Haematologica
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Published online 20 February 2008
Haematologica, Vol 93, Issue 3, 423-430 doi:10.3324/haematol.11897
Copyright © 2008 by Ferrata Storti Foundation
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Multiple Myeloma

CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation

Djordje Atanackovic1,, Yanran Cao1, Tim Luetkens1, Jens Panse1, Christiane Faltz1, Julia Arfsten1, Katrin Bartels1, Christine Wolschke2, Thomas Eiermann3, Axel R. Zander2, Boris Fehse2, Carsten Bokemeyer1, Nicolaus Kroger2

1 Department of Oncology/Hematology
2 Department of Stem Cell Transplantation and
3 Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Correspondence: Djordje Atanackovic, M.D., Department of Medicine II, Oncology/Hematology, University Medical Center, Hamburg-Eppendorf Martinistr. 52, 20246 Hamburg, Germany. E-mail: d.atanackovic{at}uke.uni-hamburg.de

Background: Very little is known about the number and function of immunosuppressive CD4+CD25+FOXP3+ T regulatory cells (Treg) in the human bone marrow and it is unclear whether bone marrow-residing Treg are capable of regenerating following allogeneic stem cell transplantation. This is particularly surprising since the bone marrow represents a major priming site for T-cell responses and Treg play important roles in the prevention of T-cell-mediated graft-versus-host disease and in promoting tumor escape from T-cell-dependent immunosurveillance.

Design and Methods: Applying flow cytometry, real-time polymerase chain reaction, and functional assays, we performed the first study on bone marrow and peripheral blood Treg in healthy donors as well as multiple myeloma patients before and after allogeneic stem cell transplantation.

Results: We found that, following the allogeneic transplantation, donor-derived CD4+CD25+FOXP3+ Treg expanded faster than conventional CD4+ T cells, leading to an accumulation of Treg in the bone marrow of transplanted patients who lack relevant thymic function. The reconstituted bone marrow-residing CD4+CD25+FOXP3+ Treg of myeloma patients after allogeneic stem cell transplantation consisted preferably of CD45RA–CCR7– memory T-cells and contained low numbers of T-cell receptor excision cycles, indicating that Treg had indeed expanded outside the thymus. Importantly, bone marrow-residing Treg of newly diagnosed and myeloma patients after allogeneic stem cell transplantation expressed high levels of transforming growth factor β and cytotoxic T-lymphocyte antigen 4, and showed a strong inhibitory function.

Conclusions: We suggest that allogeneic stem cell transplantation provides a short but significant window of opportunity for CD8+ T cells before an exuberant regeneration of immunosuppressive Treg sets in. Later after transplantation, bone marrow-residing Treg probably contribute to suppressing graft-versus-host disease but may also undermine persistent immune control of multiple myeloma.

Key words: multiple myeloma, immunology, tumor immunology, T cells, T regulatory cells, transplantation.


Related Article

Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders
Andy C. Rawstron, Alberto Orfao, Meral Beksac, Ludmila Bezdickova, Rik A. Brooimans, Horia Bumbea, Klara Dalva, Gwenny Fuhler, Jan Gratama, Dirk Hose, Lucie Kovarova, Michael Lioznov, Gema Mateo, Ricardo Morilla, Anne K. Mylin, Paola Omedé, Catherine Pellat-Deceunynck, Martin Perez Andres, Maria Petrucci, Marina Ruggeri, Grzegorz Rymkiewicz, Alexander Schmitz, Martin Schreder, Carine Seynaeve, Martin Spacek, Ruth M. de Tute, Els Van Valckenborgh, Nicky Weston-Bell, Roger G. Owen, Jesús F. San Miguel, Pieter Sonneveld, Hans E. Johnsen on behalf of the European Myeloma Network
Haematologica 2008 93: 431-438. [Abstract] [Full Text] [PDF]





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Copyright © 2008 by the Ferrata Storti Foundation.