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Over the past decade significant advancement has occurred in the biological and pathological role that Hp has in cardiovascular disease. Hp is an acute-phase protein with a role in the neutralization and clearance of free heme. Iron has tremendous potential for initiating vascular oxidation, inflammation and exacerbating coronary atherosclerosis. Hp genotype has been linked as a prognostic biomarker of acute myocardial infarction, heart failure, restenosis and cardiac transplant rejection. The increased understanding of Hp as a biomarker has provided new insights into the mechanisms of inflammation after cardiac injury and support the concept that Hp is not only an important antioxidant in vascular inflammation and atherosclerosis, but also an enhancer of inflammation in cardiac transplant.
The strongly immunogenic environment in autoimmune diseases such as lupus may pose a stringent barrier to transplantation. Despite available murine models of lupus, transplant tolerance in this setting has yet to be fully investigated in highly penetrant genetic models of disease. Such studies are of clear clinical importance because lupus is a transplant indication in which transplanted kidneys have a substantially increased risk of rejection including a role for recurrent nephritis. In the fully penetrant B6.SLE123 mouse, we determined that CD4 T follicular helper and germinal center B cells were significantly expanded compared with healthy controls. We traced this expansion to resistance of effector CD4 T and B cells in B6.SLE123 mice to regulation by either CD4 T regulatory cells (CD4Tregs) or CD8 T regulatory cells (CD8Tregs), despite demonstrating normal function by Tregs in this strain. Finally, we determined that B6.SLE123 mice resist anti-CD45RB-mediated tolerance induction to foreign islet allografts, even in the absence of islet autoimmunity. Overall, B6.SLE123 lupus-prone mice are highly resistant to transplant tolerance induction, which provides a new model of failed tolerance in autoimmunity that may elucidate barriers to clinical transplantation in lupus through further cellular and genetic dissection.
© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
BACKGROUND - In cardiac transplant recipients, the development of antibodies to the endothelial intermediate filament protein vimentin (antivimentin antibodies, AVA) has been associated with rejection and poor outcomes. However, the incidence of these antibodies prior to transplantation and their association with early rejection has not been investigated.
METHODS - Pre-transplant serum was analyzed from 50 patients who underwent de novo cardiac transplant at Johns Hopkins Hospital from 2004 to 2012. Demographic, one-yr rejection, and survival data were obtained from the transplant database.
RESULTS - The incidence of pre-transplant AVA was 34%. AVA-positive patients were younger (p = 0.03), and there was an a trend toward incidence in females (p = 0.08). Demographic data were similar among both groups. AVA positivity did not predict rejection in the first year post-transplant. There was no difference in rejection-free graft survival (53 vs. 52%, p = 0.85) at one yr. Similarly, there was no difference in graft survival at one yr (82 vs. 88%, p = 0.56) or graft survival at a median follow-up of 23 and 26 months, respectively (76 vs. 85%, p = 0.41).
CONCLUSIONS - AVA is common in the cardiac pre-transplant population with a higher incidence in the young. The presence of detectable AVA did not correlate with early post-transplant rejection or graft survival.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Delayed graft function in kidney transplant recipients is a known complication associated with increased risk of acute rejection and reduced transplant survival after 1 year. There are multiple risk factors, including prolonged cold ischemia time, donor age, and cause of donor's death. Major causes of delayed graft function are acute kidney injury in the donor, often from prolonged terminal ischemia, reflected by acute tubular injury in the recipient. However, the differential diagnosis of delayed graft function includes acute rejection, recurrence of the primary glomerular diseases, and other less commonly encountered conditions. A transplant kidney biopsy usually is required to elucidate the correct cause and initiate the right treatment, which is crucial for transplant survival. We report a case of a transplant recipient who developed delayed graft function due to an uncommon cause. After correct diagnosis, the patient's transplant function improved.
Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Seventeen days after double lung transplantation, a 56-year-old patient with idiopathic pulmonary fibrosis developed respiratory distress. Imaging revealed bilateral pulmonary infiltrates with pleural effusions and physical examination demonstrated sternal instability. Broad-spectrum antibacterial and antifungal therapy was initiated and bilateral thoracotomy tubes were placed. Both right and left pleural cultures grew a mold subsequently identified as Scopulariopsis brumptii. The patient underwent pleural irrigation and sternal debridement three times but pleural and wound cultures continued to grow S. brumptii. Despite treatment with five antifungal agents, the patient succumbed to his illness 67 days after transplantation. Autopsy confirmed the presence of markedly invasive fungal disease and pleural rind formation. The patient's organ donor had received bilateral thoracostomy tubes during resuscitation in a wilderness location. There were no visible pleural abnormalities at the time of transplantation. However, the patient's clinical course and the location of the infection, in addition to the lack of similar infection in other organ recipients, strongly suggest that Scopulariopsis was introduced into the pleural space during prehospital placement of thoracostomy tubes. This case of lethal infection transmitted through transplantation highlights the unique risk of using organs from donors who are resuscitated in an outdoor location.
© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.
We report herein application of an in situ material strategy to attenuate allograft T cell responses in a skin transplant mouse model. Functionalized peptidic membranes were used to impede trafficking of donor antigen-presenting cells (dAPCs) from skin allografts in recipient mice. Membranes formed by self-assembling peptides (SAPs) presenting antibodies were found to remain underneath grafted skins for up to 6 days. At the host-graft interface, dAPCs were targeted by using a monoclonal antibody that binds to a class II major histocompatibility complex (MHC) molecule (I-A(d)) expressed exclusively by donor cells. Using a novel cell labeling near-infrared nanoemulsion, we found more dAPCs remained in allografts treated with membranes loaded with anti-I-A(d) antibodies than without. In vitro, dAPCs released from skin explants were found adsorbed preferentially on anti-I-A(d) antibody-loaded membranes. Recipient T cells from these mice produced lower concentrations of interferon-gamma cultured ex vivo with donor cells. Taken together, the data indicate that the strategy has the potential to alter the natural course of rejection immune mechanisms in allogeneic transplant models.
Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
For the sake of therapy of diabetes, it is critical to understand human beta cell function in detail in health and disease. Current studies of human beta cell physiology in vivo are mostly limited to immunodeficient mouse models, which possess significant technical limitations. This study aimed to create a new model for the study of human islets through induction of transplant tolerance in immunosufficient mice. B6 diabetic mice were transplanted with human islets and treated with anti-CD45RB. To assess whether anti-CD45RB-induced transplant tolerance requires B cells, B6 recipients received additional anti-CD20 or B6μMT-/- mice were used. For some anti-CD45RB-treated B6μMT-/- mice, additional anti-CD25 mAb was applied at the early or late stage post-transplant. Immunohistology was performed to show the Foxp3 cells in grafted anti-CD45RB/anti-CD20-treated Foxp3-GFP B6 mice. The results showed that anti-CD45RB alone allowed indefinite graft survival in 26.6% of B6 mice, however 100% of xenografts were accepted in mice treated simultaneously with anti-CD20, and 88.9% of xenografts accepted in anti-CD45RB-treated μMT-/- mice. These μMT-/- mice accepted the islets from another human donor but rejected the islets from baboon. Additional administration of anti-CD25 mAb at the time of transplantation resulted in 100% rejection, whereas 40% of grafts were rejected while the antibody was administrated at days 60 post-transplant. Immunohistologic examination showed Foxp3+ cells accumulated around grafts. We conclude that induction of tolerance to human islets in an immunosufficient mouse model could be generated by targeting murine CD45RB and CD20. This new system will facilitate study of human islets and accelerate the dissection of the critical mechanisms underlying islet health in human disease.
© 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
BACKGROUND - There are increasing numbers of patients undergoing orthotopic heart transplantation (OHT) with left ventricular assist device (LVAD) explantation (LVAD explant-OHT). We hypothesized that LVAD explant-OHT is a more challenging surgical procedure compared to OHT without LVAD explantation and that institutional LVAD explant-OHT procedural volume would be associated with post-transplant graft survival. We sought to assess the impact of institutional volume of LVAD explant-OHT on post-transplant graft survival.
METHODS - This is a retrospective analysis of the Scientific Registry of Transplant Recipients for adult OHTs with long-term LVAD explantation. LVAD explant-OHT volume was characterized on the basis of the center's year-specific total OHT volume (OHTvol) and year-specific LVAD explant-OHT volume quartile (LVADvolQ). The effect of LVADvolQ on graft survival (death or re-transplantation) was analyzed.
RESULTS - From 2004 to 2011, 2,681 patients underwent OHT with LVAD explantation (740 with HeartMate XVE, 1,877 with HeartMate II and 64 with HeartWare devices). LVAD explant-OHT at centers falling in the lowest LVADvolQ was associated with reduced post-transplant graft survival (p = 0.022). After adjusting for annualized OHTvol (HR = 0.998, 95% CI 0.993 to 1.003, p = 0.515 and pulsatile XVE (HR = 0.842, 95% CI 0.688 to 1.032, p = 0.098), multivariate analysis confirmed a significantly (approximately 37%) increased risk of post-transplant graft failure among explant-OHT procedures occurring at centers in the lowest volume quartile (HR = 1.371, 95% CI 1.030 to 1.825, p = 0.030).
CONCLUSION - Graft survival is decreased when performed at centers falling in the lowest quartile of LVAD explant-OHT for a given year. This volume-survival relationship should be considered in the context of limited donor organ availability and the rapidly growing number of LVAD centers.
Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Modern immunosuppression and rabbit antithymocyte globulin (rATG) have facilitated the success of early steroid withdrawal (ESW) protocols. Little data exist on optimal rATG dosing in ESW protocols.
METHODS - Rejection at 12 months in era 1 (four doses of rATG, 1.25 mg/kg) vs. era 2 (three doses of rATG, 1.25 mg/kg) was the primary endpoint. Secondary endpoints included patient and graft survival, renal function and infectious complications. Factors associated with rejection at 1 year were identified.
RESULTS - 199 patients received rATG induction and ESW: 102 in era 1 and 97 in era 2. Compared to era 1, era 2 was not associated with worse outcomes, including rejection, renal function, infection or graft survival. Rejection at 1 year and uncensored graft survival differed between the dosing groups. Rejection rates were significantly higher in the <4 mg/kg group compared to the 4-5.9-mg/kg and the ≥6-mg/kg groups, whereas uncensored graft survival was the lowest in the ≥6-mg/kg group. Factors associated with rejection at 12 months included: rATG dose received of 4-5.9 versus <4 mg/kg (OR 0.20, 95% CI 0.036-0.85, p = 0.026); recipient age (per year, OR 0.94, 95% CI 0.89-1.0, p = 0.038); panel reactive antibody 10-79.9 versus <10% (OR 5.4, 95% CI 1.2-25, p = 0.030) and rATG dose held (OR 4.0, 95% CI 1.0-15, p = 0.049).
CONCLUSIONS - A comparison of rATG dosing based on era did not result in a significant difference in rejection, renal function, infection or graft survival. However, when evaluating the study population based on actual dose received there were notable differences in both rejection rates and uncensored graft survival.
© 2013 S. Karger AG, Basel.
CONTEXT - Islet transplantation can improve metabolic control for type 1 diabetes (T1D), an effect anticipated to improve insulin sensitivity. However, current immunosuppression regimens containing tacrolimus and sirolimus have been shown to induce insulin resistance in rodents.
OBJECTIVE - The objective of the study was to evaluate the effect of islet transplantation on insulin sensitivity in T1D using euglycemic clamps with the isotopic dilution method to distinguish between effects at the liver and skeletal muscle.
DESIGN, SETTING, AND PARTICIPANTS - Twelve T1D subjects underwent evaluation in the Clinical and Translational Research Center before and between 6 and 7 months after the transplant and were compared with normal control subjects.
INTERVENTION - The intervention included intrahepatic islet transplantation according to a Clinical Islet Transplantation Consortium protocol under low-dose tacrolimus and sirolimus immunosuppression.
MAIN OUTCOME MEASURES - Total body (M/Δinsulin), hepatic (1/endogenous glucose production ·basal insulin) and peripheral [(Rd - endogenous glucose production)/Δinsulin] insulin sensitivity assessed by hyperinsulinemic (1 mU·kg(-1)·min(-1)) euglycemic (∼90 mg/dL) clamps with 6,6-(2)H2-glucose tracer infusion were measured.
RESULTS - Glycosylated hemoglobin was reduced in the transplant recipients from 7.0% ± 0.3% to 5.6% ± 0.1% (P < .01). There were increases in total (0.11 ± 0.01 to 0.15 ± 0.02 dL/min·kg per microunit per milliliter), hepatic [2.3 ± 0.1 to 3.7 ± 0.4 × 10(2) ([milligrams per kilogram per minute](-1)·(microunits per milliliter)(-1))], and peripheral (0.08 ± 0.01 to 0.12 ± 0.02 dL/min·kg per microunit per milliliter) insulin sensitivity from before to after transplantation (P < .05 for all). All insulin sensitivity measures were less than normal in T1D before (P ≤ .05) and not different from normal after transplantation.
CONCLUSIONS - Islet transplantation results in improved insulin sensitivity mediated by effects at both the liver and skeletal muscle. Modern dosing of glucocorticoid-free immunosuppression with low-dose tacrolimus and sirolimus does not induce insulin resistance in this population.