawing from other immune models to provide mechanistic insight.
The lymphotoxin system (LT) regulates interactions between lymphocytes and stromal cells to maintain lymphoid microenvironmental homeostasis. Soluble LT beta‐receptor‐Ig (LTβRIg) blocks lymphocyte ...LTα1β2‐stromal cell LTβR signaling. In a murine cardiac allograft model, LTbRIg treatment reversed the tolerance induced by anti‐CD40L antibody leading to graft inflammation and fibrosis. LTβRIg treatment decreased PD‐L1 expression by blood endothelial cells, and decreased VCAM‐1 while increasing CXCL1, CXCL2, CXCL12, CCL5, CCL21 and IL‐6 expression in fibroblastic reticular cells. In secondary lymphoid organs these effects caused T‐ and B cell zone disruption, loss of CD35+ follicular dendritic cells and abnormal recruitment of CD11b+Ly6G+ neutrophils. These disruptions correlated with increased numbers of CD8+ T cells and CD11b+Ly6G+ neutrophils, and decreased numbers of CD4+ T cells and Foxp3+ regulatory T cells in the grafts. Depleting neutrophils or blocking neutrophil‐attracting chemokines restored normal histology in lymph node, spleen and grafts. Taken together, LTβRIg treatment altered stromal subset, particularly fibroblastic reticular cell, production of cytokines and chemokines, resulting in changes in neutrophil recruitment in spleen, lymph node and grafts, and inflammation and fibrosis associated with decreased Foxp3+ regulatory T cells and increased CD8+ T cell infiltration of grafts.
Lymphotoxin‐beta receptor blockade induces inflammation with neutrophils and CD8 T cells, and fibrosis in tolerized cardiac allografts.
•Silk is a novel biomaterial for islet cell delivery in vivo to treat diabetes.•Islet cell-function post transplantation is challenged by an inflammatory reaction.•Islet cell-silk contact increases ...GLUT2 transporter expression on islet cell surface.
Silk fibroin is a novel biomaterial for enhancing transplanted islet cell function and survival. This study investigated whether silk fibroin may have unique properties that improve islet function in the face of inflammatory-mediated stress during transplantation. Murine islet function was tested in vitro with either silk fibroin or alginate and challenged with inflammatory cytokines. The glucose-stimulated insulin secretion index for all conditions decreased with inflammatory cytokines, but was better preserved for islets exposed to silk compared to those exposed to alginate or medium. GLUT2 transporter expression on the cell surface of islets exposed to silk was increased compared to alginate or medium alone. Upon cytokine stress, a greater percentage of islet cells exposed to silk expressed GLUT2 on their surface. We conclude that preconditioning islets with silk fibroin stimulates islet cell surface GLUT2 expression, an increase, which persists under inflammatory stress, and may improve islet engraftment and function after transplantation.
What's Hot, What's New at WTC—Basic Science Bromberg, J. S.
American journal of transplantation,
February 2015, 2015-Feb, 2015-02-00, 20150201, Volume:
15, Issue:
2
Journal Article, Conference Proceeding
Peer reviewed
Open access
The World Transplant Congress of 2014 presented a broad swath of science that touched on many disparate aspects of cell and organ transplantation, molecular and cellular immunology, systems biology, ...development, technology and translation into humans. A number of themes emerged this year. B cell biology and antibody chemistry were prominent, as they have been for several years. T cells, co‐stimulatory blockade and regulatory T cells continue to dominate many aspects of immune research. Many new aspects of monocyte, macrophage, NK cell and NK T cell development, biology and regulation are now being explored. Diverse aspects of organ injury and the acute and chronic responses to injury are being investigated with new techniques, new targets and a resurgent vigor. Novel advances in xenotransplantation and experimental tolerance garnered much attention. Newer investigations in microbiota and nanotechnology promise significant gains in the near future. Lastly the ‘omics of DNA, RNA, proteins, metabolites, bacteria and enzyme actions promise new understanding in biological systems and how to control those systems.
This meeting report features highlights of the basic science presentations from the 2014 World Transplant Congress in San Francisco.
To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS).
A phase II trial was conducted at 10 sites in the Western ...ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls.
The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate (-1.20/month, 95% confidence interval CI -1.41 to -0.98) than that in 249 control patients (-1.01/month, 95% CI -1.11 to -0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group.
The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents.
This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months.
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