|
1
|
Maddur H, Wilson N, Patil P, Asrani S. Rejection in Liver Transplantation Recipients. J Clin Exp Hepatol 2024; 14:101363. [PMID: 38495462 PMCID: PMC10943490 DOI: 10.1016/j.jceh.2024.101363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 02/09/2024] [Indexed: 03/19/2024] Open
Abstract
Rejection following liver transplantation continues to impact transplant recipients although rates have decreased over time with advances in immunosuppression management. The diagnosis of rejection remains challenging with liver biopsy remaining the reference standard for diagnosis. Proper classification of rejection type and severity is imperative as this guides management and ultimately graft preservation. Future areas of promise include non-invasive testing for detection of rejection to reduce the morbidity associated with invasive testing and further advances in immunosuppression management to reduce toxicities associated with immunosuppression while minimizing rejection related morbidity.
Collapse
|
|
2
|
Liu X, Huang C, Cao X, Yang X, Li S, Jiang S, Lin W, Liu L, Ding X, Tang X, Miao L. A fully validated flow cytometry method to quantitatively analyze active rATG in human serum and its application in pharmacokinetic study for therapeutic drug monitoring. J Pharm Biomed Anal 2023; 234:115483. [PMID: 37454500 DOI: 10.1016/j.jpba.2023.115483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 05/14/2023] [Accepted: 05/23/2023] [Indexed: 07/18/2023]
Abstract
Rabbit anti-thymocyte globulin (rATG) has been widely used to prevent graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The therapeutic window of rATG is narrow, and it may increase the risk of relapse, viral reactivation, delayed immune reconstitution and GvHD when overexposed or underexposed. Therefore, a reliable method for detecting the rATG concentration in human serum by flow cytometry was established and fully validated for therapeutic drug monitoring. In this method, Jurkat T cells were used to capture active rATG in human serum, and PE-labeled donkey anti-rabbit IgG was used as a secondary antibody. The method showed good specificity, selectivity and excellent linearity at concentration of 0.00300-20.0 AU/mL. The intra- and interday precision values were all within 20% at four concentration levels for the analyte. The stock solutions of rATG showed no significant degradation after storage at ambient temperature for 8 h and at - 80 °C for 481 days. No significant degradation of rATG in serum was observed at ambient temperature for 6 h, during six freezethaw cycles and at - 80 °C for at least 373 days. This method was fully validated and successfully applied to monitor active rATG concentration in serum of patients with haploid-identical hematopoietic stem cell transplantation.
Collapse
Affiliation(s)
- Xiaoxue Liu
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chenrong Huang
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xuanqi Cao
- National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu, China
| | - Xiao Yang
- National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu, China
| | - Sijia Li
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | | | - Wang Lin
- Suzhou Vocational Health College, Suzhou, China
| | - Linsheng Liu
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaoliang Ding
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaowen Tang
- National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu, China.
| | - Liyan Miao
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, China; College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
| |
Collapse
|
|
3
|
Takahashi T, Teramoto M, Matsumoto K, Jaber MM, Tamaki H, Ikegame K, Yoshihara S, Kaida K. Population Pharmacokinetics of Total Rabbit Anti-thymocyte Globulin in Non-obese Adult Patients Undergoing Hematopoietic Cell Transplantation for Hematologic Malignancy. Clin Pharmacokinet 2023; 62:1081-1091. [PMID: 37284975 DOI: 10.1007/s40262-023-01252-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2023] [Indexed: 06/08/2023]
Abstract
BACKGROUND AND OBJECTIVES Rabbit anti-thymocyte globulin (rATG), a therapeutic polyclonal antibody against human T cells, is commonly used in conditioning therapy prior to allogeneic hematopoietic cell transplantation (HCT). Previous studies successfully developed an individualized rATG dosing regimen based on "active" rATG population PK (popPK) analysis, while "total" rATG can be a more logistically favorable alternative for early HCT outcomes. We conducted a novel popPK analysis of total rATG. METHODS Total rATG concentration was measured in adult human-leukocyte antigen (HLA) mismatched HCT patients who received a low-dose rATG regimen (total 2.5-3 mg/kg) within 3 days prior to HCT. PopPK modeling and simulation was performed using nonlinear mixed effect modeling approach. RESULTS A total of 504 rATG concentrations were available from 105 non-obese patients with hematologic malignancy (median age 47 years) treated in Japan. The majority had acute leukemia or malignant lymphoma (94%). Total rATG PK was described by a two-compartment linear model. Influential covariate relations include ideal body weight [positively on both clearance (CL) and central volume of distribution], baseline serum albumin (negatively on CL), CD4+ T cell dose (positively on CL), and baseline serum IgG (positively on CL). Simulated covariate effects predicted that early total rATG exposures were affected by ideal body weight. CONCLUSIONS This novel popPK model described the PK of total rATG in the adult HCT patients who received a low-dose rATG conditioning regimen. This model can be used for model-informed precision dosing in the settings with minimal baseline rATG targets (T cells), and early clinical outcomes are of interest.
Collapse
Affiliation(s)
- Takuto Takahashi
- Pediatric Stem Cell Transplantation, Boston Children's Hospital/Dana Farber Cancer Institute, Boston, MA, USA.
- Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, USA.
| | - Masahiro Teramoto
- Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Hyogo, Japan
| | - Kana Matsumoto
- Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto, Japan
| | - Mutaz M Jaber
- Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, USA
| | - Hiroya Tamaki
- Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Hyogo, Japan
| | - Kazuhiro Ikegame
- Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Hyogo, Japan
| | - Satoshi Yoshihara
- Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Hyogo, Japan
| | - Katsuji Kaida
- Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Hyogo, Japan
| |
Collapse
|
|
4
|
Copic D, Direder M, Klas K, Bormann D, Laggner M, Ankersmit HJ, Mildner M. Antithymocyte Globulin Inhibits CD8 + T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes. Cells 2023; 12:cells12030382. [PMID: 36766722 PMCID: PMC9913606 DOI: 10.3390/cells12030382] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/12/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Antithymocyte globulins (ATG) are T cell-depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with a high risk of graft rejection. Previously described effects besides the depletion of T cells have suggested additional modes of action and identified further cellular targets. METHODS We examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG at the single-cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. FINDINGS Analysis of the paracrine factors present in the plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines, including interferon-γ (IFN-γ). Furthermore, we identified an increase in the surface expression of the programmed death ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we showed that this induction is dependent on the activation of JAK/STAT signaling via the binding of IFN-γ to interferon-γ receptor 1 (IFN-γR1). Lastly, we demonstrated that the modulation of the immune regulatory axis of programmed cell death protein 1 (PD1) on activated CD8+ T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including the proliferation and granzyme B release of activated T cells. INTERPRETATION Together, our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects.
Collapse
Affiliation(s)
- Dragan Copic
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Martin Direder
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Katharina Klas
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Daniel Bormann
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Maria Laggner
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Hendrik Jan Ankersmit
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Correspondence: (H.J.A.); (M.M.); Tel.: +43-(0)1-40400-67770 (H.J.A.); +43-(0)1-40400-73507 (M.M.)
| | - Michael Mildner
- Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090 Vienna, Austria
- Correspondence: (H.J.A.); (M.M.); Tel.: +43-(0)1-40400-67770 (H.J.A.); +43-(0)1-40400-73507 (M.M.)
| |
Collapse
|
|
5
|
Storci G, Barbato F, Ricci F, Tazzari PL, De Matteis S, Tomassini E, Dicataldo M, Laprovitera N, Arpinati M, Ursi M, Maffini E, Campanini E, Dan E, Manfroi S, Santi S, Ferracin M, Bonafe M, Bonifazi F. Pre-transplant CD69+ extracellular vesicles are negatively correlated with active ATLG serum levels and associate with the onset of GVHD in allogeneic HSCT patients. Front Immunol 2023; 13:1058739. [PMID: 36713433 PMCID: PMC9880409 DOI: 10.3389/fimmu.2022.1058739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/06/2022] [Indexed: 01/15/2023] Open
Abstract
Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Rabbit anti-T lymphocyte globulin (ATLG) in addition to calcineurin inhibitors and antimetabolites is a suitable strategy to prevent GVHD in several transplant settings. Randomized studies already demonstrated its efficacy in terms of GVHD prevention, although the effect on relapse remains the major concern for a wider use. Tailoring of ATLG dose on host characteristics is expected to minimize its side effects (immunological reconstitution, relapse, and infections). Here, day -6 to day +15 pharmacokinetics of active ATLG serum level was first assayed in an explorative cohort of 23 patients by testing the ability of the polyclonal serum to bind antigens on human leukocytes. Significantly lower levels of serum active ATLG were found in the patients who developed GVHD (ATLG_AUCCD45: 241.52 ± 152.16 vs. 766.63 +/- 283.52 (μg*day)/ml, p = 1.46e-5). Consistent results were obtained when the ATLG binding capacity was assessed on CD3+ and CD3+/CD4+ T lymphocytes (ATLG_AUCCD3: 335.83 ± 208.15 vs. 903.54 ± 378.78 (μg*day)/ml, p = 1.92e-4; ATLG_AUCCD4: 317.75 ± 170.70 vs. 910.54 ± 353.35 (μg*day)/ml, p = 3.78e-5. Concomitantly, at pre-infusion time points, increased concentrations of CD69+ extracellular vesicles (EVs) were found in patients who developed GVHD (mean fold 9.01 ± 1.33; p = 2.12e-5). Consistent results were obtained in a validation cohort of 12 additional ATLG-treated HSCT patients. Serum CD69+ EVs were mainly represented in the nano (i.e. 100 nm in diameter) EV compartment and expressed the leukocyte marker CD45, the EV markers CD9 and CD63, and CD103, a marker of tissue-resident memory T cells. The latter are expected to set up a host pro-inflammatory cell compartment that can survive in the recipient for years after conditioning regimen and contribute to GVHD pathogenesis. In summary, high levels of CD69+ EVs are significantly correlated with an increased risk of GVHD, and they may be proposed as a tool to tailor ATLG dose for personalized GVHD prevention.
Collapse
Affiliation(s)
- Gianluca Storci
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesco Barbato
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy,Department of Experimental, Diagnostic and Specialty Medicine (DIMES) University of Bologna, Bologna, Italy
| | - Francesca Ricci
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | | | | | - Enrica Tomassini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Michele Dicataldo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy,Department of Experimental, Diagnostic and Specialty Medicine (DIMES) University of Bologna, Bologna, Italy
| | | | - Mario Arpinati
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Margherita Ursi
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy,Department of Experimental, Diagnostic and Specialty Medicine (DIMES) University of Bologna, Bologna, Italy
| | - Enrico Maffini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Elena Campanini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Elisa Dan
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES) University of Bologna, Bologna, Italy
| | - Silvia Manfroi
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Spartaco Santi
- Consiglio Nazionale delle Ricerche (CNR) Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", Bologna, Italy,IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Manuela Ferracin
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy,Department of Experimental, Diagnostic and Specialty Medicine (DIMES) University of Bologna, Bologna, Italy
| | - Massimiliano Bonafe
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy,Department of Experimental, Diagnostic and Specialty Medicine (DIMES) University of Bologna, Bologna, Italy
| | - Francesca Bonifazi
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy,*Correspondence: Francesca Bonifazi,
| |
Collapse
|
|
6
|
Muckenhuber M, Mucha J, Mengrelis K, How C, Reindl-Schwaighofer R, Heinzel A, Kainz V, Worel N, Berlakovich G, Edinger M, Oberbauer R, Wekerle T. Optimum timing of antithymocyte globulin in relation to adoptive regulatory T cell therapy. Am J Transplant 2023; 23:84-92. [PMID: 36695625 DOI: 10.1016/j.ajt.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 09/28/2022] [Accepted: 09/28/2022] [Indexed: 01/13/2023]
Abstract
Reducing the recipient's T cell repertoire is considered to increase the efficacy of regulatory T cell (Treg) therapy. This necessitates timing the administration of antithymocyte globulin (ATG) early enough before adoptive cell therapy (ACT) so that residual serum ATG does not deplete the transferred Tregs. The optimum time point in this regard has not been defined. Herein, we report the effects of residual serum ATG on the viability of an in vitro expanded Treg cell product used in a clinical trial of ACT in kidney transplant recipients (NCT03867617). Patients received ATG monotherapy (either 6 or 3 mg/kg body weight) without concomitant immunosuppression 2 to 3 weeks before transplantation and Treg transfer. An anti-ATG immunoglobulin G (IgG) immune response was elicited in all patients within 14 days. In turn, the elimination of total and Treg-specific ATG was accelerated substantially over control patients receiving the same dose of ATG with concomitant immunosuppression. However, ATG serum concentrations of <1 μg/mL, which had previously been reported as subtherapeutic threshold, triggered apoptosis of Tregs in vitro. Therefore, ATG levels need to decline to lower levels than those previously thought for efficacious Treg transfer. In 5 of 6 patients, such low levels of serum ATG considered safe for Treg transfer were reached within 2 weeks after ATG administration.
Collapse
Affiliation(s)
- Moritz Muckenhuber
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Jasmin Mucha
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Konstantinos Mengrelis
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Christopher How
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Roman Reindl-Schwaighofer
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Andreas Heinzel
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Verena Kainz
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Nina Worel
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Gabriela Berlakovich
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Matthias Edinger
- Leibniz Institute of Immunotherapy, Regensburg, Germany; Department of Internal Medicine 3 (Hematology and Oncology), University Hospital Regensburg, Regensburg, Germany
| | - Rainer Oberbauer
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Wekerle
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
7
|
Meesters-Ensing J, Admiraal R, Ebskamp L, Lacna A, Boelens JJ, Lindemans CA, Nierkens S. Therapeutic Drug Monitoring of Anti-Thymocyte Globulin in Allogeneic Stem Cell Transplantation: Proof of Concept. Front Pharmacol 2022; 13:828094. [PMID: 35370695 PMCID: PMC8974913 DOI: 10.3389/fphar.2022.828094] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/25/2022] [Indexed: 01/08/2023] Open
Abstract
Anti-thymocyte globulin (ATG), a polyclonal antibody, is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-vs.-host-disease (GvHD) and graft failure (GF). Overexposure to ATG leads to poor early T-cell recovery, which is associated with viral infections and poor survival. Patients with severe inflammation are at high risk for GF and GvHD, and may have active infections warranting swift T-cell recovery. As ATG exposure may be critical in these patients, individualized dosing combined with therapeutic drug monitoring (TDM) may improve outcomes. We describe the individualized dosing approach, an optimal sampling scheme, the assay to measure the active fraction of ATG, and the workflow to perform TDM. Using a previously published population pharmacokinetic (PK) model, we determine the dose to reach optimal exposures associated with low GvHD and rejection, and at the same time promote T-cell recovery. Based on an optimal sampling scheme, peak and trough samples are taken during the first 3 days of once-daily dosing. The fraction of ATG able to bind to T-cells (active ATG) is analyzed using a bio-assay in which Jurkat cells are co-cultured with patient's plasma and the binding is quantified using flow cytometry. TDM is performed based on these ATG concentrations on the third day of dosing; subsequent doses can be adjusted based on the expected area under the curve. We show that individualized ATG dosing with TDM is feasible. This approach is unique in the setting of antibody treatment and may result in better immune reconstitution post-HCT and subsequently better survival chances.
Collapse
Affiliation(s)
| | - R. Admiraal
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Department of Pediatrics, University Medical Center Utrecht, Utrecht, Netherlands
| | - L. Ebskamp
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | - A. Lacna
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | - J. J. Boelens
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - C. A. Lindemans
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Department of Pediatrics, University Medical Center Utrecht, Utrecht, Netherlands
| | - S. Nierkens
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| |
Collapse
|
|
8
|
Long-term survival with mixed chimerism in patients with AML and MDS transplanted after conditioning with targeted busulfan, fludarabine, and thymoglobulin. Bone Marrow Transplant 2021; 57:198-206. [PMID: 34741096 DOI: 10.1038/s41409-021-01518-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 10/19/2021] [Accepted: 10/22/2021] [Indexed: 11/08/2022]
Abstract
We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4 days), fludarabine (Flu, 120 [n = 23] or 250 [n = 17] mg/m2) and thymoglobulin (THY). Compared to 95 patients conditioned with Bu/Cyclophosphamide (Cy) without THY, BuFluTHY-conditioned patients had lower rates of chronic graft-vs.-host disease (GVHD). Adjusted hazard ratios (HR) for BuFlu(120)THY and BuFlu(250)THY-conditioned patients were 1.60 (95% confidence interval (CI) 0.66-3.86) and 1.87 (0.68-5.11), respectively, for relapse; 0.77 (0.30-1.99) and 1.32 (0.54-3.23) for non-relapse mortality; 0.81 (0.42-1.57) and 1.38 (0.72-2.57) for overall mortality; and 0.78 (0.30-2.05) and 1.62 (0.63-4.41) for relapse or death (failure for relapse-free survival). At one year, 45% of BuFlu(120 or 250)THY-conditioned patients had mixed CD3+ chimerism compared to 0% with BuCy (p < 0.0001). None of 7 patients with long-term mixed chimerism had chronic GVHD; two relapsed, five remained stable mixed chimeras. THY is effective in reducing chronic GVHD, and long-term mixed T-cell chimerism can be compatible with relapse-free survival. However, Thy may also be associated with an increased risk of relapse and, dose-dependent, with non-relapse mortality.
Collapse
|
|
9
|
Azzopardi N, Longuet H, Ternant D, Thibault G, Gouilleux-Gruart V, Lebranchu Y, Büchler M, Gatault P, Paintaud G. Relationship Between Antithymocyte Globulin Concentrations and Lymphocyte Sub-Populations in Kidney Transplant Patients. Clin Pharmacokinet 2021; 61:111-122. [PMID: 34292526 DOI: 10.1007/s40262-021-01053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely empirical and the question of an individualized dose is still unresolved. METHODS Data from a prospective study in 17 kidney transplant patients were used to develop a model describing the dose-concentration-response relationship of rATG with T-lymphocyte subpopulation counts over time. The model was validated using an independent cohort of kidney transplant patients treated by rATG in the same center. RESULTS Pharmacokinetics of rATG was described using a two-compartment model integrating a third compartment and a target-mediated elimination for active rATG. The kinetics of CD3+, CD4+, CD8+, and CD3-CD56+ cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3-CD56+-independent and CD3-CD56+-dependent rATG-mediated lymphocyte depletion, and a positive feedback. Elimination of rATG was influenced by age and body surface area, while its distribution was also influenced by body surface area. CD3+ proliferation rate decreased with age and CD3-CD56+-mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3+ count < 20 mm-3 for at least 7 days and a CD4+ count > 200 mm-3 at 1 year, respectively. Simulations showed that increasing or decreasing the standard 6-mg/kg dose will impact both tolerance and efficacy, while a dose decrease may be beneficial in elderly patients. CONCLUSIONS Our results can be used to design prospective clinical trials testing dose individualization based on patients' characteristics. CLINICAL TRIAL REGISTRATION Eudract No. 2009-012673-35.
Collapse
Affiliation(s)
| | - Hélène Longuet
- Department of Nephrology and Clinical Immunology, CHRU de Tours, Tours, France
| | - David Ternant
- University of Tours, EA4245 T2I, Tours, France. .,Department of Medical Pharmacology, CHRU de Tours, 37044, Tours, France.
| | - Gilles Thibault
- University of Tours, EA7501 GICC, Tours, France.,Laboratory of Immunology, CHRU de Tours, Tours, France
| | - Valérie Gouilleux-Gruart
- University of Tours, EA7501 GICC, Tours, France.,Laboratory of Immunology, CHRU de Tours, Tours, France
| | | | - Matthias Büchler
- Department of Nephrology and Clinical Immunology, CHRU de Tours, Tours, France.,University of Tours, EA4245 T2I, Tours, France
| | - Philippe Gatault
- Department of Nephrology and Clinical Immunology, CHRU de Tours, Tours, France.,University of Tours, EA4245 T2I, Tours, France
| | - Gilles Paintaud
- University of Tours, EA4245 T2I, Tours, France.,Department of Medical Pharmacology, CHRU de Tours, 37044, Tours, France
| |
Collapse
|
|
10
|
Tan X, Feng H, Guo Z, Wang L, Fu C, Sun L, Li Y, Xia Q, Hou L, Liu C, Zhu L, Chen G. Rabbit antithymocyte globulin induces human lymphocyte activation, proliferation, and apoptosis in the absence of complement: an experimental study. Transpl Int 2021; 34:930-941. [PMID: 33725365 DOI: 10.1111/tri.13864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 11/29/2022]
Abstract
Rabbit antithymocyte globulin (rATG) has become the first choice for induction therapy in HLA-presensitized patients undergoing organ transplantation. Meanwhile, complement inhibitors have been approved for preventing or treating antibody-mediated rejection in these patients. The biological effects of rATG on lymphocytes in cases of complement deficiency or significant inhibition are not yet clear. We measured lymphocyte activation, proliferation, and apoptosis in response to rATG treatment in the absence of complement. T-cell subsets were analyzed transcriptomically features to rATG stimulation. Activation-related phenotypes on T cells were determined in patients after rATG administration. We found that rATG treatment led to lymphocyte activation and proliferation in vitro without the addition of complement. A dose-dependent apoptosis in rATG-treated lymphocytes was detected, which was partially caspase-3-dependent but Fas/FasL-independent. T cells were more sensitive to rATG stimulation than were non-T cells. Both CD4+ T cells and CD8+ T cells upregulated a series of genes related to cell activation, cytokine production and apoptosis to rATG stimulation. CD69 and CD25 levels in surviving T cells were increased in patients after rATG administration. These findings indicate that rATG can stimulate lymphocyte activation, proliferation, and apoptosis in the absence of complement. Biologic effects of rATG other than complement-dependent cytotoxicity need to be concerned.
Collapse
Affiliation(s)
- Xiaosheng Tan
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Hao Feng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiliang Guo
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Cheng Fu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingjuan Sun
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yakun Li
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiangbing Xia
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Hou
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Lan Zhu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| |
Collapse
|
|
11
|
West-Thielke PM, Ipema HJ, Campbell-Lee S, Benedetti E, Kaplan B, Thielke JJ. Removal of Anti-Thymocyte Globulin by Plasma Exchange in ABO-Incompatible and Positive Crossmatch Kidney Transplant Recipients. Transplant Proc 2021; 53:1548-1553. [PMID: 33573819 DOI: 10.1016/j.transproceed.2021.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 01/08/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Recipients of ABO-incompatible (ABOI) and positive crossmatch (PXM) kidney transplants are at high risk for antibody-mediated acute rejection. Despite aggressive immunosuppression in high-risk patients, the incidence of acute rejection remains considerably higher than in other groups. No published studies have examined plasma concentrations of anti-thymocyte globulin (ATG) in patients undergoing plasma exchange. The objectives of this study were to compare plasma ATG concentrations before and after plasma exchange in ABOI and PXM kidney transplant patients to determine the amount removed. MATERIALS AND METHODS This prospective pharmacokinetic evaluation enrolled 10 patients undergoing ABOI or PXM kidney transplant at an academic medical center. Blood and waste plasma samples from 5 patients were assayed for total and active ATG concentrations. Patient records were monitored for renal function and rejection rates in the first 6 months post-transplant. RESULTS Total ATG concentrations decreased a mean of 59.78 ± 13.91% after each plasma exchange session, and active ATG levels decreased a mean of 56.8 ± 17.08%. Mean daily concentrations reflect a lack of expected ATG accumulation. Only 1 of 4 patients had detectable ATG concentrations after 30 days. After 6 months, the incidence of acute rejection in this sample was 44% and graft survival was 89%. CONCLUSIONS This is the first study to show that plasma exchange removes a substantial amount of ATG in high-risk kidney transplant patients. Based on these results, we believe these high-risk patients have been traditionally underdosed.
Collapse
Affiliation(s)
| | - Heather J Ipema
- University of Illinois at Chicago College of Pharmacy, Department of Pharmacy Practice, Chicago, Illinois
| | - Sally Campbell-Lee
- University of Illinois Medical Center, Department of Pathology, Chicago, Illinois
| | - Enrico Benedetti
- University of Illinois Medical Center, Division of Transplant Surgery, Chicago, Illinois
| | - Bruce Kaplan
- University of Illinois Medical Center, Division of Transplant Surgery, Chicago, Illinois
| | - James J Thielke
- University of Illinois at Chicago College of Pharmacy, Department of Pharmacy Practice, Chicago, Illinois
| |
Collapse
|
|
12
|
Amrani ME, Admiraal R, Willaert L, Ebskamp-van Raaij LJC, Lacna AM, Hack CE, Huitema ADR, Nierkens S, van Maarseveen EM. Quantification of T Cell Binding Polyclonal Rabbit Anti-thymocyte Globulin in Human Plasma with Liquid Chromatography Tandem-Mass Spectrometry. AAPS J 2020; 22:43. [PMID: 32030538 PMCID: PMC7005072 DOI: 10.1208/s12248-020-0419-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 01/07/2020] [Indexed: 11/30/2022] Open
Abstract
The addition of rabbit anti-human thymocyte globulin (ATG) to the conditioning regimen prior to allogeneic hematopoietic cell transplantation has significantly reduced the risk of graft-versus-host disease (GvHD) and graft failure. However, ATG has a small therapeutic window. Overexposure of ATG post-HCT hampers T cell immune reconstitution and has been associated with increased relapse rates and viral reactivations, whereas underexposure has been associated with an increased incidence of GvHD, both of which lead to increased mortality. Therapeutic drug monitoring of T cell binding ATG plasma levels provides a means to optimize dosing for patients at high risk for graft failure to ensure timely T cell immune reconstitution and subsequently increase survival chances. This manuscript describes the first liquid chromatography tandem-mass spectrometry (LC-MS/MS) method to quantify the pharmacologically active fraction of polyclonal ATG in plasma. This was achieved through immunoaffinity purification of active ATG from plasma with Jurkat T cells. After the binding and washing, samples were eluted, denatured, and trypsin-digested. Signature peptides originating from the IgG constant chain were measured with LC-MS/MS. Critical method parameters were optimized, and the method was successfully validated following European Medicines Agency (EMA) guidelines. The method covered the therapeutic range of ATG and was validated at a lower limit of quantification (LLOQ) of 1 AU/mL with an overall CV and bias of 11.8% and - 2.5%, respectively. In conclusion, we developed a LC-MS/MS-based method to quantify active polyclonal rabbit ATG in human plasma. We suggest that this novel assay can be used to monitor and optimize dosing of ATG in clinical practice.
Collapse
Affiliation(s)
- Mohsin El Amrani
- Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Room no. D.00.318A, Internal post no. D.00.204, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Rick Admiraal
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Lobke Willaert
- Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Room no. D.00.318A, Internal post no. D.00.204, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Lysette J C Ebskamp-van Raaij
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Amelia M Lacna
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - C Erik Hack
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Alwin D R Huitema
- Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Room no. D.00.318A, Internal post no. D.00.204, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
- Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Stefan Nierkens
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Erik M van Maarseveen
- Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Room no. D.00.318A, Internal post no. D.00.204, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.
| |
Collapse
|
|
13
|
Effect of plasmapheresis on ATG (Thymoglobulin) clearance prior to adoptive T cell transfer. Bone Marrow Transplant 2019; 54:2110-2116. [PMID: 30890771 DOI: 10.1038/s41409-019-0505-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/06/2019] [Accepted: 03/02/2019] [Indexed: 01/01/2023]
Abstract
The effect of anti-thymocyte globulin (ATG) on the outcome of hematopoietic stem cell transplantation (SCT) is dependent on formulation, dose and exposure. However, ATG levels are not routinely measured and therapeutic levels are not well defined. In ex vivo T cell-deplete SCT, the potential effect of residual ATG has important implications on the timing of adoptive T cell transfer. Here we measured active rabbit ATG concentration using a flow cytometry-based method that can be implemented in any laboratory. Three adult patients received 6 mg/kg Thymoglobulin over 4 days, leading to peak plasma active ATG concentration of 20.8 ± 1.4 µg/mL, suggesting volume of distribution of 16-19 L. The half-life of active ATG was 6.1 ± 0.7 days and plasmapheresis at Day 25 ± 1 post-transplant reduced mean plasma concentration from 1.25 to 0.61 µg/mL. Total ATG and active ATG do not have a constant relationship because of differences in volumes of distribution and half-lives. Thymoglobulin can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro at concentrations as low as 0.03 µg/mL, with a log-linear relationship between ATG concentration and ADCC. Plasmapheresis can remove ATG but likely has modest biological impact when performed 4 weeks after 6 mg/kg ATG.
Collapse
|
|
14
|
Oostenbrink LVE, Jol-van der Zijde CM, Kielsen K, Jansen-Hoogendijk AM, Ifversen M, Müller KG, Lankester AC, van Halteren AGS, Bredius RGM, Schilham MW, van Tol MJD. Differential Elimination of Anti-Thymocyte Globulin of Fresenius and Genzyme Impacts T-Cell Reconstitution After Hematopoietic Stem Cell Transplantation. Front Immunol 2019; 10:315. [PMID: 30894854 PMCID: PMC6414431 DOI: 10.3389/fimmu.2019.00315] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 02/06/2019] [Indexed: 01/11/2023] Open
Abstract
Anti-thymocyte globulin (ATG) is a lymphocyte depleting agent applied in hematopoietic stem cell transplantation (HSCT) to prevent rejection and Graft-vs.-Host Disease (GvHD). In this study, we compared two rabbit ATG products, ATG-Genzyme (ATG-GENZ), and ATG-Fresenius (ATG-FRES), with respect to dosing, clearance of the active lymphocyte binding component, post-HSCT immune reconstitution and clinical outcome. Fifty-eigth pediatric acute leukemia patients (n = 42 ATG-GENZ, n = 16 ATG-FRES), who received a non-depleted bone marrow or peripheral blood stem cell graft from an unrelated donor were included. ATG-GENZ was given at a dosage of 6-10 mg/kg; ATG-FRES at 45-60 mg/kg. The active component of ATG from both products was cleared at different rates. Within the ATG-FRES dose range no differences were found in clearance of active ATG or T-cell re-appearance. However, the high dosage of ATG-GENZ (10 mg/kg), in contrast to the low dosage (6-8 mg/kg), correlated with prolonged persistence of active ATG and delayed T-cell reconstitution. Occurrence of serious acute GvHD (grade III-IV) was highest in the ATG-GENZ-low dosage group. These results imply that dosing of ATG-GENZ is more critical than dosing of ATG-FRES due to the difference in clearance of active ATG. This should be taken into account when designing clinical protocols.
Collapse
Affiliation(s)
| | | | - Katrine Kielsen
- Institute for Inflammation Research, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | | | - Marianne Ifversen
- Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Klaus G Müller
- Institute for Inflammation Research, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Arjan C Lankester
- Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
| | | | - Robbert G M Bredius
- Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
| | - Marco W Schilham
- Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
| | - Maarten J D van Tol
- Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
| |
Collapse
|
|
15
|
A New Enzyme-Linked Immunosorbent Assay for a Total Anti-T Lymphocyte Globulin Determination: Development, Analytical Validation, and Clinical Applications. Ther Drug Monit 2017; 39:282-289. [PMID: 28399040 DOI: 10.1097/ftd.0000000000000407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Anti-T lymphocyte globulin (ATLG) modulates the alloreactivity of T lymphocytes, reducing the risk of immunological posttransplant complications, in particular rejection and graft-versus-host disease, after allogeneic hematopoietic stem cell transplantation (HSCT). We developed and validated a new enzyme-linked immunosorbent assay (ELISA) method to measure serum levels of total ATLG and evaluate the pharmacokinetics (PK) of the drug in children with β-Thalassemia, receiving allogeneic HSCT. METHODS Diluted serum samples were incubated with Goat-anti-Rabbit IgG antibody coated on a microtiter plate and then, with Goat-anti-Human IgG labeled with horseradish peroxidase. After incubation and washings, substrate solution was added and absorbance was read at 492 nm. ATLG concentrations in samples were determined by interpolation from a standard curve (range: 200-0.095 ng/mL), prepared by diluting a known amount of ATLG in phosphate-buffered saline (PBS). Low, medium, and high-quality control concentrations were 1.56, 6.25, and 25 ng/mL, respectively. This method was developed and validated within the acceptance criteria in compliance with the Guidelines for a biological method validation: the sensitivity of the method was 0.095 ng/mL. We analyzed serum samples from 14 children with β-Thalassemia who received ATLG (Grafalon) at a dose of 10 mg/kg administered as intravenous (IV) infusion on days -5, -4, and -3 before HSCT (day 0). Blood sampling for PK evaluation was performed on days -5, -4, and -3 before and after drug infusion; and then from day -2 to +56. RESULTS The median total ATLG levels pre-IVand post-IV were 0 and 118 mcg/mL on day -5; 85.9 and 199.2 mcg/mL on day -4; 153 and 270.9 mcg/mL on day -3, respectively. The median PK values of CL was 0.0029 (range: 0.0028-0.0057) L·kg·d, Vd was 0.088 (range: 0.025-0.448) L/kg and t1/2 was 20.2 (range: 5.8-50.2) days. CONCLUSIONS These data suggest that given the marked interindividual variability of total ATLG disposition, the development of a validated ELISA method and the possibility to measure PK parameters in paediatric populations are essential steps to optimize drug therapeutic regimens.
Collapse
|
|
16
|
Buszko M, Jakic B, Ploner C, Hoertnagl P, Mayerl C, Wick G, Cappellano G. In vitro immunoregulatory effects of thymoglobulin on human immune cell subpopulations. Immunol Lett 2017; 186:1-8. [PMID: 28389319 DOI: 10.1016/j.imlet.2017.04.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/29/2017] [Accepted: 04/03/2017] [Indexed: 12/19/2022]
Abstract
Thymoglobulin (ATG) is a polyclonal rabbit antibody against human thymocytes used as a T cell-depleting agent in organ transplantation. Its polyclonal character suggests that its effect may go far beyond just T cell depletion. The aim of this study was to further elucidate possible mechanisms underlying the suppressive activity of ATG. For in vitro studies, human peripheral blood mononuclear cells (PBMC) were incubated with ATG or control Ig for various time points. Foxp3+ regulatory cells (Tregs) and monocytes were phenotypically analyzed by flow cytometry and functionally tested by in vitro suppression assays. Cytokine levels were determined by quantitative RT- PCR, Multiplex or ELISA techniques. In vitro, the frequencies of Foxp3+ Tregs increased when human PBMC were stimulated with ATG as compared with stimulation by rabbit Ig or without stimulation. ATG-treated cells suppressed proliferation of autologous PBMC stimulated with anti-CD3 and anti-CD28 monoclonal antibodies and this suppression could be reversed by exogenous IL-2. The Foxp3+ expression dropped down on day 10, which suggests that it is transient. Monocytes and natural killer cells stimulated with ATG down-modulated CD16. Monocytes suppressed the proliferation of autologous PBMC. However, there were not statistically significant differences in IL-10, TNF-α and TGF-β1 secretion by monocytes stimulated with ATG or control rabbit Ig. These findings suggest that ATG has immunomodulatory effects that go beyond T cell depletion and induction of Foxp3+ Tregs. The induction of immunosuppressive monocytes might have a protective role in delaying transplant rejection.
Collapse
Affiliation(s)
- Maja Buszko
- Laboratory of Autoimmunity, Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Bojana Jakic
- Laboratory of Autoimmunity, Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Ploner
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Austria
| | - Paul Hoertnagl
- Central Institute for Blood Transfusion & Immunological Department, Medical University of Innsbruck, Innsbruck, Austria
| | - Christina Mayerl
- Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Wick
- Laboratory of Autoimmunity, Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Giuseppe Cappellano
- Laboratory of Autoimmunity, Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
| |
Collapse
|
|
17
|
Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II. Clin Pharmacokinet 2016; 55:551-93. [PMID: 26620047 DOI: 10.1007/s40262-015-0340-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.
Collapse
|
|
18
|
Antithymocyte Globulin at Clinically Relevant Concentrations Kills Leukemic Blasts. Biol Blood Marrow Transplant 2016; 22:815-24. [DOI: 10.1016/j.bbmt.2016.01.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 01/04/2016] [Indexed: 01/03/2023]
|
|
19
|
Wang DC, Wang X, Chen C. Effects of anti-human T lymphocyte immune globulins in patients: new or old. J Cell Mol Med 2016; 20:1796-9. [PMID: 27084794 PMCID: PMC4988288 DOI: 10.1111/jcmm.12860] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 02/29/2016] [Indexed: 02/06/2023] Open
Abstract
Multiple studies demonstrated that anti‐human T lymphocyte immune globulins (ATG) can decrease the incidence of acute and chronic graft rejection in cell or organ transplants. However, further in‐depth study indicates that different subgroups may benefit from either different regimes or alteration of them. Studies among renal transplant patients indicate that low immunological risk patients may not gain the same amount of benefit and thus tilt the risk versus benefit consideration. This may hold true for low immunological risk patients receiving other organ transplants and would be worth further investigation. The recovery time of T cells and natural killer (NK) cells also bears consideration and the impact that it has on the severity and incidence of opportunistic infections closely correlated with the dosage of ATG. The use of lower doses of ATG in combination with other induction medications may offer a solution. The finding that ATG may lose efficacy in cases of multiple transplants or re‐transplants in the case of heart transplants may hold true for other transplantations. This may lead to reconsideration of which induction therapies would be most beneficial in the clinical setting. These studies on ATG done on different patient groups will naturally not be applicable to all, but the evidence accrued from them as a whole may offer us new and different perspectives on how to approach and potentially solve the clinical question of how to best reduce the mortality associated with chronic host‐versus‐graft disease.
Collapse
Affiliation(s)
- Diane C Wang
- Department of Respiratory Medicine, The First Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiangdong Wang
- Department of Respiratory Medicine, The First Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chengshui Chen
- Department of Respiratory Medicine, The First Hospital of Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
20
|
Ippoliti G, Lucioni M, Leonardi G, Paulli M. Immunomodulation with rabbit anti-thymocyte globulin in solid organ transplantation. World J Transplant 2015; 5:261-266. [PMID: 26722653 PMCID: PMC4689936 DOI: 10.5500/wjt.v5.i4.261] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/17/2015] [Accepted: 10/13/2015] [Indexed: 02/05/2023] Open
Abstract
Rabbit anti-thymocyte globulin’s manifold mechanisms of action may be attribuited to its polyclonal nature. Its T-cell depleting effect on lymphoid cells is well established: Occurring in the blood and secondary lymphoid tissues, depletion proceeds through complement-dependent lysis, opsonization and apoptotic pathways. Clinical studies have shown that rabbit anti-thymocyte globulin’s immunomodulatory effect extends beyond the initial T-cell depletion and up to the period during which lymphocyte populations begin to recover. The drug is able to mediate immunomodulation and graft tolerance by functionally inactivating cell surface receptors involved in antigen recognition, leukocyte trafficking and leukocyte endothelium adhesion. The complex and prolonged immunomodulation induced by this drug contributes to its efficacy in solid organ transplantation, mainly by reducing the incidence of acute graft rejection.
Collapse
|
|
21
|
Population pharmacokinetic modeling of Thymoglobulin(®) in children receiving allogeneic-hematopoietic cell transplantation: towards improved survival through individualized dosing. Clin Pharmacokinet 2015; 54:435-46. [PMID: 25466602 DOI: 10.1007/s40262-014-0214-6] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
BACKGROUND AND OBJECTIVES To prevent graft-versus-host disease and rejection in hematopoietic cell transplantation (HCT), children receive Thymoglobulin(®), a polyclonal antibody acting mainly by depleting T cells. The therapeutic window is critical as over-exposure may result in delayed immune reconstitution of donor T cells. In this study, we describe the population pharmacokinetics of Thymoglobulin(®) as a first step towards an evidence-based dosing regimen of Thymoglobulin(®) in pediatric HCT. METHODS Serum active Thymoglobulin(®) concentrations were measured in all pediatric HCTs performed between 2004 and 2012 in two pediatric HCT centers in The Netherlands. Population pharmacokinetic analysis was performed using NONMEM(®) version 7.2. RESULTS A total of 3,113 concentration samples from 280 pediatric HCTs were analyzed, with age ranging from 3 months to 23 years old. The cumulative Thymoglobulin(®) dose was 10 mg/kg in 94 % of the patients given in 4 consecutive days. A model incorporating parallel linear and concentration-dependent clearance of Thymoglobulin(®) was identified. Body weight [for linear clearance (CL) and central volume of distribution] as well as lymphocyte count pre-Thymoglobulin(®) infusion (for CL) were important covariates. As such, the current dosing regimen results in higher exposure in children with a higher bodyweight and/or a lower lymphocyte count pre-Thymoglobulin(®) infusion. CONCLUSION This model can be used to develop an individual dosing regimen for Thymoglobulin(®), based on both body weight and lymphocyte counts, once the therapeutic window has been determined. This individualized regimen may contribute to a better immune reconstitution and thus outcome of allogeneic HCT.
Collapse
|
|
22
|
Ansari D, Lund LH, Stehlik J, Andersson B, Höglund P, Edwards L, Nilsson J. Induction with anti-thymocyte globulin in heart transplantation is associated with better long-term survival compared with basiliximab. J Heart Lung Transplant 2015; 34:1283-91. [DOI: 10.1016/j.healun.2015.04.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 04/01/2015] [Accepted: 04/16/2015] [Indexed: 11/16/2022] Open
|
|
23
|
Anwar S, Larson DS, Naimi N, Ashraf M, Culiberk N, Liapis H, Wei C, Reiser J, Brennan DC. A case report of adrenocorticotropic hormone to treat recurrent focal segmental glomerular sclerosis post-transplantation and biomarker monitoring. Front Med (Lausanne) 2015; 2:13. [PMID: 25853133 PMCID: PMC4367432 DOI: 10.3389/fmed.2015.00013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 02/27/2015] [Indexed: 12/26/2022] Open
Abstract
Background: Recurrent focal segmental glomerular sclerosis (rFSGS) in renal transplant recipients (RTR) is difficult to predict and treat. Early rFSGS is likely from circulating factors and preformed antibodies. Methods: We present the case of a 23-year-old white man who presented with rFSGS and acute renal failure, requiring dialysis 9-months after a 1-haplotype matched living-related transplant. We retrospectively analyzed serum samples from various clinical stages for rFSGS biomarkers: serum glomerular albumin permeability (Palb), soluble urokinase-type plasminogen activator receptor (suPAR) serum level with suPAR-β3 integrin signaling on human podocytes, and angiotensin II type I receptor-antibody (AT1R-Ab) titer. Results: All biomarkers were abnormal at 1-year pre-transplant prior to initiation of dialysis and at the time of transplant. After initiation of hemodialysis, β3 integrin activity on human podocytes, in response to patient serum, as well as AT1R-Ab were further elevated. At the time of biopsy-proven recurrence, all biomarkers were abnormally high. One week after therapy with aborted plasmapheresis (secondary to intolerance), and high dose steroids, the Palb and suPAR-β3 integrin activity remained significantly positive. After 12-weeks of treatment with high-dose steroids, rituximab, and galactose, the patient remained hemodialysis-dependent. Three-months after his initial presentation, we commenced adrenocorticotropic hormone (ACTH, Acthar® Gel), 80 units subcutaneously twice weekly. Four-weeks later, he was able to discontinue dialysis. After 8-months of maintenance ACTH therapy, his serum creatinine stabilized at 1.79 mg/dL with <1 g of proteinuria. Conclusion: ACTH therapy was associated with improvement in renal function within 4 weeks. The use of rFSGS biomarkers may aid in predicting development of rFSGS.
Collapse
Affiliation(s)
- Siddiq Anwar
- Department of Medicine, Washington University School of Medicine , St. Louis, MO , USA
| | - Derek S Larson
- Department of Medicine, Washington University School of Medicine , St. Louis, MO , USA
| | - Nima Naimi
- Department of Medicine, Washington University School of Medicine , St. Louis, MO , USA
| | - Muhammad Ashraf
- Department of Medicine, Washington University School of Medicine , St. Louis, MO , USA
| | - Nancy Culiberk
- Department of Medicine, Washington University School of Medicine , St. Louis, MO , USA
| | - Helen Liapis
- Department of Pathology, Washington University School of Medicine , St. Louis, MO , USA
| | - Changli Wei
- Department of Medicine, Rush University Medical Center , Chicago, IL , USA
| | - Jochen Reiser
- Department of Medicine, Rush University Medical Center , Chicago, IL , USA
| | - Daniel C Brennan
- Department of Medicine, Washington University School of Medicine , St. Louis, MO , USA
| |
Collapse
|
|
24
|
Page E, Kwun J, Oh B, Knechtle S. Lymphodepletional strategies in transplantation. Cold Spring Harb Perspect Med 2013; 3:3/7/a015511. [PMID: 23818516 DOI: 10.1101/cshperspect.a015511] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Because lymphocytes were shown to mediate transplant rejection, their depletion has been studied as a mechanism of preventing rejection and perhaps inducing immunologic tolerance. Agents that profoundly deplete lymphocytes have included monoclonal antibodies, cytotoxic drugs, and radiation. We have studied several such agents but focused on antibodies that deplete not only peripheral blood lymphocytes, but also lymph node lymphocytes. Depletion of lymph node T lymphocytes appears to permit peripheral tolerance at least for T cells in animal models. Nevertheless, B-cell responses may be resistant to such approaches, and T memory cells are likewise relatively resistant to depleting antibodies. We review the experimental and clinical approaches to depletion strategies and outline some of the pitfalls of depletion, such as limitations of currently available agents, duration of tolerance, infection, and malignancy. It is notable that most tolerogenic strategies that have been attempted experimentally and clinically include depleting agents even when they are not named as the underlying strategy. Thus, there is an implicitly acknowledged role for reducing the precursor frequency of donor antigen-specific lymphocytes when approaching the daunting goal of transplant tolerance.
Collapse
Affiliation(s)
- Eugenia Page
- Department of Surgery, Division of Transplantation, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | | | | | | |
Collapse
|
|
25
|
Franquesa M, Baan CC, Korevaar SS, Engela AU, Roemeling-van Rhijn M, Weimar W, Betjes MGH, Grinyo JM, Hoogduijn MJ. The effect of rabbit antithymocyte globulin on human mesenchymal stem cells. Transpl Int 2013; 26:651-8. [DOI: 10.1111/tri.12109] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 01/04/2013] [Accepted: 04/04/2013] [Indexed: 11/28/2022]
Affiliation(s)
| | - Carla C. Baan
- Transplantation Laboratory; Internal Medicine; Erasmus MC; Rotterdam; the Netherlands
| | - Sander S. Korevaar
- Transplantation Laboratory; Internal Medicine; Erasmus MC; Rotterdam; the Netherlands
| | - Anja U. Engela
- Transplantation Laboratory; Internal Medicine; Erasmus MC; Rotterdam; the Netherlands
| | | | - Willem Weimar
- Transplantation Laboratory; Internal Medicine; Erasmus MC; Rotterdam; the Netherlands
| | - Michiel G. H. Betjes
- Transplantation Laboratory; Internal Medicine; Erasmus MC; Rotterdam; the Netherlands
| | - Josep M. Grinyo
- Experimental Nephrology and Nephrology Department; Bellvitge Hospital-UB-IDIBELL; Barcelona; Spain
| | - Martin J. Hoogduijn
- Transplantation Laboratory; Internal Medicine; Erasmus MC; Rotterdam; the Netherlands
| |
Collapse
|
|
26
|
Goh BK, Chedid MF, Gloor JM, Raghavaiah S, Stegall MD. The impact of terminal complement blockade on the efficacy of induction with polyclonal rabbit antithymocyte globulin in living donor renal allografts. Transpl Immunol 2012; 27:95-100. [PMID: 22813834 DOI: 10.1016/j.trim.2012.07.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Revised: 06/29/2012] [Accepted: 07/02/2012] [Indexed: 11/23/2022]
Abstract
BACKGROUND Eculizumab, a potent inhibitor of terminal complement activation, appears promising in reducing early antibody-mediated rejection in positive crossmatch kidney transplantation. However, its concomitant use with polyclonal rabbit antithymocyte globulin (rATG) might reduce the efficacy of rATG. This study aimed to evaluate the effect of eculizumab on the efficacy of rATG in vivo and determine the role of complement in rATG-induced lymphocyte cell depletion. PATIENTS AND METHODS Thirty-six kidney transplant recipients were classified into 3 groups according to induction regime: anti-IL-2 receptor antibody alone induction group (basiliximab, n=8); rATG induction (n=20), and rATG+eculizumab induction group (n=8). Peripheral blood T-cell subsets and NK cells were measured 3-4 days after transplant (after 3 doses of rATG). RESULTS Compared to anti-IL-2 receptor antibody induction group, both groups treated with rATG demonstrated significant depletion of all T-cell subsets (CD3-positive cells) (P<0.0001 for rATG vs. anti-IL-2 receptor antibody induction group; P<0.001 for rATG+eculizumab vs. anti-IL-2 receptor antibody group). However, while T-cell counts were low in all rATG-treated patients, eculizumab treatment resulted in higher peripheral blood T-cell counts in rATG treated patients (P=0.005). Before induction, median total lymphocyte counts were normal for the three study groups. By 1, 4 months and 1 year, median the total lymphocyte count was normal for the anti-IL-2 receptor antibody group but was below normal range or at the lower edge of normality for rATG and rATG+eculizumab groups. CONCLUSIONS This small-sample size study suggests that peripheral T cells are depleted by rATG in the presence of terminal complement inhibition. However, eculizumab appears to have a mild inhibitory effect on peripheral blood T-cell depletion by rATG in kidney transplant recipients.
Collapse
Affiliation(s)
- Brian K Goh
- Division of Transplantation Surgery and William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | |
Collapse
|
|
27
|
Effects of different serum-levels of ATG after unrelated donor umbilical cord blood transplantation. Transpl Immunol 2012; 27:59-62. [DOI: 10.1016/j.trim.2012.06.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Revised: 06/04/2012] [Accepted: 06/07/2012] [Indexed: 11/24/2022]
|
|
28
|
Joseph A, Neff K, Richard J, Gao L, Bangari D, Joly M, Culm-Merdek K, Garman R, Williams J, Richards S, Ruzek M. Transient Low-Dose Methotrexate Induces Tolerance to Murine Anti-Thymocyte Globulin and Together They Promote Long-Term Allograft Survival. THE JOURNAL OF IMMUNOLOGY 2012; 189:732-43. [DOI: 10.4049/jimmunol.1103601] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
29
|
Wang CJ, Tuffaha A, Zhang D, Diederich DA, Wetmore JB. A CD3+ count-based thymoglobulin induction regimen permits delayed introduction of calcineurin inhibitors in kidney transplantation. Clin Transplant 2012; 26:900-9. [PMID: 22672562 DOI: 10.1111/j.1399-0012.2012.01656.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2012] [Indexed: 12/01/2022]
Abstract
BACKGROUND Withholding calcineurin inhibitors (CNIs) can be considered when graft function is inadequate following kidney transplantation (KT). Thymoglobulin (rATG) can be used to prevent acute rejection while CNIs are being withheld. Here, we report our results of a novel CNI-sparing induction protocol, which utilizes a CD3+ cell count-based rATG treatment regimen when delayed graft function (DGF) develops in the immediate postoperative period. METHODS In a cohort of 153 consecutive deceased-donor KT recipients, all received a single intraoperative dose of basiliximab; 84 subsequently developed DGF and therefore received rATG (rATG+ group), while 69 demonstrated immediate graft function and received CNIs (rATG- group). RESULTS In the rATG+ group, mean duration of therapy was 8.5±6.0 d, permitting CNI initiation to be delayed until postoperative day 10.3±6.2. Cumulative dose of rATG was only 5.1±4.5 mg/kg while targeting CD3+ counts of ≤30 cells/mm3. CD3+ counts were reduced to a mean of 16.7±17.0 cells/mm3 during therapy. At one yr, patient and graft survival rates were 97.6% and 92.9%, respectively, while the frequency of infections and malignancies were not significantly increased compared to the rATG- group. CONCLUSION A unique induction regimen successfully delayed CNI initiation by using modest doses of rATG to deplete CD3+ cells, while yielding excellent long-term graft outcome without increased risk of infection or malignancy.
Collapse
Affiliation(s)
- Connie J Wang
- Division of Nephrology and Hypertension, Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
| | | | | | | | | |
Collapse
|
|
30
|
van den Hoogen MWF, Hoitsma AJ, Hilbrands LB. Anti-T-cell antibodies for the treatment of acute rejection after renal transplantation. Expert Opin Biol Ther 2012; 12:1031-42. [DOI: 10.1517/14712598.2012.689278] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
31
|
Anti-thymocyte globulin for conditioning in matched unrelated donor hematopoietic cell transplantation provides comparable outcomes to matched related donor recipients. Bone Marrow Transplant 2012; 47:1513-9. [PMID: 22580767 DOI: 10.1038/bmt.2012.81] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Rabbit anti-thymocyte globulin (ATG) is used as prophylaxis against GVHD following allogeneic hematopoietic cell transplantation (HCT). At our institution, ATG is exclusively used in the conditioning of matched unrelated donor (URD) transplant recipients. A total of 50 URD HCT recipients who received ATG (ATG group) were retrospectively compared with 48 matched related donor (MRD) HCT recipients who did not receive ATG (no ATG group). There were no significant differences between the groups in rates of day 100 mortality, acute GVHD or relapse. Chronic GVHD incidence was significantly lower in the ATG group (P = 0.007). At a median follow-up of 36 months in the entire cohort, 50% patients are alive in the ATG group and 63% of the patients are alive in the no ATG group (P = 0.13). We conclude that the administration of ATG to patients undergoing URD HCT preserves the anti-leukemia benefit of the transplant, while reducing the risk of developing GVHD, resulting in OS rates that are comparable to MRD HCT recipients.
Collapse
|
|
32
|
Jol-van der Zijde CM, Bredius RGM, Jansen-Hoogendijk AM, Raaijmakers S, Egeler RM, Lankester AC, van Tol MJD. IgG antibodies to ATG early after pediatric hematopoietic SCT increase the risk of acute GVHD. Bone Marrow Transplant 2011; 47:360-8. [PMID: 21892212 DOI: 10.1038/bmt.2011.166] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Anti-thymocyte globulin (ATG), raised in rabbits, is frequently used in allogeneic hematopoietic SCT (HSCT), to prevent graft rejection and acute GVHD. In solid organ transplant patients, antibodies to rabbit IgG result in an enhanced clearance of ATG. The occurrence of such antibodies in HSCT recipients and their clinical impact is unknown. Concentrations of ATG and anti-ATG antibodies were measured in 72 pediatric HSCT recipients treated with ATG as part of the conditioning. Anti-ATG antibodies were detected in 20 children (28%), all transplanted with a non-depleted graft. IgG anti-ATG, alone or combined with IgM and/or IgA anti-ATG, appeared in 10 children. Four patients developed IgG anti-ATG antibodies early (before day 22) post-HSCT. They had steep drops in ATG levels and showed rapid T-cell recovery, which was associated with a significantly increased risk of acute GVHD. In six patients IgG anti-ATG responses occurred later (range 28-46 days) after HSCT without an increased risk of GVHD. A total of 10 children only mounted an IgM (and IgA) anti-ATG response, which was without major impact on ATG levels. These results indicate that early development of IgG anti-ATG antibodies has a major impact on acute GVHD. Routine analysis ATG/anti-ATG Ab measurement should be considered.
Collapse
Affiliation(s)
- C M Jol-van der Zijde
- Department of Pediatric Stem Cell Transplantation, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands.
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Yamane A, Mori T, Kato J, Ono Y, Okamoto S. Discrepancy in the kinetics of total and active anti-thymocyte globulin blood concentrations in recipients of allogeneic hematopoietic stem cell transplantation. Int J Hematol 2011; 93:406-407. [PMID: 21380930 DOI: 10.1007/s12185-011-0778-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2011] [Revised: 01/19/2011] [Accepted: 01/21/2011] [Indexed: 11/30/2022]
Affiliation(s)
- Akiko Yamane
- Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
- Novartis Pharma Program for Clinical Therapeutics of Hematologic Malignancy, Keio University School of Medicine, Tokyo, Japan
| | - Takehiko Mori
- Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Jun Kato
- Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
- Novartis Pharma Program for Clinical Therapeutics of Hematologic Malignancy, Keio University School of Medicine, Tokyo, Japan
| | - Yukako Ono
- Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Shinichiro Okamoto
- Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| |
Collapse
|
|
34
|
Hadaya K, Avila Y, Valloton L, de Rham C, Bandelier C, Ferrari-Lacraz S, Pascual M, Pantaleo G, Martin PY, Buhler L, Villard J. Natural killer cell receptor—Repertoire and functions after induction therapy by polyclonal rabbit anti-thymocyte globulin in unsensitized kidney transplant recipients. Clin Immunol 2010; 137:250-60. [DOI: 10.1016/j.clim.2010.07.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2010] [Revised: 06/21/2010] [Accepted: 07/18/2010] [Indexed: 01/02/2023]
|
|
35
|
Podgorny PJ, Ugarte-Torres A, Liu Y, Williamson TS, Russell JA, Storek J. High rabbit-antihuman thymocyte globulin levels are associated with low likelihood of graft-vs-host disease and high likelihood of posttransplant lymphoproliferative disorder. Biol Blood Marrow Transplant 2010; 16:915-26. [PMID: 20226870 DOI: 10.1016/j.bbmt.2010.02.027] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Accepted: 02/28/2010] [Indexed: 01/30/2023]
Abstract
Rabbit-antithymocyte globulin (ATG) given with conditioning has the potential to decrease the likelihood of graft-versus-host disease (GVHD) or graft failure and to increase the likelihood of relapse or infections. After a given ATG dose, serum ATG levels are variable. Here we determined ATG levels on days 7 and 28 in 153 patients whose conditioning included 4.5 mg/kg ATG (thymoglobulin). Median follow-up was 547 days (range: 14-1519, minimum for patients who have not died, relapsed, developed second malignancy, or had graft failure, 365). Both high day 7 levels and high day 28 levels were associated with low likelihoods of grade II-IV acute GVHD and chronic GVHD needing systemic immunosuppressive therapy, and a high likelihood of posttransplant lymphoproliferative disorder (PTLD). Patients with day 7 ATG levels above 0.803 mg/L had 0.52-fold risk of developing chronic GVHD needing systemic therapy (P = 0.012) and patients with day 7 ATG levels above 1.436 mg/L had 5.84-fold risk of developing PTLD (P = 0.001) compared to patients with lower ATG levels. There was no association of ATG levels with relapse, death, or non-PTLD infections. Association with graft failure could not be evaluated due to only 4 graft failures in the cohort. In conclusion, patients with slow clearance of ATG have a low risk of GVHD, but a high risk of PTLD. The clearance of this relatively low dose of ATG does not impact the likelihood of relapse, death, or non-PTLD infections.
Collapse
Affiliation(s)
- Peter J Podgorny
- The University of Calgary and Alberta Health Services, Calgary, Alberta, Canada.
| | | | | | | | | | | |
Collapse
|
|
36
|
Deeks ED, Keating GM. Rabbit antithymocyte globulin (thymoglobulin): a review of its use in the prevention and treatment of acute renal allograft rejection. Drugs 2009; 69:1483-512. [PMID: 19634926 DOI: 10.2165/00003495-200969110-00007] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Rabbit antithymocyte globulin (rATG) [Thymoglobulin(R); Thymoglobuline(R)] is a purified, pasteurized preparation of polyclonal gamma immunoglobulin raised in rabbits against human thymocytes that is indicated for the prevention and/or treatment of renal transplant rejection in several countries worldwide. rATG induction in combination with immunosuppressive therapy is more effective in preventing episodes of acute renal graft rejection in adult renal transplant recipients than immunosuppressive therapy without induction. The efficacy of rATG induction is generally better than that of equine antithymocyte globulin (eATG) induction and generally no different from that of basiliximab or low-dose daclizumab induction in this patient population. However, in high-risk patients, rATG induction was more effective than daclizumab or basiliximab induction in preventing acute renal graft rejection. In the treatment of renal graft rejection in adult renal transplant recipients, rATG was more effective than eATG in terms of the successful response rate, although the agents generally did not differ with regard to most other endpoints. Both induction and treatment with rATG are generally well tolerated, although adverse events, such as fever, leukopenia and thrombocytopenia, appear more common with rATG than with other antibody preparations. The overall incidence of infection associated with rATG induction was generally no different from that seen with eATG or basiliximab induction, although was higher with rATG than with basiliximab in high-risk patients. The incidence of cytomegalovirus (CMV) disease generally did not differ between rATG and eATG induction, and there was no significant difference between rATG and daclizumab induction with regard to the incidence of CMV infections or the proportion of patients who received treatment for a CMV episode or infection. Relative to basiliximab, the incidence of CMV infection was generally higher with rATG, except in high-risk patients. In the treatment of acute renal rejection, the nature and incidence of infections were generally similar with rATG and eATG. The incidence of malignancies is generally low with rATG therapy and generally does not differ from that seen with other agents. Further prospective comparative studies would be beneficial in order to definitively position rATG with respect to other antibody preparations. In the meantime, available clinical data suggest that rATG is an effective and generally well tolerated option for the prevention and treatment of acute renal graft rejection in renal transplant recipients.
Collapse
Affiliation(s)
- Emma D Deeks
- Wolters Kluwer Health, Adis, Auckland, New Zealand
| | | |
Collapse
|
|
37
|
In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin. Transplantation 2009; 88:170-9. [PMID: 19623011 DOI: 10.1097/tp.0b013e3181abc061] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Polyclonal rabbit anti-human thymocyte globulin (Thymoglobulin) is used clinically for immunosuppression in solid organ transplantation; however, it is difficult to fully characterize the effects of this agent in humans. METHODS A surrogate rabbit anti-murine thymocyte globulin (mATG) was generated analogously to the commercial product Thymoglobulin and in vivo activities were evaluated, including pharmacokinetics, T-cell depletion, dose response and kinetics, depletion/sparing of T-cell subsets or other leukocyte populations, and depletion in different lymphoid organs. RESULTS Within 1 day, T cells are depleted by mATG in the blood, spleen, lymph node, and bone marrow down to doses of 1 mg/kg. Although mATG binds and depletes thymocytes in vitro, there is no thymocyte depletion in vivo at any dose level, suggesting decreased antibody accessibility to the thymus. After two doses of mATG given 3 days apart, T-cell reconstitution begins as early as day 9 and returns to basal levels by day 21 and 29 for CD4 and CD8 T cells, respectively. There is also preferential depletion of naïve T cells that results in increased ratios of regulatory and memory T cells within 1 day after mATG administration. Depletion of natural killer-T cells, natural killer cells, plasma cells, and plasmablasts occurs, but is modest and more transient compared with T cells. B cells, macrophages, dendritic cells, hematopoetic stem cells, and bone marrow stromal cells seem resistant to mATG depletion. CONCLUSIONS These studies characterize the depletive effects of mATG in normal mice and provide insight into mechanisms of action of Thymoglobulin.
Collapse
|
|
38
|
Call SK, Kasow KA, Barfield R, Madden R, Leung W, Horwitz E, Woodard P, Panetta JC, Baker S, Handgretinger R, Rodman J, Hale GA. Total and active rabbit antithymocyte globulin (rATG;Thymoglobulin) pharmacokinetics in pediatric patients undergoing unrelated donor bone marrow transplantation. Biol Blood Marrow Transplant 2009; 15:274-8. [PMID: 19167688 DOI: 10.1016/j.bbmt.2008.11.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2008] [Accepted: 11/17/2008] [Indexed: 11/25/2022]
Abstract
Rabbit antithymocyte globulin (rATG; Thymoglobulin) is currently used to prevent or treat graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation (HSCT). The dose and schedule of rATG as part of the preparative regimen for unrelated donor (URD) bone marrow transplantation (BMT) have not been optimized in pediatric patients. We conducted a prospective study of 13 pediatric patients with hematologic malignancies undergoing URD BMT at St. Jude Children's Research Hospital from October 2003 to March 2005, to determine the pharmacokinetics and toxicities of active and total rATG. The conditioning regimen comprised total body irradiation (TBI), thiotepa, and cyclophosphamide (Cy); cyclosporine (CsA) and methotrexate (MTX) were administered as GVHD prophylaxis. Patients received a total dose of 10 mg/kg rATG, and serial blood samples were assayed for total rATG by enzyme linked immunosorbent assay (ELISA) and active rATG by florescein activated cell sorting (FACS). We found that our weight-based dosing regimen for rATG was effective and well tolerated by patients. The half-lives of total and active rATG were comparable to those from previous studies, and despite high doses our patients had low maximum concentrations of active and total rATG. There were no occurrences of grade iii-iv GVHD even in patients having low peak rATG levels, and the overall incidence of grade II GVHD was only 15%. None of the patients had serious infections following transplantation. These data support the use of a 10 mg/kg dose of rATG in children with hematologic malignancies because it can be administered without increasing the risk of graft rejection, or serious infection in pediatric patients with a low rate of GVHD. These conclusions may not apply to patients with nonmalignant disorders.
Collapse
Affiliation(s)
- Sandra K Call
- Department of Pharmaceutical Services, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Ballen K. New trends in transplantation: the use of Thymoglobulin®. Expert Opin Drug Metab Toxicol 2009; 5:351-5. [DOI: 10.1517/17425250902755100] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
|
|
40
|
Stauch D, Dernier A, Sarmiento Marchese E, Kunert K, Volk HD, Pratschke J, Kotsch K. Targeting of natural killer cells by rabbit antithymocyte globulin and campath-1H: similar effects independent of specificity. PLoS One 2009; 4:e4709. [PMID: 19266059 PMCID: PMC2651595 DOI: 10.1371/journal.pone.0004709] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Accepted: 01/07/2009] [Indexed: 12/31/2022] Open
Abstract
T cell depleting strategies are an integral part of immunosuppressive regimens widely used in the hematological and solid organ transplant setting. Although it is known to induce lymphocytopenia, little is known about the effects of the polyclonal rabbit antithymocyte globulin (rATG) or the monoclonal anti-CD52 antibody alemtuzumab on Natural Killer (NK) cells in detail. Here, we demonstrate that induction therapy with rATG following kidney/pancreas transplantation results in a rapid depletion of NK cells. Treatment of NK cells with rATG and alemtuzumab in vitro leads to impairment of cytotoxicity and induction of apoptosis even at a 10-fold lower concentration (0.1 microg/ml) compared with T and B cells. By generating Fc-parts of rATG and alemtuzumab we illustrate that their ligation to FcgammaRIII (CD16) is sufficient for the significant induction of degranulation, apoptosis and inflammatory cytokine release (FasL, TNFalpha and IFNgamma) exclusively in CD3(-)CD56(dim) NK cells whereas application of rATG and alemtuzumab F(ab) fragments abolishes these effects. These findings are of general importance as our data suggest that NK cells are also mediators of the clinically relevant cytokine release syndrome and that their targeting by therapeutic antibodies should be considered as they are functionally relevant for the effective clearance of opportunistic viral infections and anti-tumor activity posttransplantation.
Collapse
Affiliation(s)
- Diana Stauch
- Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Annelie Dernier
- Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | | | - Kristina Kunert
- Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Hans-Dieter Volk
- Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Charité Universitätsmedizin, Campus Virchow, Berlin, Germany
| | - Katja Kotsch
- Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| |
Collapse
|
|
41
|
Toor A, Rodriguez T, Bauml M, Mathews H, Shanti S, Senitzer D, Kini A, Norton J, Parthasarathy M, Mohideen N, Petrowsky C, Bonilla B, Smith S, Stiff P. Feasibility of conditioning with thymoglobulin and reduced intensity TBI to reduce acute GVHD in recipients of allogeneic SCT. Bone Marrow Transplant 2008; 42:723-31. [PMID: 18711352 PMCID: PMC7101790 DOI: 10.1038/bmt.2008.244] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Murine studies using anti-T-cell antibodies for conditioning in allogeneic SCT demonstrate engraftment with low rates of GVHD. On the basis of this preclinical model, we conditioned 30 patients with advanced hematologic malignancies with rabbit antithymocyte globulin (ATG) and TBI, to reduce rates of fatal acute GVHD. Patients were enrolled in two sequential groups: cohort 1 received ATG 10 mg/kg in divided doses (days -4 to -1)+200 cGy TBI (n=16), and cohort 2 received ATG (days -10 to -7)+450 cGy TBI (n=14). Median donor blood chimerism for the combined group was 94, 93 and 93% in the first, second and third months after transplant. Only three developed grade II acute GVHD despite 43% of patients receiving unrelated donor transplants. One-year survival was 71+/-11 and 54+/-14%, respectively, in recipients of related and unrelated donor SCT. Donor lymphocyte infusions were needed in 12 patients for the management of relapse and for mixed donor-recipient chimerism in 4 patients. We conclude that 10 mg/kg ATG and TBI allows engraftment with a low risk of acute GVHD; however, further dose optimization of ATG is required to achieve a balance between GVHD and disease relapse.
Collapse
Affiliation(s)
- A Toor
- Bone Marrow Transplant Program, Department of Internal Medicine, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Gloor JM, Moore SB, Schneider BA, Degoey SR, Stegall MD. The Effect of Antithymocyte Globulin on Anti–Human Leukocyte Antigen Antibody Detection Assays. Transplantation 2007; 84:258-64. [PMID: 17667819 DOI: 10.1097/01.tp.0000269615.91036.52] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND We evaluated the effect of antithymocyte globulin (ATG) on anti-human leukocyte antigen (HLA) antibody assays. METHODS We tested sera from six in vivo ATG-treated kidney transplant patients after measuring serum concentrations, as well as six nonsensitized sera with ATG added in vitro. T- and B-cell complement-dependent cytotoxicity (CDC), flow cytometric (FXM), and solid-phase HLA class I and II assays based on antigen-coated microspheres and enzyme-linked immunosorbent assay (ELISA) were studied. Sera were then retested after treatment to remove ATG. RESULTS We found that ATG affects test results differently depending on whether sera is obtained from in vivo treated patients or added in vitro. In vitro treated sera produced ATG concentration-dependent positive results for T/B CDC, FXM, and flow bead testing for HLA I/II, while the ELISA-based assay was unaffected. In vivo treated sera from ATG-treated patients produced positive test results for T CDC and T/B FXM, while the B-cell CDC crossmatch remained negative. Solid phase assays were minimally affected using in vivo treated sera. After ATG extraction, all tests became negative. CONCLUSION We conclude that ATG produces positive results in anti-HLA antibody testing, and treatment to remove ATG abolishes this effect. This treatment allows ATG-treated patients to be monitored for anti-HLA antibodies.
Collapse
Affiliation(s)
- James M Gloor
- Department of Nephrology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
| | | | | | | | | |
Collapse
|
|
43
|
Flaman F, Zieroth S, Rao V, Ross H, Delgado DH. Basiliximab Versus Rabbit Anti-thymocyte Globulin for Induction Therapy in Patients After Heart Transplantation. J Heart Lung Transplant 2006; 25:1358-62. [PMID: 17097501 DOI: 10.1016/j.healun.2006.09.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2006] [Revised: 08/03/2006] [Accepted: 09/09/2006] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND The use of basiliximab or rabbit anti-thymocyte globulin (RATG) for induction therapy has significantly reduced the incidence of acute rejection episodes post-transplantation. The purpose of this study was to compare the safety and efficacy of basiliximab vs RATG in a population of adult heart transplant recipients. METHODS We retrospective analyzed the safety and efficacy of basiliximab compared with RATG among 48 adult heart transplant recipients at our center. Twenty-five patients received basiliximab (20 mg on days 0 and 4 after heart transplantation), and 23 patients received RATG (1.5 mg/kg for 3 days). A standard triple-drug immunosuppression regimen was administered to all patients. RESULTS The average biopsy score (ABS) at 1 month was 0.79 +/- 0.18 in the Basiliximab Group vs 0.47 +/- 0.2 in the RATG group (p = 0.023) and at 3 months was 0.75 +/- 0.24 in the Basiliximab Group vs 0.46 +/- 0.12 in the RATG Group (p = 0.032). At 6 months after transplantation, the difference between groups was not statistically significant (0.97 +/- 0.23 vs 0.58 +/- 0.17, p = .14). At 12 months the ABS was 0.85 +/- 0.4 in the Basiliximab Group vs 0.63 +/- 0.15 in the RATG Group (p = 0.12), and the number of episodes of infection was similar in both groups (19 vs 26; p = 0.16). There was no correlation between cumulative cyclosporine doses and rejection. Creatinine clearance levels were not statistically different between groups at baseline and up to 12 months after heart transplantation. Three patients died in the Basiliximab Group, and 2 patients died in the RATG Group. CONCLUSIONS Rabbit anti-thymocyte globulin is more effective than basiliximab for prevention of rejection episodes after heart transplantation. Both induction agents provide similar safety profile.
Collapse
Affiliation(s)
- Flavia Flaman
- Division of Cardiology and Transplant, Toronto General Hospital, Toronto, Ontario, Canada
| | | | | | | | | |
Collapse
|
|
44
|
Deeg HJ, Storer BE, Boeckh M, Martin PJ, McCune JS, Myerson D, Heimfeld S, Flowers ME, Anasetti C, Doney KC, Hansen JA, Kiem HP, Nash RA, O'Donnell PV, Radich JP, Sandmaier BM, Scott BL, Sorror ML, Warren EH, Witherspoon RP, Woolfrey A, Appelbaum FR, Storb R. Reduced incidence of acute and chronic graft-versus-host disease with the addition of thymoglobulin to a targeted busulfan/cyclophosphamide regimen. Biol Blood Marrow Transplant 2006; 12:573-84. [PMID: 16635793 DOI: 10.1016/j.bbmt.2005.12.036] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2005] [Accepted: 12/17/2005] [Indexed: 11/28/2022]
Abstract
To reduce the incidence of graft-versus-host disease (GVHD), we added Thymoglobulin (THY) to dose-adjusted oral busulfan plus cyclophosphamide (targeted BUCY). The starting dose of THY was 4.5 mg/kg given over days -3, -2, and -1, escalated in steps of 1.5 mg/kg in cohorts of 15 evaluable patients. Escalation was dependent on acute GVHD incidence and Epstein-Barr virus reactivation. Fifty-six patients with myelodysplastic syndrome and other myeloid disorders underwent transplantation with peripheral blood progenitor cells from related (n=30) or unrelated (n=26) donors. All but 2 patients achieved engraftment, and 56% survived in remission beyond 1 year. The incidence of acute GVHD was 50%, and that of chronic GVHD was 34%. The highest THY dose was 6.0 mg/kg, a dose at which 1 patient experienced Epstein-Barr virus reactivation. Nine patients did not receive the prescribed THY dose. Results were comparable for related and unrelated transplants and for patients given 4.5 or 6.0 mg/kg THY. Among 27 myelodysplastic syndrome patients (14 with related and 13 with unrelated donors) who underwent transplantation concurrently with targeted BUCY without THY, the incidence of acute and chronic GVHD was 82%. Thus, THY 4.5 to 6.0 mg/kg seemed beneficial for GVHD prevention in BUCY-conditioned patients who underwent transplantation with peripheral blood progenitor cells, although relapse-free survival did not differ significantly from that in comparable historical controls not given THY.
Collapse
Affiliation(s)
- H Joachim Deeg
- Fred Hutchinson Cancer Research Center and University of Washington School of Medicine, Seattle, Washington 98109-1024, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA, Laport GG, Stockerl-Goldstein KE, Johnston LJ, Hoppe RT, Bloch DA, Blume KG, Negrin RS, Strober S. Protective conditioning for acute graft-versus-host disease. N Engl J Med 2005; 353:1321-31. [PMID: 16192477 DOI: 10.1056/nejmoa050642] [Citation(s) in RCA: 244] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Conditioning with total lymphoid irradiation plus antithymocyte serum protects mice against acute graft-versus-host disease (GVHD) after hematopoietic-cell transplantation. We tested this strategy in humans. METHODS Thirty-seven patients with lymphoid malignant diseases or acute leukemia underwent an experimental conditioning regimen with 10 doses of total lymphoid irradiation (80 cGy each) plus antithymocyte globulin, followed by an infusion of HLA-matched peripheral-blood mononuclear cells from related or unrelated donors who received granulocyte colony-stimulating factor. RESULTS Of the 37 transplant recipients, only 2 had acute GVHD after hematopoietic-cell transplantation. Potent antitumor effects in patients with lymphoid malignant diseases were shown by the change from partial to complete remission. In the transplant recipients who underwent conditioning with total lymphoid irradiation and antithymocyte globulin, the fraction of donor CD4+ T cells that produced interleukin-4 after in vitro stimulation increased by a factor of five, and the proliferative response to alloantigens in vitro was reduced, as compared with normal control subjects and control subjects who underwent conditioning with a single dose of total-body irradiation (200 cGy). CONCLUSIONS A regimen of total lymphoid irradiation plus antithymocyte globulin decreases the incidence of acute GVHD and allows graft antitumor activity in patients with lymphoid malignant diseases or acute leukemia treated with hematopoietic-cell transplantation.
Collapse
Affiliation(s)
- Robert Lowsky
- Department of Medicine, Stanford University School of Medicine, Stanford, Calif, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Bone Marrow Transplant 2005; 35:171-7. [PMID: 15531901 DOI: 10.1038/sj.bmt.1704745] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Patients with sickle cell disease (N = 3) and thalassemia (N = 1) with high-risk features received hematopoietic stem cell transplantations (HCT) to induce stable (full or partial) donor engraftment. Patients were 9-30 years of age. Fludarabine, rabbit anti-thymocyte globulin (ATG), and 200 cGy total body irradiation were administered pre-transplant. Patients received bone marrow (N = 3) or peripheral blood stem cells (N = 1) from HLA-identical siblings, followed by mycophenolate mofetil and cyclosporine for post-grafting immunosuppression. Significant lymphopenia, but only moderate neutropenia and thrombocytopenia developed post transplant. No grade IV nonhematological toxicities or acute graft-versus-host disease (GVHD) were observed. At 3 months after transplantation, three of four patients had evidence of donor myeloid chimerism (range, 15-100%). However, after post transplant immunosuppression was discontinued, graft rejection occurred in all but one patient. This patient is now doing well 27 months post transplant with full donor engraftment. One patient died after a second transplant, and another patient experienced a stroke as her graft was being rejected. These results suggest that stable donor engraftment after nonmyeloablative HCT is difficult to achieve among immunocompetent patients with hemoglobinopathies and that new approaches will need to be developed before wider application of this transplantation method for hemoglobinopathies.
Collapse
Affiliation(s)
- J T Horan
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
| | | | | | | | | |
Collapse
|
|
47
|
Bearden CM, Book BK, Sidner RA, Pescovitz MD. Removal of therapeutic anti-lymphocyte antibodies from human sera prior to anti-human leukocyte antibody testing. J Immunol Methods 2005; 300:192-9. [PMID: 15896799 DOI: 10.1016/j.jim.2005.03.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2005] [Accepted: 02/21/2005] [Indexed: 11/30/2022]
Abstract
Both monoclonal (e.g. Orthoclone (OKT3), rituximab) and polyclonal (e.g. ATGAM, Thymoglobulin (Thymo)) anti-lymphocyte Abs (ALAs) are used extensively in organ transplantation for immunosuppression induction, desensitization, and treatment of acute rejection. ALAs often interfere with post transplant immunologic monitoring. We describe a method that uses magnetic beads to selectively remove ALAs from patient serum. Rabbit anti-mouse Fc-specific (180 mug), or rabbit anti-mouse Fab-specific (180 microg), or rabbit anti-horse heavy and light chain-specific and rabbit anti-horse F(ab')2 (200 microg) (Jackson Immunoresearch) was adsorbed to 6.7 x 10(8) Dynabeads M-280 conjugated with sheep anti-rabbit IgG (Dynal Biotech). Fifty microliters of normal human serum (NHS) with 2 microg/ml of OKT3 or 100 microg/ml ATGAM, Thymo, or rituximab were incubated with conjugated beads for several incubations. NHS containing ALAs before and after treatment by the protocol were incubated with human lymphocytes and labeled with FITC-antibody to immunoglobulin of the species used to produce the particular ALA. Residual ALA was determined using flow cytometry. Average median channel for serum with or without ALA was 11.1 and 0.120, respectively for OKT3; 64.4 and 0.344 for ATGAM; 108.5 and 0.200 for Thymo; and 1022.5 and 11.4 for rituximab. Treatment lowered the median channel for serum with OKT3 to 0.103, 0.309 for ATGAM, 0.199 for Thymo, and 12.1 for rituximab. ALAs can be effectively removed from serum by the use of magnetic beads conjugated with Ab specific for ALA thereby permitting immunologic monitoring without interference.
Collapse
|
|
48
|
Rowley SD, Goldberg SL, Pecora AL, Hsu JS, Brecher BA, Butrin L, Kobbe K, McKiernan P, Preti R. Unrelated donor hematopoietic stem cell transplantation for patients with hematologic malignancies using a nonmyeloablative conditioning regimen of fludarabine, low-dose total body irradiation, and rabbit antithymocyte globulin. Biol Blood Marrow Transplant 2005; 10:784-93. [PMID: 15505609 DOI: 10.1016/j.bbmt.2004.08.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Hematopoietic stem cell chimerism can be established after low-dose conditioning regimens, although the risk of donor cell rejection increases for unrelated donor transplantations. We added pretransplantation rabbit antithymocyte globulin (6 mg/kg) to an established conditioning regimen of fludarabine (90 mg/m2) and single-fraction total body irradiation (200 cGy) followed by postgrafting immunosuppression with cyclosporine A and mycophenolate mofetil for 22 patients with hematologic malignancies. One patient rejected the graft and successfully underwent transplantation with cells from a second donor by using the same conditioning regimen. The actuarial probability of developing acute graft-versus-host disease grade II to IV before day 100 was 40%, although 9 of 14 patients who survived beyond 100 days developed chronic graft-versus-host disease. These data support a hypothesis that the addition of antithymocyte globulin decreases the risk of graft-versus-host and host-versus-graft reactions when combined with a nonmyeloablative conditioning regimen of fludarabine and total body irradiation.
Collapse
Affiliation(s)
- Scott D Rowley
- Adult Blood and Marrow Transplant Program, Hackensack University Medical Center, Hackensack, New Jersey 07601, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Waller EK, Langston AA, Lonial S, Cherry J, Somani J, Allen AJ, Rosenthal H, Redei I. Pharmacokinetics and pharmacodynamics of anti-thymocyte globulin in recipients of partially HLA-matched blood hematopoietic progenitor cell transplantation. Biol Blood Marrow Transplant 2003; 9:460-71. [PMID: 12869960 DOI: 10.1016/s1083-8791(03)00127-7] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Polyclonal anti-thymocyte globulin (ATG) administered before allogeneic blood hematopoietic progenitor cell transplantation reduces the risks of graft rejection and graft-versus-host disease, but may delay posttransplant immune reconstitution caused by delayed clearance of ATG from the blood. We studied graft-versus-host disease, infections, and the kinetics of immune reconstitution in 28 patients with very poor-risk hematologic malignancies who received lymphocyte-depleted, CD34(+) cell-enriched hematopoietic progenitor cell grafts from partially HLA-matched related donors (PMRD). The incidence of these clinical events was correlated with blood ATG levels in 19 transplant recipients who received rabbit ATG (r-ATG, thymoglobulin) during conditioning. Total r-ATG and the fraction of ATG antibodies that bind human cells (active ATG) were measured for up to 45 days posttransplantation using enzyme-linked immunosorbent assay and flow cytometry assays. Three patients received equine ATG (e-ATG; total dose of 60 mg/kg/day), 3 patients received 10 mg/kg r-ATG, and 22 patients received 6 mg/kg r-ATG during conditioning. All evaluable patients engrafted. Median numbers of blood CD4(+) and CD8(+) T cells at 100 days posttransplantation were 15 and 8 cells/microL, respectively. Acute graft-versus-host disease developed in 3 of 3 recipients of e-ATG and 1 of 25 recipients of r-ATG. Rapid T-cell reconstitution was seen only in younger patients. Overall mortality was 93% (26/28 patients) with poor immune reconstitution contributing to death in 21 of 28 patients. Recipients of 6 mg/kg r-ATG had peak levels of total and active r-ATG of 64+/-20 microg/mL and 9.2+/-5.8 microg/mL, respectively, with clearance of active r-ATG (t(1/2)6 days) to sub-therapeutic levels (<1 microg/mL) by a median of 15 days posttransplantation (range, 8-38 days). Delayed immune reconstitution is likely a consequence of ex vivo and in vivo purging of donor T cells in the graft coupled with inadequate thymic function rather than persistence of active r-ATG in the blood for months posttransplantation.
Collapse
Affiliation(s)
- Edmund K Waller
- Winship Cancer Institute, Emory University, 1701 Uppergate Dr, Atlanta, GA 30322, USA.
| | | | | | | | | | | | | | | |
Collapse
|