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Journal ArticleDOI

Induction Therapy With Thymoglobulin After Heart Transplantation: Impact of Therapy Duration on Lymphocyte Depletion and Recovery, Rejection, and Cytomegalovirus Infection Rates

TL;DR: The 7-day treatment led to more efficient and prolonged lymphocyte depletion and significantly less rejection at 1 year, without an increase in cytomegalovirus infection rate.
Abstract: Background This retrospective single-center study compared lymphocyte depletion in 144 heart transplant recipients using 2 different induction protocols with Thymoglobulin (Genzyme Transplant, Cambridge, MA). Methods Thymoglobulin (1.5 mg/kg) was given to 105 patients for 7 days (Thymo7) and 39 patients for 5 days (Thymo5). Results Patient clinical characteristics were similar except that the Thymo7 group had a higher prevalence of women (33% vs 15%, p = 0.04), gender mismatch (35% vs 19%, p = 0.07), donor African American race (19% vs 2%, p = 0.008), older donor age (35 ± 13 vs 31 ± 12, p = 0.08), and higher pre-transplant creatinine (1.43 ± 0.67 vs 1.25 ± 0.48 mg/dl, p = 0.095). Seventy-five percent of the Thymo7 group reached target (absolute lymphocyte count ≤200) and 42% at 21 days ( p = 0.002). Thymo7 patients had significantly lower rejection rates (≥1B) within the first year (7% vs 22%, p = 0.02). No humoral rejection occurred. At 1 year, freedom from rejection was 93% in the Thymo7 group vs 80% in the Thymo5 group ( p = 0.007), and cytomegalovirus disease (9% and 5%, p = 0.5) and bacterial infection (26% vs 32%, p = 0.5) were similar. One-year actuarial survival was 92% ± 3% in the Thymo7 and 100% in the Thymo5 group ( p = 0.07), and at 3 years, 85 ± 4% and 90 ± 6%, respectively ( p = 0.4). Conclusions Both Thymoglobulin regimens were well tolerated. The 7-day treatment led to more efficient and prolonged lymphocyte depletion and significantly less rejection at 1 year, without an increase in cytomegalovirus infection rate.
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Journal ArticleDOI
TL;DR: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Starlings R: University of Chicago, Chicago, Illinois,USA; Chan M: university of Alberta, Edmonton, Alberta, Canada ; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA.
Abstract: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesu, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Task Force 2 Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Task Force 3 Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruna, La Coruna, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Independent Reviewers Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.

1,346 citations

Journal ArticleDOI
28 Aug 2014-Drugs
TL;DR: Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.
Abstract: In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin® was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn’s disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.

58 citations

Journal ArticleDOI
01 Jul 2013
TL;DR: Patients with cardiac sarcoidosis undergoing heart transplantation have acceptable long-term outcomes without evidence of recurrence of sarcoideosis in the allograft when maintained on low-dose corticosteroids.
Abstract: Background Cardiac sarcoidosis with end-stage heart failure has a poor prognosis without transplantation The rates of sarcoid recurrence and rejection are not well established after heart transplantation Methods A total of 19 heart transplant recipients with sarcoid of the explanted heart were compared with a contemporaneous control group of 1,050 heart transplant recipients without cardiac sarcoidosis Assessed outcomes included 1st-year freedom from any treated rejection, 5-year actuarial survival, 5-year freedom from cardiac allograft vasculopathy (CAV), 5-year freedom from nonfatal major adverse cardiac events (NF-MACE), and recurrence of sarcoid in the allograft or other organs Patients with sarcoidosis were maintained on low-dose corticosteroids after transplantation Results There were no significant differences between the sarcoid and control groups in 1st-year freedom from any treated rejection (79% and 90%), 5-year posttransplantation survival (79% and 83%), 5-year freedom from CAV (68% and 78%), and 5-year freedom from NF-MACE (90% and 88%) Causes of death (n = 5) in the sarcoid group were coccidioidomycosis, pneumonia, rejection, hemorrhage, and CAV No patient had recurrence of sarcoidosis in the cardiac allograft Three of 19 patients (16%) experienced recurrence of extracardiac sarcoid, with no mortality Conclusions Patients with cardiac sarcoidosis undergoing heart transplantation have acceptable long-term outcomes without evidence of recurrence of sarcoidosis in the allograft when maintained on low-dose corticosteroids Progression of extracardiac sarcoid was uncommon, possibly related to immunosuppression In patients with cardiac sarcoidosis, heart transplantation is a viable treatment modality

48 citations

Journal ArticleDOI
15 Oct 2011-Heart
TL;DR: This study is the first to identify the normal changes of TDI and MPI of both ventricles during the first year after HTx, which indicates an increase in LV mass and impairment of bi-ventricular systolic and diastolic function occur early afterHTx with gradual improvement during thefirst year.
Abstract: Objective Expected values of tissue Doppler imaging (TDI) velocities and myocardial performance index (MPI) after heart transplantation (HTx) have not been evaluated. This study assessed left and right ventricular (LV and RV) structure and function during the first year after HTx using these indexes. Methods and results Echocardiography including MPI and TDI systolic (S′), early (E′) and late (A′) diastolic velocities of RV and LV were performed in 20 donors (mean age 35±13 years) and serially in 20 recipients (mean age 59±9 years) during the first year after HTx. Increase in LV mass occurred at 7 days, with normalisation at 3 months (p Conclusions This study is the first to identify the normal changes of TDI and MPI of both ventricles during the first year after HTx. An increase in LV mass and impairment of bi-ventricular systolic and diastolic function occur early after HTx with gradual improvement during the first year. No significant changes in myocyte size were observed, but there was a substantial increase in fibrosis.

43 citations

Journal ArticleDOI
TL;DR: Experts from Germany, Austria, and Switzerland convened to identify indications for rATG induction in heart transplantation and to develop an algorithm for its use based on patient characteristics and the importance of donor‐specific antibodies (DSA) in predicting graft failure.
Abstract: Clinical data relating to rabbit antithymocyte globulin (rATG) induction in heart transplantation are far less extensive than for other immunosuppressants, or indeed for rATG in other indications. This was highlighted by the low grade of evidence and the lack of detailed recommendations for prescribing rATG in the International Society for Heart and Lung Transplantation (ISHLT) guidelines. The heart transplant population includes an increasing frequency of patients on mechanical circulatory support (MCS), often with ongoing infection and/or presensitization, who are at high immunological risk but also vulnerable to infectious complications. The number of patients with renal impairment is also growing due to lengthening waiting times, intensifying the need for strategies that minimize calcineurin inhibitor (CNI) toxicity. Additionally, the importance of donor-specific antibodies (DSA) in predicting graft failure is influencing immunosuppressive regimens. In light of these developments, and in view of the lack of evidence-based prescribing criteria, experts from Germany, Austria, and Switzerland convened to identify indications for rATG induction in heart transplantation and to develop an algorithm for its use based on patient characteristics.

43 citations


Cites background from "Induction Therapy With Thymoglobuli..."

  • ...5 mg/kg/day was given for 7 days in 166 high-risk heart transplant patients and for 5 days in 87 lower-risk patients, reported similar rates of rejection and survival to 1 year and no increase in infection or malignancy with the longer dosing regimen [79], but other comparative analyses of different doses are lacking....

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References
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Journal ArticleDOI
TL;DR: The continuing risk for lymphoma with time post‐transplantation, the contribution of immunosuppression to increased risk, and continuing poor outcomes in patients with post-transplant lymphoma are highlighted.

1,005 citations


"Induction Therapy With Thymoglobuli..." refers background in this paper

  • ...The disadvantage of using these powerful mmunosuppressants is the possibility of increased aderse events, including the incidence of infections in he early phase(6) and malignancies in the long-term.(7,8) No published reports, to our knowledge, have comared different regimens of polyclonal anti-thymocyte lobulin (ATG) on cellular rejection....

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  • ...Cytolytic therapy is considered to raise the incidence f malignancy in post-transplant patients.(1,7,8) In a large eries of 474 patients, Rinaldi et al(21) examined the ffect of immunosuppression on the development of...

    [...]

  • ...Retrospecive studies have suggested that cytolytic therapy educes the risk of early rejection(10) –13 but has potenial adverse effects, including increased incidence of nfection and malignancy.(7,8) Use of induction with he monoclonal antibody OKT3 has declined during he past several years because of poor tolerability....

    [...]

Journal ArticleDOI
TL;DR: Among patients at high risk for acute rejection or delayed graft function who received a renal transplant from a deceased donor, induction therapy consisting of a 5-day course of antithymocyte globulin, as compared with basiliximab, reduced the incidence and severity of acute rejection but not the incidence of delayed graftfunction.
Abstract: Background Induction therapy reduces the frequency of acute rejection and delayed graft function after transplantation. A rabbit antithymocyte polyclonal antibody or basiliximab, an interleukin-2 receptor monoclonal antibody, is most commonly used for induction. Methods In this prospective, randomized, international study, we compared short courses of antithymocyte globulin and basiliximab in patients at high risk for acute rejection or delayed graft function who received a renal transplant from a deceased donor. Patients taking cyclosporine, mycophenolate mofetil, and prednisone were randomly assigned to receive either rabbit antithymocyte globulin (1.5 mg per kilogram of body weight daily, 141 patients) during transplantation (day 0) and on days 1 through 4 or basiliximab (20 mg, 137 patients) on days 0 and 4. The primary end point was a composite of acute rejection, delayed graft function, graft loss, and death. Results At 12 months, the incidence of the composite end point was similar in the two groups (P=0.34). The antithymocyte globulin group, as compared with the basiliximab group, had lower incidences of acute rejection (15.6% vs. 25.5%, P=0.02) and of acute rejection that required treatment with antibody (1.4% vs. 8.0%, P=0.005). The antithymocyte globulin group and the basiliximab group had similar incidences of graft loss (9.2% and 10.2%, respectively), delayed graft function (40.4% and 44.5%), and death (4.3% and 4.4%). Though the incidences of all adverse events, serious adverse events, and cancers were also similar between the two groups, patients receiving antithymocyte globulin had a greater incidence of infection (85.8% vs. 75.2%, P=0.03) but a lower incidence of cytomegalovirus disease (7.8% vs. 17.5%, P=0.02). Conclusions Among patients at high risk for acute rejection or delayed graft function who received a renal transplant from a deceased donor, induction therapy consisting of a 5-day course of antithymocyte globulin, as compared with basiliximab, reduced the incidence and severity of acute rejection but not the incidence of delayed graft function. Patient and graft survival were similar in the two groups. (ClinicalTrials.gov number, NCT00235300 [ClinicalTrials.gov].).

655 citations

Journal ArticleDOI
05 Apr 2007-Leukemia
TL;DR: ATG provides multifaceted immunomodulation paving the way for future applications and suggesting that the use of ATG should be included in the immunosuppression therapeutic armamentarium to help reduce the incidence of organ rejection and GVHD.
Abstract: The success of allogeneic stem cell transplantation and solid-organ transplantation owes much to improvements in the immunosuppressive regimens that prevent graft-versus-host disease (GVHD) or suppress allograft rejection. A better understanding of the immune mechanisms underlying induction of immunological tolerance is the key to successful transplantation. Polyclonal antibodies such as antithymocyte globulins (ATG) have been used for decades. The common belief is that ATG efficacy relies on its capacity to deplete T lymphocytes. The aim of this review is to offer an overview of the recent findings that have been demonstrated in ATG's immunomodulatory activity. The polyclonal nature of ATG is reflected in its diverse effects on the immune system: (1) T-cell depletion in blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis; (2) modulation of key cell surface molecules that mediate leukocyte/endothelium interactions; (3) induction of apoptosis in B-cell lineages; (4) interference with dendritic cell functional properties; and (5) induction of regulatory T and natural killer T cells. As a consequence, ATG provides multifaceted immunomodulation paving the way for future applications and suggesting that the use of ATG should be included in the immunosuppression therapeutic armamentarium to help reduce the incidence of organ rejection and GVHD.

492 citations

Journal ArticleDOI
TL;DR: It is reported for the first time that ATG but not anti-CD52 mAb (alemtuzumab) or the IL-2R antagonists causes rapid and sustained expansion of CD4+CD25+ T cells when cultured with human peripheral blood lymphocytes.
Abstract: T cell-depleting agents are being tested as part of clinical tolerance strategies in humans with autoimmunity and transplantation. The immunosuppressive activity of anti-thymocyte globulin (ATG) has been thought to result primarily from depletion of peripheral lymphocytes. Herein is reported for the first time that ATG but not anti-CD52 mAb (alemtuzumab) or the IL-2R antagonists causes rapid and sustained expansion of CD4+CD25+ T cells when cultured with human peripheral blood lymphocytes. These cells display enhanced expression of the regulatory markers glucocorticoid-induced TNF receptor, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and forkhead box P3 and efficiently suppress a direct alloimmune response of the original responder lymphocytes. It is interesting that the cells do not suppress memory responses to the recall antigen mumps. Ex vivo expansion of regulatory T cells is due mainly to conversion of CD4+CD25- into CD4+CD25+ T cells and to a lesser degree to proliferation of natural CD4+CD25+ T cells. The induction of regulatory T cells depends on production of Th2 cytokines in the generating cultures. These novel data suggest that ATG not only may promote expansion/generation of regulatory T cells but also may be useful in future ex vivo expansion of these cells for cellular therapy in autoimmunity and clinical transplantation.

363 citations

Journal ArticleDOI
TL;DR: Basiximab induction therapy allows delayed initiation of cyclosporine after cardiac transplantation without an increase in rejection and reduces the risk of post-operative renal dysfunction.
Abstract: Background Cyclosporine (CsA) is frequently initiated as induction therapy in patients undergoing orthotopic heart transplantation, but our experience has identified a significant rate of post-operative renal dysfunction. We therefore devised a renal-sparing cyclosporine-free induction regimen consisting of the early administration basiliximab, an interleukin-2 receptor monoclonal antibody, followed by the late initiation of cyclosporine on post-operative Day 4. Methods Between September 1998 and December 1999, we treated 25 patients at risk for post-operative renal dysfunction (high-risk basiliximab group) with the new induction regimen and another 33 patients not at risk (low-risk CsA group) for renal dysfunction with our standard cyclosporine protocol. We identified a historical control group (1996 through 1998) of 32 patients at risk for renal dysfunction (high-risk CsA group) who had received our standard cyclosporine protocol. Results The increase in serum creatinine levels after transplantation was less in the high-risk basiliximab group (−0.1 ± 0.7) than in the high-risk CsA group (0.5 ± 1.0, p p = .13). Conclusion Basiliximab induction therapy allows delayed initiation of cyclosporine after cardiac transplantation without an increase in rejection and reduces the risk of post-operative renal dysfunction.

99 citations

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