Explore the vast range of titles available.

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes.

RituxiCAN-C4 combined an open-labeled randomized controlled trial (RCT) in 7 UK centers to assess whether rituximab could stabilize kidney function in patients with chronic rejection, with an exploratory analysis of how B cell-depletion influenced T cell anti-donor responses relative to outcome. Between January 2007 and March 2015, 59 recruits were enrolled after screening, 23 of whom consented to the embedded RCT. Recruitment was halted when in a pre-specified per protocol interim analysis, the RCT was discovered to be significantly underpowered. This report therefore focuses on the exploratory analysis, in which we confirmed that when B cells promoted CD4+ anti-donor IFNγ production assessed by ELISPOT, this associated with inferior clinical outcome; these patterns were inhibited by optimized immunosuppression but not rituximab. B cell suppression of IFNγ production, which associated with number of transitional B cells and correlated with slower declines in kidney function was abolished by rituximab, which depleted transitional B cells for prolonged periods. We conclude that in this patient population, optimized immunosuppression but not rituximab promotes anti-donor alloresponses associated with favorable outcomes. Registered with EudraCT (2006-002330-38) and www.ClinicalTrials.gov, identifier: NCT00476164.

Regulatory T cells (Treg cells) are a small subset of immune cells that are dedicated to curbing excessive immune activation and maintaining immune homeostasis. Accordingly, deficiencies in Treg cell development or function result in uncontrolled immune responses and tissue destruction and can lead to inflammatory disorders such as graft-versus-host disease, transplant rejection and autoimmune diseases. As Treg cells deploy more than a dozen molecular mechanisms to suppress immune responses, they have potential as multifaceted adaptable smart therapeutics for treating inflammatory disorders. Indeed, early-phase clinical trials of Treg cell therapy have shown feasibility, tolerability and potential efficacy in these disease settings. In the meantime, progress in the development of chimeric antigen receptors and in genome editing (including the application of CRISPR–Cas9) over the past two decades has facilitated the genetic optimization of primary T cell therapy for cancer. These technologies are now being used to enhance the specificity and functionality of Treg cells. In this Review, we describe the key advances and prospects in designing and implementing Treg cell-based therapy in autoimmunity and transplantation.

Solid organ transplantation is a curative therapy for hundreds of thousands of patients with end-stage organ failure. However, long-term outcomes have not improved, and nearly half of transplant recipients will lose their allografts by 10 years after transplant. One of the major challenges facing clinical transplantation is antibody-mediated rejection (AMR) caused by anti-donor HLA antibodies. AMR is highly associated with graft loss, but unfortunately there are few efficacious therapies to prevent and reverse AMR. This Review describes the clinical and histological manifestations of AMR, and discusses the immunopathological mechanisms contributing to antibody-mediated allograft injury as well as current and emerging therapies.

Background Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMIGD) is a disease entity classified under the group of “Monoclonal gammopathy-related kidney diseases”, and can recur after transplant. Clinical remission of proteinuria in patients with PGNMIGD has been previously shown following anti-B cell and/or anti-plasma cell therapies. Our case is the first to show complete histologic resolution of the glomerular monoclonal IgG kappa deposits in a case of recurrent PGNMIGD in renal allograft after rituximab and steroid treatment. This is a novel finding and it shows that the deposits are amenable to therapy. This case also highlights the importance of IgG subclass staining in the recognition of the monoclonal nature of the deposits. It is particularly important in PGNMIGD because only 20 to 30% of patients with this disease are reported to have detectable monoclonal gammopathy, and the deposits do not have any organized substructure on electron microscopic examination. Morphologically, they resemble polyclonal immune-type deposits seen in other immune complex glomerulonephritides such as lupus nephritis, infection-associated glomerulonephritis, and membranoproliferative glomerulonephritis (MPGN type I). Case presentation The patient is a 44 year old Caucasian male who received a living unrelated donor kidney transplant for end-stage renal disease diagnosed 7 years before transplant. The reported native kidney biopsy diagnosis was membranoproliferative glomerulonephritis (MPGN) with IgG, C3 and kappa restricted deposits. Fourteen months post-transplant, he presented with abrupt worsening of graft function, proteinuria and serum IgG kappa monoclonal spike. Allograft biopsy was consistent with recurrent PGNMIGD, considering the native kidney diagnosis and interval post-transplant. He underwent plasmapheresis, IV pooled immune globulin, steroid pulse and taper, and anti-CD-20 Rituximab therapy. Patient had gradual decline in proteinuria and complete resolution of the immune deposits on repeat biopsy 3 months later. Unfortunately he subsequently developed chronic antibody-mediated rejection and transplant glomerulopathy and graft failure 34 months post-transplant. Conclusions In a transplant setting, repeat allograft biopsies are frequently performed for graft dysfunction. This provides a good opportunity to study the evolution of the immune deposits following treatment. Our case shows complete histologic resolution of the deposits in allograft PGNMIGD.

Modern immunosuppression regimens effectively control acute rejection and decrease graft loss in the first year after transplantation; however, these regimens do not have a durable effect on long-term graft survival owing to a combination of drug toxicities and the emergence of chronic alloimmune responses. Eliminating drugs and their toxicities while maintaining graft acceptance has been the primary aim of cellular therapies. Tregs suppress both autoimmune and alloimmune responses and are particularly effective in protecting allografts in experimental transplant models. Further, Treg-based therapies are selective, do not require harsh conditioning, and do not have a risk of graft-versus-host disease. Trial designs should consider the distinct immunological features of each transplanted organ, Treg preparations, dose, and frequency, and the ability to detect and quantify Treg effects in a given transplant environment. In this Review, we detail the ongoing clinical trials of Treg therapy in liver and kidney transplantation. Integration of Treg biology gleaned from preclinical models and experiences in human organ transplantation should allow for optimization of trial design that will determine the potential efficacy of a given therapy and provide guidelines for further therapeutic development.

Kidney transplantation is the best possible treatment for many patients with end-stage renal failure, but progressive dysfunction and eventual allograft loss with return to dialysis is associated with increased mortality and morbidity. Immune injury from acute or chronic rejection and non-immune causes, such as nephrotoxicity from calcineurin inhibitors, ischaemia-reperfusion injury, recurrent glomerular disease, and allograft BK viral infection, are potential threats. Serial monitoring of renal function enables early recognition of chronic allograft dysfunction, and investigations such as therapeutic drug concentrations, urinalysis, imaging, and a diagnostic biopsy should be undertaken before irreversible nephron loss has occurred. Specific interventions targeting the pathophysiological cause of dysfunction include strengthening of immunosuppression for chronic rejection, or calcineurin inhibitor minimisation, substitution, or elimination if nephrotoxicity dominates. Recommended proactive preventive measures are control of hypertension, proteinuria, dyslipidaemia, diabetes, smoking, and other comorbidities. Strategies to maintain transplant function and improve long-term graft survival are important goals of translational research.

Failure to engraft after hematopoietic stem cell transplantation (graft dysfunction) or to sustain engraftment (graft rejection) is a formidable complication due to many possible factors. These include inadequate stem cell numbers, infections, graft-versus-host disease and immunological mediated processes. Fortunately, this complication is uncommon and can be overcome by additional hematopoietic stem cell infusions. Multiple treatment alternatives have been explored including hematopoietic growth factors, additional infusions of stem cells alone, with augmented immunosuppression or with additional cytotoxic therapy. Various sources of the additional stem cells are feasible including the original donor, using another donor, using stem cells collected from the marrow or after cytokine mobilization from the peripheral blood. This report will overview this complication and review the various studies that have attempted to define both cause and therapy. However, a lack of well-designed prospective studies has made definitive recommendations difficult although basic principles have been established.

The introduction of C4d in daily clinical practice in the late nineties aroused an ever-increasing interest in the role of antibody-mediated mechanisms in allograft rejection. As a marker of classical complement activation, C4d made it possible to visualize the direct link between anti-donor antibodies and tissue injury at sites of antibody binding in a graft. With the expanding use of C4d worldwide several limitations of C4d were identified. For instance, in ABO-incompatible transplantations C4d is present in the majority of grafts but this seems to point at ‘graft accommodation’ rather than antibody-mediated rejection. C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy. In all these fields, C4d holds promise to detect patients at risk for the consequences of antibody-mediated disease. Moreover, the emergence of new therapeutics that block complement activation makes C4d a marker with potential to identify patients who may possibly benefit from these drugs. This review provides an overview of the past, present, and future perspectives of C4d as a biomarker, focusing on its use in solid organ transplantation and discussing its possible new roles in autoimmunity and pregnancy.

Induction of immune tolerance is the Holy Grail in transplantation medicine and autoimmunity. Currently, patients are required to use immunosuppressive drugs for the rest of their lives, resulting in unwanted side effects and complication from global suppression of the immune response. It is well established that regulatory T cells (Tregs) are critical for the maintenance of immune tolerance towards self-antigens by several mechanisms of immune regulation, in parallel with intrathymic deletion of self-reactive T cells during ontogeny. Therefore, approaches for increasing Treg numbers or function in vivo could provide an all-purpose solution for tolerance induction. Currently, most state-of-the-art therapeutics for treating autoimmune diseases or preventing allograft rejection work either by general immunosuppression or blocking inflammatory reactions and are non-specific. Hence, these approaches cannot provide satisfactory long-term results, let alone a cure. However, in animal models the therapeutic potential of Treg expansion for inducing effective tolerance has now been demonstrated in various models of autoimmunity and allogeneic transplantation. Here, we focus on therapies for increasing the size of the Treg pool by expanding endogenous Treg numbers in vivo or by adoptive transfer of Tregs. In particular, we discuss IL-2 based approaches (low dose IL-2, IL-2 complexes) for inducing Treg expansion in vivo as well as cell-based approaches (polyclonal, antigen specific, or cell engineered) for adoptive Treg therapy. We also mention new questions arising from the first clinical studies on Treg therapy in the fields of transplantation and autoimmunity.