A prospective, randomized trial of complete avoidance of steroids in liver transplantation with follow‐up of over 7 years

Objectives Steroids are a mainstay of treatment in orthotopic liver transplantation ( OLT ) and are associated with significant morbidity. This trial was conducted to assess the efficacy of steroids avoidance. Methods Patients undergoing OLT between June 2002 and April 2005 were entered into a prospective, randomized trial of complete steroids avoidance and followed until November 2011. Recipients received either standard therapy ( n = 50) or complete steroids avoidance ( n = 50). Analyses were performed on an intention‐to‐treat basis. The mean follow‐up of all recipients was 2095 ± 117 days. Sixteen (32%) recipients randomized to the steroids avoidance group ultimately received steroids for clinical indications. Results Incidences of diabetes and hypertension prior to or after OLT were similar in both groups, as was the incidence of rejection. Patient and graft survival rates at 1, 3 and 5 years were lower in the steroids avoidance group than in the standard therapy group (patient survival: 1‐year, 80% versus 86%; 3‐year, 68% versus 76%; 5‐year, 60% versus 72%; graft survival: 1‐year, 76% versus 76%; 3‐year, 64% versus 74%; 5‐year, 56% versus 72%), but the differences were not statistically different. Conclusions Complete steroids avoidance provides liver transplant recipients with minimal benefit and appears to result in a concerning trend towards decreased graft and recipient survival. The present data support the use of at least a short course of steroids after liver transplantation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97180/1/hpb576.pd

Transplantation tolerance: lessons from experimental rodent models

Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, rodent models have become an invaluable tool for elucidating the mechanisms of tolerance to alloantigens. Importantly, rodent models can be adapted to ensure that they reflect more accurately the immune status of human transplant recipients. More recently, the development of genetically modified mice has enabled specific insights into the cellular and molecular mechanisms that play a key role in both the induction and maintenance of tolerance to be obtained and more complex questions to be addressed. This review highlights strategies designed to induce alloantigen specific immunological unresponsiveness leading to transplantation tolerance that have been developed through the use of experimental models

A Mentee's perspective on Dr. Anthony Monaco: the quiet giant of transplantation

A mentee's perspective of an academic journey on a path paved by a pioneering transplant surgeon-scientist

Immunoregulation of transplant arteriosclerosis

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Immunoregulation of transplant arteriosclerosis

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

CD4+ Regulatory T Cells Generated in Vitro with IFN-γ and Allogeneic APC Inhibit Transplant Arteriosclerosis

We have developed a method to generate alloreactive regulatory T cells in vitro in the presence of interferon (IFN)-γ and donor antigen presenting cells (APCs). We hypothesized that these IFN-γ–conditioned T cells (Tcon) would reduce transplantation-associated arteriosclerosis. Tcon were generated from mouse (CBA.Ca, H-2k) CD4+ T cells cultured in the presence of IFN-γ for 14 days. These cultures were pulsed with bone marrow–derived B6 (H-2b) APC. 1 × 105 CD25−CD4+ effector T cells from naive H-2k mice were then cotransferred with 4 × 105 Tcon into CBA-rag−/− mice. One day later, these mice received a fully allogenic B6 CD31−/− abdominal aorta transplant. Transfer of CD25−CD4+ effectors resulted in 29.7 ± 14.5% luminal occlusion of allogeneic aortic grafts after 30 days. Cotransfer of Tcon reduced this occlusion to 11.7 ± 13.1%; P < 0.05. In addition, the CD31− donor endothelium was fully repopulated by CD31+ recipient endothelial cells in the absence of Tcon, but not in the presence of Tcon. In some experiments, we cotransplanted B6 skin with aortic grafts to ensure enhanced reactivation of the regulatory cells, which led to an additional reduction in vasculopathy (1.9 ± 3.0% luminal occlusion). In the presence of Tcon, CD4+ T cell infiltration into grafts was markedly reduced by a regulatory mechanism that included reduced priming and proliferation of CD25−CD4+ effectors. These data illustrate the potential of ex vivo generated regulatory T cells for the inhibition of transplant-associated vasculopathy

Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant

Donor brain death (BD) is an inherent part of lung transplantation (LTx) and a key contributor to ischemia-reperfusion injury (IRI). Complement activation occurs as a consequence of BD in other solid organ Tx and exacerbates IRI, but the role of complement in LTx has not been investigated. Here, we investigate the utility of delivering nebulized C3a receptor antagonist (C3aRA) pretransplant to BD donor lungs in order to reduce post-LTx IRI. BD was induced in Balb/c donors, and lungs nebulized with C3aRA or vehicle 30 minutes prior to lung procurement. Lungs were then cold stored for 18 hours before transplantation into C57Bl/6 recipients. Donor lungs from living donors (LD) were removed and similarly stored. At 6 hours and 5 days post-LTx, recipients of BD donor lungs had exacerbated IRI and acute rejection (AR), respectively, compared to recipients receiving LD lungs, as determined by increased histopathological injury, immune cells, and cytokine levels. A single pretransplant nebulized dose of C3aRA to the donor significantly reduced IRI as compared to vehicle-treated BD donors, and returned IRI and AR grades to that seen following LD LTx. These data demonstrate a role for complement inhibition in the amelioration of IRI post-LTx in the context of donor BD