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ABSTRACT: After HLA class I-mismatched stem cell transplantation, allo-HLA-directed CD8 T cell responses can be activated without the help of CD4 T cells if memory CD8 T cells cross-reactive against the allo-HLA class I are present or if naïve CD8 T cells are administered during inflammatory conditions. However, in the absence of inflammatory conditions, cooperation between CD4 and CD8 T cells likely is required for an effective primary CD8 T cell response directed against allo-HLA class I. In this study we investigated whether a coordinated response of CD8 and CD4 T cells could be demonstrated in an HLA class I-directed immune response in a patient who developed severe graft-versus-host disease (GVHD) after the administration HLA-A2-mismatched donor lymphocyte infusion in the absence of inflammatory conditions. A previously administered donor lymphocyte infusion from the same donor did not lead to an immune response, excluding the presence of a substantial pool of CD8 T cells cross-reactive against HLA-A2 within the memory T cell compartment of the donor. Analysis of isolated donor CD8 and CD4 T cell clones activated during the GVHD revealed a polyclonal CD8 T cell response directed against the mismatched HLA-A2 and a polyclonal CD4 T cell response recognizing HLA-A2-derived peptides presented in HLA class II. In addition, leukemic blasts present at the time of the emergence of GVHD expressed HLA-A2 and HLA class II and could activate both the CD4 and CD8 alloreactive T cells. Our results demonstrate that the GVHD was mediated by a cooperative CD4 and CD8 response directed against the mismatched HLA-A2 and suggest that leukemic blasts possibly activated this CD8 and CD4 T cell response.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2012; 18(2):210-9. · 3.15 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) are multipotent progenitor cells that have emerged as a promising tool for clinical application. Further clinical interest has been raised by the observation that MSCs are immunoprivileged and, more important, display immunosuppressive capacities. These properties may be of therapeutic value in allogeneic transplantation to prevent graft rejection and to prevent and treat graft-versus-host disease. In the present study, we examined the in vivo immunomodulatory properties of MSCs in murine models of allogeneic bone marrow (BM) transplantation. Sublethally irradiated recipients received allogeneic BM with or without host or donor MSCs. The addition of host MSCs significantly enhanced the long-term engraftment associated with tolerance to host and donor antigens. However, the infusion of donor MSCs was associated with significantly increased rejection of allogeneic donor BM cells. Moreover, we showed that the injection of merely allogeneic donor MSCs in naive mice was sufficient to induce a memory T-cell response. Although the observed engraftment-promoting effects of host MSCs in vivo support the therapeutic potential of MSCs, our results also indicate that allogeneic MSCs are not intrinsically immunoprivileged and that under appropriate conditions, allogeneic MSCs induce a memory T-cell response resulting in rejection of an allogeneic stem cell graft.
Blood 10/2006; 108(6):2114-20. · 9.90 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) are not only able to evade the immune system, but they have also been demonstrated to exert profound immunosuppressive properties on T cell proliferation. However, their effect on the initiators of the immune response, the dendritic cells (DCs), are relatively unknown. In the present study, the effects of human MSCs on the differentiation and function of both CD34+ -derived DCs and monocyte-derived DCs were investigated. The presence of MSCs during differentiation blocked the differentiation of CD14+CD1a- precursors into dermal/interstitial DCs, without affecting the generation of CD1a+ Langerhans cells. In line with these observations, MSCs also completely prevented the generation of immature DCs from monocytes. The inhibitory effect of MSCs on DC differentiation was dose dependent and resulted in both phenotypical and functional modifications, as demonstrated by a reduced expression of costimulatory molecules and hampered capacity to stimulate naive T cell proliferation. The inhibitory effect of MSCs was mediated via soluble factors. Taken together, these data demonstrate that MSCs, next to the antiproliferative effect on T cells, have a profound inhibitory effect on the generation and function of both CD34+ -derived and monocyte-derived DCs, indicating that MSCs are able to modulate immune responses at multiple levels.
The Journal of Immunology 09/2006; 177(4):2080-7. · 5.79 Impact Factor
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ABSTRACT: Umbilical cord blood (UCB) is considered as an attractive alternative source of hematopoietic stem cells for allogeneic stem cell transplantations in patients who lack human leukocyte antigen (HLA)-matched donors. However, the low cell dose adversely affects hematopoietic recovery and therefore limits application of UCB transplantation in adults. Transplantation of multiple UCB units could be a strategy to overcome cell dose limitations.
To investigate the effect of double cord transplantation, nonobese diabetic/severe combined immunodeficient mice were transplanted with human hematopoietic progenitor cells (CD34(+)) derived from two UCB units with HLA disparity. Human cell engraftment and donor origin was determined by flow cytometry.
Double CB transplantation resulted in increased engraftment levels in the bone marrow and peripheral blood in comparison with recipients of a single unit. Because this effect could be due to the higher cell dose (2.10(5) vs 1.10(5) cells), double CB transplantation was compared with single units containing equal cell numbers (2.10(5)). In some cases, engraftment levels in recipients of single units containing 2.10(5) cells were significantly higher than after transplantation of 1.10(5) cells. These engraftment levels were similar to those observed after double CB transplantation. Chimerism analysis indicated that increased engraftment in recipients of two units was predominantly derived from one unit, whereas in other cases the contribution of the two units was similar.
These results indicate that engraftment may be enhanced by addition of a second unrelated CB that might be attributed to a cell dose effect or due to a graft-facilitating effect.
Experimental Hematology 11/2005; 33(10):1249-56. · 2.90 Impact Factor
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ABSTRACT: Previously, we have found that human culture-expanded fetal lung-derived mesenchymal stem cells (MSC) promote the engraftment of umbilical cord blood (UCB)-derived CD34((+)) cells. The high frequency of MSC in fetal lung allowed us to study whether this represented a biological feature of these cells or a property that was acquired during expansion in culture.
Irradiated NOD/SCID mice (n=80) were transplanted with 0.1x10(6) UCB CD34(+) cells in the presence or absence of 10(6) primary nonexpanded or culture-expanded fetal lung, liver, or BM CD45(-) cells, or with nonexpanded fetal lung liver or BM CD45(-) cells only.
In comparison with transplantation of UCB CD34(+) cells only, cotransplantation of UCB CD34(+) cells and primary fetal lung or BM CD45(-) cells resulted in a significantly higher level of engraftment (% hCD45(+) cells) in BM, PB, and spleen. In addition, primary mesenchymal cells derived from adult BM had a similar promoting effect. The engraftment-enhancing effect was similar to that of culture-expanded fetal lung and BM MSC. Primary mesenchymal cells, but not culture-expanded MSC, were detected in recipient mice, suggesting that the primary cells were able to home and that this capacity was lost after expansion.
These results show that primary mesenchymal cells from fetal lung and BM promote the engraftment of UCB-derived CD34(+) cells to a similar degree as culture-expanded MSC, indicating that it reflects a biological property of primary MSC that is preserved during expansion in culture.
Experimental Hematology 11/2003; 31(10):881-9. · 2.90 Impact Factor
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ABSTRACT: We previously found that human fetal lung is a rich source of mesenchymal stem cells (MSC). Here we characterize and analyze the frequency and function of MSC in other second-trimester fetal tissues.
Single cell suspensions of fetal bone marrow (BM), liver, lung, and spleen were made and analyzed by flow cytometry for the expression of CD90, CD105, CD166, SH3, SH4, HLA-ABC, HLA-DR, CD34 and CD45. We assessed the frequency of MSC by limiting dilution assay.
The frequency of MSC in BM was significantly higher than in liver, lung, and spleen (p<0.05). On primary non-expanded cells from fetal liver, lung and spleen the number of cells positive for mesenchymal markers was significantly higher within the CD34 positive population than within the CD34 negative population. The phenotype of the culture-expanded MSC was similar for all fetal tissues, i.e. CD90, CD105, CD166, SH3, SH4 and HLA-ABC positive and CD34, CD45 and HLA-DR negative. Culture-expanded cells from all tissues were able to differentiate along adipogenic and osteogenic pathways. However, adipogenic differentiation was less in MSC derived from spleen, and osteogenic differentiation was reduced in liver-derived MSC (p<0.05).
Our results indicate that culture-expanded MSC derived from second-trimester fetal tissues, although phenotypically similar, exhibit heterogeneity in differentiating potential. We speculate that these differences may be relevant for the clinical application of MSC.
Haematologica 08/2003; 88(8):845-52. · 6.42 Impact Factor
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Willy A Noort, Alwine B Kruisselbrink,
Pieternella S in't Anker,
Marjolein Kruger,
Rutger L van Bezooijen,
Roelf A de Paus,
Mirjam H M Heemskerk,
Clemens W G M Löwik,
J H Falkenburg,
Roel Willemze,
Willem E Fibbe
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ABSTRACT: Mesenchymal stem cells (MSC) have been implicated as playing an important role in hematopoietic stem cell engraftment. We identified and characterized a new population of MSC derived from human fetal lung. In cotransplantation experiments, we examined the homing of MSC as well as the effect on engraftment of human umbilical cord blood (UCB)-derived CD34(+) cells in NOD/SCID mice.
Culture-expanded fetal lung-derived CD34(+) cells were characterized by immune phenotyping and cultured under conditions promoting differentiation to osteoblasts or adipocytes. Irradiated (3.5 Gy) NOD/SCID mice (n = 51) were transplanted intravenously with 0.03 to 1.0 x 10(6) UCB CD34(+) cells in the presence or absence of 1 x 10(6) culture-expanded fetal lung-derived MSC, irradiated CD34(-) cells, B cells, or with cultured MSC only.
Culture-expanded fetal lung CD34(+) cells were identified as MSC based on phenotype (CD105(+), SH3(+), SH4(+), CD160(+)) and their multilineage potential. Cotransplantation of low doses of UCB CD34(+) cells and MSC resulted in a three-fold to four-fold increase in bone marrow engraftment after 6 weeks, whereas no such effect was observed after cotransplantation of irradiated CD34(-) or B cells. Homing experiments indicated the presence of MSC in the lung, but not in the bone marrow, of NOD/SCID mice.
We identified a population of MSC derived from human fetal lung. Upon cotransplantation, MSC, but not irradiated CD34(-) or B cells, promote engraftment of UCB CD34(+) cells in bone marrow, spleen, and blood by mechanisms that may not require homing of MSC to the bone marrow.
Experimental Hematology 09/2002; 30(8):870-8. · 2.90 Impact Factor
