Impaired T-cell activation and cytokine productivity after transplantation of positively selected CD34+ allogeneic hematopoietic stem cells

TY - JOUR

T1 - Impaired T-cell activation and cytokine productivity after transplantation of positively selected CD34+ allogeneic hematopoietic stem cells

AU - Eyrich, Matthias

AU - Leiler, Christine

AU - Croner, Tanja

AU - Lang, Peter

AU - Schumm, Michael

AU - Mascher, Beate

AU - Schilbach, Karin

AU - Klingebiel, Thomas

AU - Handgretinger, Rupert

AU - Niethammer, Dietrich

AU - Schlegel, Paul G

PY - 2004

Y1 - 2004

N2 - Transplantation of positively selected, CD34(+) peripheral blood stem cells from alternative donors frequently results in delayed immune reconstitution. A shift towards a type 2 cytokine production might be a major contributing factor. We therefore decided to measure IFN-gamma, IL-2, IL-4, and IL-10 after stimulation of peripheral mononuclear cells with PMA/ionomycin and on a single cell level by intracellular cytokine staining during different stages of immune reconstitution. Immediately after transplantation, secretion of all selected cytokines was substantially diminished, and remained subnormal compared to controls until the end of the first year despite normalizing T-cell levels. IL-2 was predominantly produced by CD4(+)CD45RA(+) naïve, whereas IFN-gamma originated mainly from CD8(+)CD45RO(+) memory T cells. Secretion of IL-2 was correlated with the numbers of naive CD4(+) T cells, whereas IFN-gamma secretion correlated with total CD3(+) T-cell counts. IL-4 and IL-10 were produced by CD4(+) and CD8(+) memory T cells; secretion of these cytokines was low, however, and did not increase during follow-up. Therefore, a shift towards a preferential production of type 2 cytokines could not be observed. Analysis of CD69 upregulation upon stimulation revealed a deficiency in patient T-cell activation, which unexpectedly comprised both naïve and memory T-cell subpopulations. Therefore, we suggest that a defect in T-cell activation intrinsic to the host and not graft-versus-host disease, post-transplant immunosuppression or a shift towards a type 2 cytokine pattern contributes to the impaired production of cytokines post-transplant. Further studies will focus on the elimination of host factors that may adversely affect T-cell function after transplantation.

AB - Transplantation of positively selected, CD34(+) peripheral blood stem cells from alternative donors frequently results in delayed immune reconstitution. A shift towards a type 2 cytokine production might be a major contributing factor. We therefore decided to measure IFN-gamma, IL-2, IL-4, and IL-10 after stimulation of peripheral mononuclear cells with PMA/ionomycin and on a single cell level by intracellular cytokine staining during different stages of immune reconstitution. Immediately after transplantation, secretion of all selected cytokines was substantially diminished, and remained subnormal compared to controls until the end of the first year despite normalizing T-cell levels. IL-2 was predominantly produced by CD4(+)CD45RA(+) naïve, whereas IFN-gamma originated mainly from CD8(+)CD45RO(+) memory T cells. Secretion of IL-2 was correlated with the numbers of naive CD4(+) T cells, whereas IFN-gamma secretion correlated with total CD3(+) T-cell counts. IL-4 and IL-10 were produced by CD4(+) and CD8(+) memory T cells; secretion of these cytokines was low, however, and did not increase during follow-up. Therefore, a shift towards a preferential production of type 2 cytokines could not be observed. Analysis of CD69 upregulation upon stimulation revealed a deficiency in patient T-cell activation, which unexpectedly comprised both naïve and memory T-cell subpopulations. Therefore, we suggest that a defect in T-cell activation intrinsic to the host and not graft-versus-host disease, post-transplant immunosuppression or a shift towards a type 2 cytokine pattern contributes to the impaired production of cytokines post-transplant. Further studies will focus on the elimination of host factors that may adversely affect T-cell function after transplantation.

KW - Antigens, CD/blood

KW - Antigens, CD34/blood

KW - CD4-Positive T-Lymphocytes/immunology

KW - CD8-Positive T-Lymphocytes/immunology

KW - Child

KW - Cytokines/blood

KW - Humans

KW - Interleukins/blood

KW - Lymphocyte Activation/immunology

KW - Lymphocytes/immunology

KW - Regression Analysis

KW - Retrospective Studies

KW - Stem Cell Transplantation

KW - T-Lymphocytes/immunology

U2 - 10.1038/sj.thj.6200397

DO - 10.1038/sj.thj.6200397

M3 - SCORING: Journal article

C2 - 15297850

VL - 5

SP - 329

EP - 340

JO - HEMATOL J

JF - HEMATOL J

SN - 1466-4860

IS - 4

ER -