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

TY - JOUR

T1 - CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation.

AU - Atanackovic, Djordje

AU - Cao, Yanran

AU - Luetkens, Tim

AU - Panse, Jens

AU - Faltz, Christiane

AU - Arfsten, Julia

AU - Bartels, Katrin

AU - Wolschke, Christine

AU - Eiermann, Thomas

AU - Zander, Axel R.

AU - Fehse, Boris

AU - Bokemeyer, Carsten

AU - Kröger, Nicolaus

PY - 2008

Y1 - 2008

N2 - 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 beta 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.

AB - 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 beta 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.

U2 - 10.3324/haematol.11897

DO - 10.3324/haematol.11897

M3 - SCORING: Zeitschriftenaufsatz

VL - 93

SP - 423

EP - 430

JO - HAEMATOLOGICA

JF - HAEMATOLOGICA

SN - 0390-6078

IS - 3

M1 - 3

ER -