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ABSTRACT: Despite extensive research on T cells and potent immunosuppressive regimens that target cellular mediated rejection, few regimens have been proved to be effective on antibody-mediated rejection (AMR), particularly in the chronic setting. C4d deposition in the graft has been proved to be a useful marker for AMR; however, there is an imperfect association between C4d and AMR. While complement has been considered as the main player in acute AMR, the effector mechanisms in chronic AMR are still debated. Recent studies support the role of NK cells and direct effects of antibody on endothelium cells in a mechanism suggesting the presence of a complement-independent pathway. Here, we review the history, currently available systems and progress in experimental animal research. Although there are consistent findings from human and animal research, transposing the experimental results from rodent to human has been hampered by the differences in endothelial functions between species. We briefly describe the findings from patients and compare them with results from animals, to propose a combined perspective.
Human immunology 07/2012; · 2.55 Impact Factor
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ABSTRACT: Denileukin diftitox (DD), a fusion protein comprising IL-2 and diphtheria toxin, was initially expected to enhance antitumor immunity by selectively eliminating regulatory T cells (Tregs) displaying the high-affinity IL-2R (α-β-γ trimers). Although DD was shown to deplete some Tregs in primates, its effects on NK cells (CD16(+)CD8(+)NKG2A(+)CD3(-)), which constitutively express the intermediate-affinity IL-2R (β-γ dimers) and play a critical role in antitumor immunity, are still unknown. To address this question, cynomolgus monkeys were injected i.v. with two doses of DD (8 or 18 μg/kg). This treatment resulted in a rapid, but short-term, reduction in detectable peripheral blood resting Tregs (CD4(+)CD45RA(+)Foxp3(+)) and a transient increase in the number of activated Tregs (CD4(+)CD45RA(-)Foxp3(high)), followed by their partial depletion (50-60%). In contrast, all NK cells were deleted immediately and durably after DD administration. This difference was not due to a higher binding or internalization of DD by NK cells compared with Tregs. Coadministration of DD with IL-15, which binds to IL-2Rβ-γ, abrogated DD-induced NK cell deletion in vitro and in vivo, whereas it did not affect Treg elimination. Taken together, these results show that DD exerts a potent cytotoxic effect on NK cells, a phenomenon that might impair its antitumoral properties. However, coadministration of IL-15 with DD could alleviate this problem by selectively protecting potentially oncolytic NK cells, while allowing the depletion of immunosuppressive Tregs in cancer patients.
The Journal of Immunology 05/2012; 188(12):6063-70. · 5.79 Impact Factor
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ABSTRACT: To tilt the immunologic balance toward tolerance and away from rejection, non-human primate recipients of cardiac allografts were treated with interleukin (IL)-2/Fc, mutant (m) antagonist type mIL-15/Fc, and sirolimus.
Heterotopic heart transplants were performed on 8 fully mismatched cynomolgus macaques. An untreated control recipient rejected its graft by post-operative Day 6. The remaining 7 animals received oral or intramuscular immunosuppression with sirolimus. A recipient treated with sirolimus alone rejected at the end of 28 days of immunosuppression. The remaining 6 monkeys also received IL-2/Fc and mIL-15/Fc intramuscularly until 28 days after transplant. One animal received a second 28-day course of fusion protein starting at Day 50. In these 6 animals, sirolimus was continued for 28 days (n = 4) or until protein levels were low (n = 2).
In the 4 monkeys treated with a 28-day course of sirolimus and fusion proteins, mean graft survival was 51.5 days (range, 28-76 days). The animal receiving a second course of fusion protein rejected its graft on Day 177, despite detectable levels of the fusion proteins and sirolimus. The central memory, effector memory, and naïve CD4(+) and CD8(+) T-cell populations in the peripheral blood did not change significantly during fusion protein administration. A 2.5-fold expansion in CD4(+)CD25(+) lymphocytes occurred in recipients treated with fusion proteins and sirolimus that was not observed in the recipient treated with sirolimus alone.
Although IL-2/Fc, mIL-15/Fc, and sirolimus administered in this manner permitted modest prolongation of graft survival and expansion of CD4(+)CD25(+) T cells, tolerance was not achieved.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 02/2012; 31(4):427-35. · 3.54 Impact Factor
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ABSTRACT: The development of immunosuppressive drugs to control adaptive immune responses has led to the success of transplantation as a therapy for end-stage organ failure. However, these agents are largely ineffective in suppressing components of the innate immune system. This distinction has gained in clinical significance as mounting evidence now indicates that innate immune responses play important roles in the acute and chronic rejection of whole organ allografts. For instance, whereas clinical interest in natural killer (NK) cells was once largely confined to the field of bone marrow transplantation, recent findings suggest that these cells can also participate in the acute rejection of cardiac allografts and prevent tolerance induction. Stimulation of Toll-like receptors (TLRs), another important component of innate immunity, by endogenous ligands released in response to ischemia/reperfusion is now known to cause an inflammatory milieu favorable to graft rejection and abrogation of tolerance. Emerging data suggest that activation of complement is linked to acute rejection and interferes with tolerance. In summary, the conventional wisdom that the innate immune system is of little importance in whole organ transplantation is no longer tenable. The addition of strategies that target TLRs, NK cells, complement, and other components of the innate immune system will be necessary to eventually achieve long-term tolerance to human allograft recipients.
Frontiers in immunology. 01/2012; 3:73.
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Ognjenka Nadazdin,
Svjetlan Boskovic,
Siew-Lin Wee,
Hiroshi Sogawa,
Ichiro Koyama,
Robert B Colvin,
R Neal Smith,
Georges Tocco,
David H O'Connor,
Julie A Karl, Joren C Madsen,
David H Sachs,
Tatsuo Kawai,
A Benedict Cosimi,
Gilles Benichou
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ABSTRACT: The relative contribution of direct and indirect allorecognition pathways to chronic rejection of allogeneic organ transplants in primates remains unclear. In this study, we evaluated T and B cell alloresponses in cynomolgus monkeys that had received combined kidney/bone marrow allografts and myeloablative immunosuppressive treatments. We measured donor-specific direct and indirect T cell responses and alloantibody production in monkeys (n = 5) that did not reject their transplant acutely but developed chronic humoral rejection (CHR) and in tolerant recipients (n = 4) that never displayed signs of CHR. All CHR recipients exhibited high levels of anti-donor Abs and mounted potent direct T cell alloresponses in vitro. Such direct alloreactivity could be detected for more than 1 y after transplantation. In contrast, only two of five monkeys with CHR had a detectable indirect alloresponse. No indirect alloresponse by T cells and no alloantibody responses were found in any of the tolerant monkeys. Only one of four tolerant monkeys displayed a direct T cell alloresponse. These observations indicate that direct T cell alloresponses can be sustained for prolonged periods posttransplantation and result in alloantibody production and chronic rejection of kidney transplants, even in the absence of detectable indirect alloreactivity.
The Journal of Immunology 09/2011; 187(9):4589-97. · 5.79 Impact Factor
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ABSTRACT: More than 11 million Americans live with chronic lung disease; in search for an alternative to donor organs, we attempted to regenerate lungs based on perfusion decellularized lung scaffolds that can be transplanted similar to a donor organ.
Cadaveric rat lungs were decellularized by detergent perfusion. Resulting scaffolds were mounted in bioreactors and seeded with endothelial and fetal lung cells. Biomimetic organ culture was maintained for 7 days. Resulting bioartificial left lungs were transplanted in orthotopic position after left pneumonectomy in rats. Cadaveric left lung transplants and pneumonectomies served as controls. Blood gas analyses, compliance testing, and fluoroscopies were performed on postoperative days 1, 7, and 14. Lungs were removed for final analysis on day 14.
Perfusion decellularization of cadaveric lungs yielded acellular scaffolds with intact architecture and matrix composition. Alveolar volumes, number, and size were comparable in bioartificial and native lungs, as were gas exchange, vital capacity and compliance in vitro. After using improved graft preservation and postoperative weaning protocols, animals could be fully recovered, and bioartificial lung constructs provided oxygenation as long as 7 days at levels comparable to cadaveric lung transplants. Compliance, gas exchange, and radiographic appearance gradually declined over the subsequent 7 days owing to progressive graft consolidation and inflammation.
Perfusion decellularization of cadaveric lungs yields intact scaffolds that can be seeded with cells to generate bioartificial lung grafts. After orthotopic transplantation, grafts are perfused by the recipient's circulation, ventilated through the recipient's airway and provide gas exchange in vivo for 7 days.
The Annals of thoracic surgery 09/2011; 92(3):998-1005; discussion 1005-6. · 3.74 Impact Factor
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Gregory R Veillette,
Hisashi Sahara,
Andrew J Meltzer,
Mathew J Weiss,
Yoshiko Iwamoto,
Karen M Kim,
Bruce R Rosengard,
James S Allan,
Stuart L Houser,
David H Sachs,
Gilles Benichou, Joren C Madsen
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ABSTRACT: Recent studies in mice and patients suggest that posttransplantation induction of autoimmune responses to tissue-specific antigens contributes to the rejection of major histocompatibility complex mismatched allotransplants. The relevance of this phenomenon to the rejection of major and minor histocompatibility-mismatched allografts performed in large-animal models remains to be established.
Miniature swine were immunized with cardiac myosin (CM) in Freund's adjuvant and received heterotopic, minor antigen-mismatched heart transplants. T-cell (proliferation and delayed type hypersensitivity [DTH]) and B-cell (antibody) responses specific to CM were measured. The rejection of heart transplants was assessed histologically.
Three of four swine that were immunized with CM before receiving a minor antigen-mismatched heart transplant exhibited potent DTH, T-cell proliferation and antibody responses to CM and rejected their grafts acutely. The fourth swine, which failed to mount a significant DTH response to CM and displayed low and transient anti-CM antibody titers, demonstrated long-term allograft survival.
This large-animal study supports the relevance of autoimmunity to CM in the rejection of minor antigen disparate cardiac allotransplants.
Transplantation 06/2011; 91(11):1187-91. · 4.00 Impact Factor
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ABSTRACT: We have previously observed that donor bone marrow hematopoietic stem cells successfully induce transient mixed chimerism and renal allograft tolerance following non-myeloablative conditioning of the recipient. Stem cells isolated from the peripheral blood (PBSC) may provide similar benefits. We sought to determine the most effective method of mobilizing PBSC for this approach and the effects of differing conditioning regimens on their engraftment.
A standard dose (10 μg/kg) or high dose (100 μg/kg) of granulocyte colony-stimulating factor (GCSF) with or without stem cell factor (SCF) was administered to the donor, and PBSC were collected by leukapheresis. Cynomolgus monkey recipients underwent a nonmyeloablative conditioning regimen (total body irradiation, thymic irradiation, and ATG) with splenectomy (splenectomy group) or a short course of anti-CD154 antibody (aCD154) (aCD154 group). Recipients then received combined kidney and PBSC transplantation and a 1-mo post-transplant course of cyclosporine.
Treatments with either two cytokines (GCSF+SCF) or high dose GCSF provided significantly more hematopoietic progenitor cells than standard dose GCSF alone. Recipients in the aCD154 group developed significantly higher myeloid and lymphoid chimerism (P < 0.0001 and P = 0.0002, respectively) than those in the splenectomy group. Longer term renal allograft survival without immunosuppression was also observed in the aCD154 group, while two of three recipients in the splenectomy group rejected their allografts soon after discontinuation of immunosuppression.
Protocols including administration of two cytokines (GCSF + SCF) or high dose GCSF alone significantly mobilized more PBSC than standard dose GCSF alone. The recipients of PBSC consistently developed excellent chimerism and survived long-term without immunosuppression, when treated with CD154 blockade.
Journal of Surgical Research 06/2011; 168(2):294-300. · 2.25 Impact Factor
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Ognjenka Nadazdin,
Svjetlan Boskovic,
Toru Murakami,
Georges Tocco,
Rex-Neal Smith,
Robert B Colvin,
David H Sachs,
James Allan, Joren C Madsen,
Tatsuo Kawai,
A Benedict Cosimi,
Gilles Benichou
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ABSTRACT: Transplant tolerance, defined as indefinite allograft survival without immunosuppression, has been regularly achieved in laboratory mice but not in nonhuman primates or humans. In contrast to laboratory mice, primates regularly have high frequencies of alloreactive memory T cells (TMEMs) before transplantation. These TMEMs are poorly sensitive to conventional immunosuppression and costimulation blockade, and the presence of donor-reactive TMEMs in primates may account for their resistance to transplant tolerance protocols that have proven consistently effective in mice. We measured the frequencies of anti-donor TMEMs before and after transplantation in a series of rejecting and tolerant monkeys that underwent nonmyeloablative conditioning, short-term immunosuppression, and combined allogeneic kidney/cell transplantation. Transplants were acutely rejected in all the monkeys with high numbers of donor-specific TMEMs before transplantation. In contrast, long-term survival was observed in the recipients harboring lower frequencies of anti-donor TMEMs before transplantation. Similar amounts of TMEM homeostatic expansion were recorded in all transplanted monkeys upon hematopoietic reconstitution; however, only the tolerant monkeys had no expansion or activation of donor-reactive TMEMs after transplantation. These results indicate that the presence of high frequencies of host donor-reactive TMEMs before transplantation impairs tolerance induction to kidney allografts in this nonhuman primate model. Indeed, recipients harboring a low anamnestic reactivity to their donor before transplantation were successfully rendered tolerant via infusion of donor cells and short-term immunosuppression. This suggests that selection of allogeneic donors with low memory responses in recipients may be essential to successful transplant tolerance induction in patients.
Science translational medicine 06/2011; 3(86):86ra51. · 7.80 Impact Factor
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ABSTRACT: Mouse renal allografts have a remarkable ability to promote acceptance across full major histocompatibility complex incompatibilities in certain strain combinations without immunosuppression. The mechanism is unknown but is believed to involve immunoregulation. This study tests whether Foxp3(+) T-regulatory cells are responsible in the early phase of graft acceptance, using B6.Foxp3(DTR) mice that express diphtheria toxin receptor (DTR) in Foxp3(+) cells. The administration of DT to B6.Foxp3(DTR) recipients with accepted DBA/2 kidneys, 3 weeks to 3 months after transplantation, caused a marked depletion of Foxp3 cells and triggered acute cellular rejection, manifested by a sudden increase in blood urea nitrogen within a week. None of the controls showed an increase in blood urea nitrogen, including DT-treated B6 wild-type recipients of DBA/2 kidneys or B6.Foxp3(DTR) recipients of isografts. Accepted DBA/2 allografts showed prominent lymphoid sheaths around arteries containing numerous CD3(+)Foxp3(+) cells, CD4(+) cells, dedritic cells, and B cells, which was independent of CCR4. The lymphoid sheaths disintegrate after Foxp3 depletion, accompanied by widespread CD8 interstitial mononuclear inflammation, tubulitis, and endarteritis. The Foxp3 depletion caused an increased frequency of donor-reactive cells in the spleen by interferon (IFN) γ enzyme-linked immunosorbent spot (ELISPOT) assays and increased expression of the maturation markers, CD86 and IA(b), on dendritic cells in the spleen and kidney. We conclude that Foxp3(+) cells are needed to maintain acceptance of major histocompatibility complex-incompatible renal allografts in the first 3 months after transplantation and may act by inhibiting DC maturation.
American Journal Of Pathology 04/2011; 178(4):1635-45. · 4.89 Impact Factor
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ABSTRACT: Most studies of vascular disease in transplanted organs have used combinations involving disparities determined by genes of the major histocompatibility complex (MHC). This report describes examples of coronary vascular disease occurring in transplanted mouse hearts involving isolated, non-H2-determined incompatibilities.
Mice, incompatible in respect of HY, H4, or H60, were selected. For H60, the incompatibility depended on breeding congenic pairs or the introduction of H60 by transgenic methods because the latter method results in more widespread expression. Transplant survival was determined, and the appearance and prevalence of coronary artery vasculopathy (CAV) was established by appropriate histologic methods.
Advanced changes of CAV were found at 56 days in transplants involving incompatibilities confined to HY or H4. In both combinations, skin grafts were also rejected. H60 incompatibility does not result in skin graft rejection and only a minority of heart transplants shows evidence of CAV. If heart transplants are preceded by skin grafts bearing both H60 and HY incompatibilities to promote "help" in generating immunity, H60 incompatible hearts develop advanced CAV. Heart transplants in all non-MHC categories ostensibly survive in excellent condition throughout this period despite their CAV.
CAV can develop as a consequence of non-MHC incompatibilities alone and even when antigens are sparsely expressed on cardiac tissue. Presensitization leads to much more severe vascular disease. Human leukocyte antigen compatible kidney transplants may also develop vascular disease and patients manifesting reactivity to MHC antigens should also be more prone to develop vascular disease because of undetectable non-MHC incompatibilities.
Transplantation 03/2011; 91(8):847-52. · 4.00 Impact Factor
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ABSTRACT: The development of immunosuppressive drugs to control adaptive immune responses has led to the success of heart transplantation as a therapy for end-stage heart failure. However, these agents are largely ineffective in suppressing components of the innate immune system. This distinction has gained clinical significance as mounting evidence now indicates that innate immune responses have important roles in the acute and chronic rejection of cardiac allografts including cardiac allograft vasculopathy (CAV). Whereas clinical interest in natural killer (NK) cells was once largely confined to the field of bone marrow transplantation, recent findings suggest that these cells can also participate in the acute rejection of cardiac allografts and in the development of CAV. Stimulation of Toll-like receptors (TLRs), another important component of innate immunity, by endogenous ligands released in response to ischemia/reperfusion is now known to cause an inflammatory milieu favorable to graft rejection. Finally, new data indicate that activation of complement is linked to acute rejection and CAV. In summary, the conventional wisdom that the innate immune system is of little importance in whole-organ transplantation is no longer tenable. The addition of strategies that target TLRs, NK cells, and complement will be necessary to prevent CAV completely and to eventually achieve long-term tolerance to cardiac allografts.
Kidney international. Supplement 12/2010;
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ABSTRACT: PURPOSE OF REVIEW: A series of recent studies defy conventional wisdom by showing that natural killer (NK) cells exert a powerful and long-lasting influence on the immune response to whole organ allografts. The early activation of NK cells following transplantation is associated with killing of allogeneic target cells and release of immunomodulatory chemokines and cytokines, which can contribute to either rejection or tolerance. Here, we review findings describing NK cell receptors, potential mediators and mechanisms underlying the dual influence of NK cells in solid organ transplantation. RECENT FINDINGS: New studies show that NK cells can discriminate between self and foreign tissues and play a key role in the initiation and regulation of adaptive immune responses after solid organ transplantation. Depending upon the types of NK cell receptors engaged and the nature of cytokines released, early NK cell activation can promote either rejection or tolerance. SUMMARY: Solid organ transplantation is associated with the early activation of NK cells, which are then licensed to kill allogeneic target cells directly or via antibody-dependent cellular cytotoxicity and release various chemokines and immunomodulatory cytokines. Depending upon the nature of NK cell subsets activated and their ability to kill allogeneic target cells and release certain types of cytokines, NK cells can promote the activation/expansion of pro-inflammatory Th1 cells or regulatory Th2/Treg cells thus tilting the balance of alloimmunity towards rejection or tolerance. An in-depth understanding of these mechanisms will be necessary in order to design therapies targeting NK cells in human transplantation.
Current opinion in organ transplantation 12/2010; · 1.22 Impact Factor
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Bimalangshu R Dey,
Stephen S Chung,
Thomas R Spitzer,
Hui Zheng,
Thomas E Macgillivray,
David C Seldin,
Steven McAfee,
Karen Ballen,
Eyal Attar,
Thomas Wang,
Jordan Shin,
Christopher Newton-Cheh,
Stephanie Moore,
Vaishali Sanchorawala,
Martha Skinner, Joren C Madsen,
Marc J Semigran
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ABSTRACT: Patients with light chain (AL) amyloidosis who present with severe heart failure due to cardiac involvement rarely survive more than 6 months. Survival after cardiac transplantation is markedly reduced due to the progression of amyloidosis. Autologous stem-cell transplantation (ASCT) has become a common therapy for AL amyloidosis, but there is an exceedingly high treatment-related mortality in patients with heart failure.
We developed a treatment strategy of cardiac transplant followed by ASCT. Twenty-six patients were evaluated, and of 18 eligible patients, nine patients underwent cardiac transplantation. Eight of these patients subsequently received an ASCT.
Six of seven evaluable patients achieved a complete hematologic remission, and one achieved a partial remission. At a median follow-up of 56 months from cardiac transplant, five of seven patients are alive without recurrent amyloidosis. Their survival is comparable with 17,389 patients who received heart transplants for nonamyloid heart disease: 64% in nonamyloid vs. 60% in amyloid patients at 7 years (P=0.83). Seven of eight transplanted patients have had no evidence of amyloid in their cardiac allograft.
This demonstrates that cardiac transplantation followed by ASCT is feasible in selected patients with AL amyloidosis and heart failure, and that such a strategy may lead to improved overall survival.
Transplantation 10/2010; 90(8):905-11. · 4.00 Impact Factor
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Jay A Graham,
Michael Fray,
Stephanie de Haseth,
Kang Mi Lee,
Moh-Moh Lian,
Catharine M Chase, Joren C Madsen,
James Markmann,
Gilles Benichou,
Robert B Colvin,
A Benedict Cosimi,
Shaoping Deng,
James Kim,
Alessandro Alessandrini
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ABSTRACT: The mechanism by which regulatory T (Treg) cells suppress the immune response is not well defined. A recent study has shown that β-catenin prolongs Treg cell survival. Because β-catenin is regulated by glycogen synthase kinase 3β (GSK-3β)-directed phosphorylation, we focused on GSK-3β and the role it plays in Treg cell function. Inhibition of GSK-3β led to increased suppression activity by Treg cells. Inhibitor-treated Treg cells exhibited prolonged FoxP3 expression and increased levels of β-catenin and of the antiapoptotic protein Bcl-xL. Systemic administration of GSK-3β inhibitor resulted in prolonged islet survival in an allotransplant mouse model. Our data suggest that GSK-3β could be a useful target in developing strategies designed to increase the stability and function of Treg cells for inducing allotransplant tolerance or treating autoimmune conditions.
Journal of Biological Chemistry 10/2010; 285(43):32852-9. · 4.77 Impact Factor
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ABSTRACT: We sought to assess early and late survival and cardiovascular-specific mortality after surgical repair of acute ascending aortic dissection and the effect of differences in surgical technique, patient characteristics, and preoperative diagnostic testing.
Between 1979 and 2003, 195 consecutive patients underwent repair for acute ascending aortic dissection within 2 weeks of the onset of symptoms. Mean follow-up was 7.0 +/- 5.9 years (range, 0-26 years) and was 100% complete.
Patients were aged 62 +/- 15 years on average and were mostly male (66%) and hypertensive (69%). Risk of death early and late after the operation decreased over the study period, with hospital mortality decreasing from 21% to 4% when comparing the first and most recent quartiles (P = .007, chi(2) test for trend). At 1, 5, 10, and 20 years postoperatively, survival was 84%, 69%, 55%, and 30%, respectively, and freedom from cardiovascular death was 86%, 80%, 71%, and 51%, respectively. Additional independent risk factors for death were older age (P < .001), renal dysfunction (P < .003), syncope (P = .007), and peripheral vascular disease (P = .006). During the study period, echocardiographic and computed tomographic diagnostic imaging replaced routine aortic angiographic analysis, and operative techniques involved more frequent use of open distal anastomoses, retrograde cerebral perfusion, earlier restoration of antegrade perfusion, and a conservative approach to aortic arch repair. Freedom from reoperation on the aorta or aortic valve was 93% and 84% at 5 and 10 years, respectively.
Early and late survival after repair of acute ascending aortic dissection has improved progressively over 25 years in association with noticeable changes in preoperative and intraoperative management. Aortic reoperations were infrequent during follow-up.
The Journal of thoracic and cardiovascular surgery 05/2009; 138(6):1349-57.e1. · 3.41 Impact Factor
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ABSTRACT: As a result of advances in surgical techniques, immunosuppressive therapy, and postoperative management, lung transplantation has become an established therapeutic option for individuals with a variety of end-stage lung diseases. The current 1-year actuarial survival rate following lung transplantation is approaching 80%. However, the 5- year actuarial survival rate has remained virtually unchanged at approximately 50% over the last 15 years due to the processes of acute and chronic lung allograft rejection (1). Clinicians still rely on a vast array of immunosuppressive agents to suppress the process of graft rejection, but find themselves limited by an inescapable therapeutic paradox. Insufficient immunosuppression results in graft loss due to rejection, while excess immunosuppression results in increased morbidity and mortality from opportunistic infections and malignancies. Indeed, graft rejection, infection, and malignancy are the three principal causes of mortality for the lung transplant recipient. One should also keep in mind that graft loss in a lung transplant recipient is usually a fatal event, since there is no practical means of long-term mechanical support, and since the prospects of re-transplantation are low, given the shortage of acceptable donor grafts. This chapter reviews the current state of immunosuppressive therapy for lung transplantation and suggests alternative paradigms for the management of future lung transplant recipients.
Frontiers in Bioscience 02/2009; 14:1627-41. · 3.52 Impact Factor
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PEDIATRICS 06/2008; 121(6):1258-60. · 4.47 Impact Factor
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ABSTRACT: It is not known whether tolerance can be induced in a strong proinflammatory milieu or whether the induction of tolerance can prevent interferon (IFN)-gamma-associated graft injury. To address these questions, we studied the effects of rIFN-gamma infusion on porcine cardiac allograft survival.
Recombinant interferon (rIFN)-gamma was continuously infused into the left anterior descending artery of hearts transplanted into major histocompatibility complex-inbred miniature swine treated with a 12-day course of cyclosporine A. Group 1 recipients received a nearly syngeneic heart, group 2 recipients received a class I disparate heart, and group 3 recipients were cotransplanted with a class I-disparate heart and kidney, a procedure demonstrated to induce tolerance to both grafts. A fourth group of animals were not transplanted but received intracoronary rIFN-gamma infusion into the native heart.
rIFN-gamma perfusion not only accelerated the acute rejection of class I-disparate hearts (mean survival time, 19+/-7.21 vs. 38+/-8.19; P=0.025) but caused near-syngeneic heart transplants, which otherwise survived indefinitely, to reject within 35 days. In contrast, rIFN-gamma perfusion had no demonstrable effects on hearts grafts in tolerant recipients or on autologous hearts.
These results suggest that tolerance induction can occur in the presence of IFN-gamma-mediated inflammation, and that tolerance induction can prevent the tissue injury caused by the overproduction of IFN-gamma. This suggests that the beneficial effects of tolerance may include protection from nonspecific inflammatory responses, such as those produced by ischemia-reperfusion injury and brain death.
Transplantation 03/2008; 85(3):314-22. · 4.00 Impact Factor
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ABSTRACT: Despite significant improvements in early post-transplantation survival rates, long-term patient and graft survival have remained poor, due in large part to the vexing problem of chronic allograft rejection. Attempts to combat this problem with intensification of immunosuppression have led to concomitant increases in the rates of fatal malignancies and infections. In cardiac transplantation, chronic rejection is manifested primarily by a disease entity known as cardiac allograft vasculopathy, an occlusive narrowing of the coronary vessels. In lung transplantation, chronic rejection is typified by obliterative bronchiolitis, an airflow limiting narrowing of the bronchioles. From an immunologic standpoint, chronic rejection is believed to be the end result of repeated immune and non-immune insults to the graft. This review examines the pathophysiology of heart and lung chronic, with emphasis on both immune and non-immune causes.
Frontiers in Bioscience 02/2008; 13:2980-8. · 3.52 Impact Factor
