Heterogeneous clearance of antithymocyte globulin after CD34+-selected allogeneic hematopoietic progenitor cell transplantation.
Abstract: Antithymocyte globulins (ATG) are purified, concentrated preparations of polyclonal immunoglobulin G from hyperimmune serum of horses or rabbits immunized with human thymus lymphocytes. Both the horse and the rabbit products induce immunosuppression as a result of lymphocyte depletion and immune modulation. The exact mechanism of action is unknown but may include T-cell clearance from the circulation and modulation of T-cell activation, homing, and cytotoxic activities. Both horse and rabbit ATG include multiple antibodies against T-cell surface antigens and have been used extensively in allogeneic hematopoietic progenitor cell transplantation (HPCT) for the treatment and prevention of graft-versus-host disease or graft rejection. To quantify the active ATG after HPCT, we developed a flow-based assay to measure residual ATG capable of binding to lymphocytes. In contrast to prior assays that measure total rabbit or horse immunoglobulin, this assay quantitates only the antibody capable of binding to lymphocytes, which presumably reflects the functionally active fraction of the xenoantiserum. Thirty patients with hematologic malignancies underwent T cell-depleted HPCT and had ATG levels assayed during the peritransplantation period. The time required for ATG levels to decay to background was quite variable (mean, 46 days; range, 14-91 days), although most patients demonstrated a rapid early clearance followed by a slower decline. The actual mean half-life was 6.8 days (range, 2.4-14.0 days). The persistence of ATG for months after administration has significant implications for the pace of immune reconstitution after transplantation and is a potentially confounding variable in any study that involves early administration of donor lymphocyte infusions or other cellular transfer. These findings indicate that ATG levels should be explicitly measured in studies that involve early donor lymphocyte administration so that proper conclusions regarding dose, safety, and efficacy can be reached.
Publication Date: 2005-07-26 PubMed ID: 16041311DOI: 10.1016/j.bbmt.2005.05.001Google Scholar: Lookup
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- Clinical Trial
- Journal Article
- Research Support
- N.I.H.
- Extramural
- Research Support
- U.S. Gov't
- P.H.S.
Summary
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The research article discusses the varying clearance rates of antithymocyte globulins (ATG) in patients with hematologic malignancies who underwent CD34+-selected allogeneic hematopoietic progenitor cell transplantation (HPCT), a treatment for blood-related conditions.
About Antithymocyte Globulins (ATG)
- ATGs are purified, concentrated preparations of a type of antibody called immunoglobulin G, sourced from the hyperimmune serum of horses or rabbits that have been immunized with human thymus lymphocytes.
- The specific functions of ATGs, while still somewhat unknown, include inducing immunosuppression by depleting lymphocytes and modifying the activity of T-cells, a vital component of the immune system.
- The multiple antibodies in both horse and rabbit ATGs target T-cell surface antigens and are frequently used in allogeneic hematopoietic progenitor cell transplantation (HPCT) for treating and preventing graft-versus-host disease or graft rejection.
The Aim of the Study
- The researchers aimed to develop a flow-based assay capable of measuring the remaining active ATG after HPCT, specifically the ATG capable of binding to lymphocytes.
- Unlike previous assays that measured the total rabbit or horse immunoglobulin, this assay sought to quantify only the antibody capable of binding to lymphocytes, which presumably represents the functional component of the xenoantiserum.
Findings of the Study
- The performance of the assay on thirty patients with hematologic malignancies who had undergone T cell-depleted HPCT revealed a highly variable decay time of ATG levels to the backdrop—mean decay time about 46 days with a range of 14-91 days. However, most patients showed a speedy initial clearance followed by a slower decline.
- This means that ATG has an average half-life of about 6.8 days, with a range of 2.4-14.0 days.
- The persistence of ATG for months after administration can significantly affect the speed of immune reconstitution after transplantation. It could also serve as a potentially confounding variable in any research involving the early administration of donor lymphocyte infusions or other cellular transference.
Implications of the Study
- These findings underscore the need for explicit measurement of ATG levels in studies involving the early administration of donor lymphocytes. This is to draw valid conclusions about dose, safety, and efficacy.
Cite This Article
APA
Kakhniashvili I, Filicko J, Kraft WK, Flomenberg N.
(2005).
Heterogeneous clearance of antithymocyte globulin after CD34+-selected allogeneic hematopoietic progenitor cell transplantation.
Biol Blood Marrow Transplant, 11(8), 609-618.
https://doi.org/10.1016/j.bbmt.2005.05.001 Publication
Researcher Affiliations
- Blood and Marrow Transplant Program, Division of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
MeSH Terms
- Adult
- Aged
- Antigens, CD34
- Antilymphocyte Serum / administration & dosage
- Antilymphocyte Serum / blood
- Female
- Hematologic Neoplasms / therapy
- Hematopoietic Stem Cell Transplantation
- Humans
- Immunosuppressive Agents / administration & dosage
- Immunosuppressive Agents / blood
- Lymphocyte Depletion / methods
- Male
- Middle Aged
- T-Lymphocytes / immunology
- Transplantation, Homologous
Grant Funding
- K08 AI049952-01A1 / NIAID NIH HHS
- 1R21CA091552 / NCI NIH HHS
- KO8AI49952 / NIAID NIH HHS
Citations
This article has been cited 9 times.- 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 Feb 6;22(2):43.
- Dabas R, Jamani K, Kangarloo SB, Dharmani-Khan P, Williamson TS, Ousia S, Durand C, Morris D, Mahoney D, Savoie L, Chaudhry A, Jimenez-Zepeda VH, Khan FM, Daly A, Storek J. Antirelapse effect of pretransplant exposure to rabbit antithymocyte globulin.. Blood Adv 2019 May 14;3(9):1394-1405.
- 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.
- McCune JS, Bemer MJ, Long-Boyle J. Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II.. Clin Pharmacokinet 2016 May;55(5):551-93.
- Admiraal R, van Kesteren C, Jol-van der Zijde CM, van Tol MJ, Bartelink IH, Bredius RG, Boelens JJ, Knibbe CA. Population pharmacokinetic modeling of Thymoglobulin(®) in children receiving allogeneic-hematopoietic cell transplantation: towards improved survival through individualized dosing.. Clin Pharmacokinet 2015 Apr;54(4):435-46.
- Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P, Ugarte-Torres A, Khan FM, Luider J, Auer-Grzesiak I, Mansoor A, Russell JA, Daly A, Stewart DA, Maloney D, Boeckh M, Storek J. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation.. Cytotherapy 2012 Nov;14(10):1258-75.
- Filicko-O'Hara J, Grosso D, Flomenberg PR, Friedman TM, Brunner J, Drobyski W, Ferber A, Kakhniashvili I, Keever-Taylor C, Mookerjee B, Talano JA, Wagner JI, Korngold R, Flomenberg N. Antiviral responses following L-leucyl-L-leucine methyl esther (LLME)-treated lymphocyte infusions: graft-versus-infection without graft-versus-host disease.. Biol Blood Marrow Transplant 2009 Dec;15(12):1609-19.
- Friedman TM, Filicko-O'Hara J, Mookerjee B, Wagner JL, Grosso DA, Flomenberg N, Korngold R. T cell repertoire complexity is conserved after LLME treatment of donor lymphocyte infusions.. Biol Blood Marrow Transplant 2007 Dec;13(12):1439-47.
- Ternant D, Büchler M, Bénéton M, Alván G, Ohresser M, Touchard G, Hurault de Ligny B, Toupance O, Watier H, Lebranchu Y, Paintaud G. Interindividual variability in the concentration-effect relationship of antilymphocyte globulins - a possible influence of FcgammaRIIIa genetic polymorphism.. Br J Clin Pharmacol 2008 Jan;65(1):60-8.
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