Rabbit antithymocyte globulin (Thymoglobulin®) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients

被引：27

作者：

Na, Il-Kang ^{[1
,2
,5
]}

Wittenbecher, Friedrich ^{[1
]}

Dziubianau, Mikalai ^{[3
]}

Herholz, Anne

Mensen, Angela ^{[2
]}

Kunkel, Desiree ^{[4
]}

Blau, Olga ^{[1
]}

Blau, Igor ^{[1
]}

Thiel, Eckhard ^{[1
]}

Uharek, Lutz ^{[1
]}

Scheibenbogen, Carmen ^{[2
,3
]}

Rieger, Kathrin ^{[1
]}

Thiel, Andreas ^{[3
]}

机构：

[1] Charite, Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany

[2] Charite CVK, Inst Med Immunol, Berlin, Germany

[3] Charite CVK, Berlin Brandenburg Ctr Regenerat Therapies BCRT, Berlin, Germany

[4] Charite CVK, BCRT Flow Cytometry Lab, Berlin Brandenburg Ctr Regenerat Therapies BCRT, Berlin, Germany

[5] Expt & Clin Res Ctr, Berlin, Germany

来源：

HAEMATOLOGICA-THE HEMATOLOGY JOURNAL | 2013年 / 98卷 / 01期

关键词：

VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; ANTI-THYMOCYTE GLOBULIN; PERIPHERAL-BLOOD; MULTIPLE-SCLEROSIS; HELPER-CELLS; RECONSTITUTION; MECHANISMS; DEPLETION; REPERTOIRE;

D O I：

10.3324/haematol.2012.067611

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Rabbit antithymocyte globulin-Genzyme (TM) is used to prevent graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Common disadvantages of treatment are infectious complications. The effects of rabbit antithymocyte globulin-Genzyme (TM) on thymic function have not been well-studied. Multicolor flow cytometry was used to analyze the kinetics of conventional and regulatory T cells in adult patients treated (n=12) or not treated (n=8) with rabbit antithymocyte globulin-Genzyme (TM) during the first 6 months after allogeneic hematopoietic stem cell transplantation. Patients treated with rabbit antithymocyte globulin-Genzyme (TM) had almost undetectable levels of recent thymic emigrants (CD45RA(+) CD31(+)) of both conventional and regulatory CD4 T cells throughout the 6 months after allogeneic hematopoietic stem cell transplantation whereas CD4(+) CD45RA-memory T cells were less affected, but their levels were also significantly lower than in patients not treated with rabbit antithymocyte globulin-Genzyme (TM). In vitro, rabbit antithymocyte globulin-Genzyme (TM) induced apoptosis and cytolysis of human thymocytes, and its cytotoxic effects were greater than those of rabbit antithymocyte globulin-Fresenius (TM). Rabbit antithymocyte globulin-Genzyme (TM) in combination with a conditioning regimen strongly impairs thymic recovery of both conventional and regulatory CD4(+) T cells. The sustained depletion of conventional and regulatory CD4(+) T cells carries a high risk of both infections and graft-versus-host disease. Our data indicate that patients treated with rabbit antithymocyte globulin-Genzyme (TM) could benefit from thymus-protective therapies and that trials comparing this product with other rabbit antithymocyte globulin preparations or lymphocyte-depleting compounds would be informative. (C) 2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.067611

引用

页码：23 / 30

页数：8

共 41 条

[1] Memory CD4+ T cells do not induce graft-versus-host disease [J].

Anderson, BE ;

McNiff, J ;

Yan, J ;

Doyle, H ;

Mamula, M ;

Shlomchik, MJ ;

Shlomchik, WD .

JOURNAL OF CLINICAL INVESTIGATION, 2003, 112 (01) :101-108

[2]

ASHIHARA E, 1994, BONE MARROW TRANSPL, V13, P377

[3] Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group [J].

Basara, N ;

Baurmann, H ;

Kolbe, K ;

Yaman, A ;

Labopin, M ;

Burchardt, A ;

Huber, C ;

Fauser, AA ;

Schwerdtfeger, R .

BONE MARROW TRANSPLANTATION, 2005, 35 (10) :1011-1018

[4] Transfer of aflogeneic CD62L- memory T cells without graft-versus-host disease [J].

Chen, BJ ;

Cui, XY ;

Sempowski, GD ;

Liu, CX ;

Chao, NJ .

BLOOD, 2004, 103 (04) :1534-1541

[5] Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation [J].

Clave, Emmanuel ;

Busson, Marc ;

Douay, Corinne ;

de Latour, Regis Peffault ;

Berrou, Jeannig ;

Rabian, Claire ;

Carmagnat, Maryvonnick ;

Rocha, Vanderson ;

Charron, Dominique ;

Socie, Gerard ;

Toubert, Antoine .

BLOOD, 2009, 113 (25) :6477-6484

[6] Imbalance of regulatory T cells in human autoimmune diseases [J].

Dejaco, C ;

Duftner, C ;

Grubeck-Loebenstein, B ;

Schirmer, M .

IMMUNOLOGY, 2006, 117 (03) :289-300

[7] Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution [J].

Douek, DC ;

Vescio, RA ;

Betts, MR ;

Brenchley, JM ;

Hill, BJ ;

Zhang, L ;

Berenson, JR ;

Collins, RH ;

Koup, RA .

LANCET, 2000, 355 (9218) :1875-1881

[8] Reconstitution of the T-cell compartment after bone marrow transplantation: Restoration of the repertoire by thymic emigrants [J].

Dumont-Girard, F ;

Roux, E ;

van Lier, RA ;

Hale, G ;

Helg, C ;

Chapuis, B ;

Starobinski, M ;

Roosnek, E .

BLOOD, 1998, 92 (11) :4464-4471

[9] Altered naive CD4 and CD8 T cell homeostasis in patients with relapsing-remitting multiple sclerosis:: thymic versus peripheral (non-thymic) mechanisms [J].

Duszczyszyn, DA ;

Beck, JD ;

Antel, J ;

Bar-Or, A ;

Lapierre, Y ;

Gadag, V ;

Haegert, DG .

CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2006, 143 (02) :305-313

[10] CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation [J].

Edinger, M ;

Hoffmann, P ;

Ermann, J ;

Drago, K ;

Fathman, CG ;

Strober, S ;

Negrin, RS .

NATURE MEDICINE, 2003, 9 (09) :1144-1150

← 1 2 3 4 5 →