Ex vivo expansion of long‐term culture initiating marrow cells by IL‐10, SCF, and IL‐3

Keil, Felix; Elahi, Fanny M.; Greinix, Hildegard; Fritsch, Gerhard; Louda, Norbert; Petzer, Andreas; Prinz, Erika; Kalhs, Peter; Lechner, Klaus; Geißler, Klaus

doi:10.1046/j.1537-2995.2002.00102.x

Cited by 9 publications

(8 citation statements)

References 41 publications

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“…[44][45][46] Additionally, IL-10 has contributed to the expansion of both CFU-GMs and primitive long-term colony-initiating cells (LTC-ICs). 47,48 Production of such cytokines could impact the hematopoietic microenvironment. For example, the stem cell niche in the bone marrow may be associated with osteoblasts that are capable of binding and recruiting T cells.…”

Section: Discussionmentioning

confidence: 99%

Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation

Hanash

Levy

2005

Blood

156

119

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IntroductionBone marrow transplantation (BMT) is a potentially curative treatment for both hematologic and nonhematologic diseases, but the wider use of allogeneic BMT is limited by the frequent and severe outcome of graft-versus-host disease (GVHD). 1 Unfortunately, efforts to reduce GVHD by removing donor T cells from the graft have resulted in poor engraftment and elevated disease recurrence, indicating a pivotal role of donor T cells in promoting engraftment of the donor hematopoietic compartment. 2,3 CD8 T cells have been found to be much more potent facilitators of both initial and long-term engraftment than CD4 T cells in murine transplantation models. 4,5 However, both CD8 and CD4 T cells are capable of mediating GVHD. Moreover, attempting to reduce GVHD by limiting perforin and FasL function has not prevented GVHD, and CD8 T cells would likely have detrimental effects on engraftment and the capacity for graft-versus-leukemia (GVL) responses. 5-9 Therefore, identifying cell populations capable of supporting allogeneic hematopoietic stem/progenitor cell (HSPC) engraftment without inducing GVHD could circumvent the hazards of conventional T cells, thereby broadening the pool of acceptable donors.Although unfractionated CD4 T cells have not been shown to possess efficient facilitating potential, the CD25 ϩ regulatory fraction, representing approximately 10% of peripheral CD4 T cells, represents a potentially attractive alternative to CD8 T cells for promotion of engraftment. 4,5 Identified by their role in suppressing autoimmunity, CD4 ϩ CD25 ϩ T cells have demonstrated a capacity to inhibit T-cell activation in vitro and T-cell-mediated autoimmune disease in vivo. 10,11 This T-cell suppression has been employed to inhibit alloreactive responses and prevent GVHD in murine models of hematopoietic transplantation. [12][13][14][15] Although suppression has been demonstrated in vitro to require signaling via their antigen receptor, CD4 ϩ CD25 ϩ suppressor cells and responder T cells can have distinct T-cell-receptor (TCR) specificities. 16,17 Little is presently understood regarding CD4 ϩ CD25 ϩ antigen recognition in vivo. With regard to their application to transplantations, it is interesting to consider the possibility that donor CD4 ϩ CD25 ϩ T cells could be activated by transplanted selfantigens and/or recipient-derived alloantigens. 16,[18][19][20][21][22] We therefore hypothesized that appropriate TCR signaling of donor CD4 ϩ CD25 ϩ T cells would occur after transplantation, and this population could assist donor HSPCs in overcoming the host resistance independent of the specter of GVHD.The present studies have assessed the capacity of donor CD4 ϩ CD25 ϩ T cells to support engraftment of donor bone marrow grafts in a complete major histocompatibility complex (MHC)-mismatched (B6 3 BALB/c) BMT model. The transplantation of CD4 ϩ CD25 ϩ T cells into sublethally conditioned recipients resulted in decreased rejection of both lineage-committed and multipotential donor hematopoietic progenitors within the firs...

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Section: Discussionmentioning

confidence: 99%

Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation

Hanash

Levy

2005

Blood

156

119

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“…The frequency of LTC-IC was calculated as the reciprocal of the concentration of test cells that gives 37% negative cultures using Poisson statistics (17,18). In previous experiments, in one LTC-IC of unmanipulated bone marrow, the proliferative capacity was three CFC per LTC-IC (15). Bone marrow cells were cultured for 6 weeks at a concentration of 1ϫ10 6 cells/mL in a total volume of 4 mL per dish containing 12.5% fetal calf serum (Gibco, Gaithersburg, MD), 12.5% horse serum (Gibco), 1ϫ10 Ϫ6 M hydrocortisone (Sigma, St. Louis, MO), and 5ϫ10 Ϫ4 M ␣-thioglycerol (Sigma).…”

Section: Long-term Culturementioning

confidence: 92%

“…Before nonmyeloablative HSCT, 2 and 4 weeks after conditioning therapy, long-term cultures were performed as described (15). To evaluate frequency and proliferative capacity, bone marrow cells were plated on an irradiated 1:1 mixture of M2-10B4 murine stroma cells (a kind gift from Donna E. Hogge, Terrry Fox Laboratory, Vancouver, Canada) and cultured in 96-well plates (A/S Nunc, Roskilde, Denmark) at different cell concentrations as described (16).…”

Section: Long-term Culturementioning

confidence: 99%

“…Studies looking at LTC-IC after allogeneic transplants have shown a severe and long-lasting depletion of the LTC-IC compartment, but in these patients, dose of conditioning therapy was significant higher(19, 20). Recently, we published the frequency and proliferative capacity of healthy bone marrow progenitors, and the number of LTC-IC was higher if compared with patients receiving NST, suggesting some myelosuppressive effect of chemotherapy that was given before NST(15).Storb et al have shown in littermates that lymph node irradiation and posttransplant immunosuppressive therapy are sufficient to create mixed donor chimerism in the bone marrow…”

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confidence: 99%

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Rapid Establishment of Long-Term Culture-Initiating Cells of Donor Origin After Nonmyeloablative Allogeneic Hematopoietic Stem-Cell Transplantation, and Significant Prognostic Impact of Donor T-Cell Chimerism on Stable Engraftment and Progression-Free Survival

Keil

Prinz²,

Moser³

et al. 2003

Transplantation

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“…All these factors were chosen because they are early-acting cytokines that are proved to work on SCs according to the scientific literature. [18][19][20][21] Autologous cord blood plasma was taken from Ficoll gradients and peripheral blood plasma was obtained from 1 healthy donor. After 3 days 50% of the fresh medium was added to each well.…”

Section: Cell Expansionmentioning

confidence: 99%

Ex-Vivo Expanded Umbilical Cord Blood Stem Cells Retain Capacity for Myocardial Regeneration

Schlechta

Wiedemann

Kittinger

et al. 2010

Circ J

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Background: Umbilical cord blood (UCB) is a source of human hematopoietic precursor cells (HPCs), a stem cell (SC) type that has been used in several trials for myocardial repair. A certain minimal number of cells is required for measurable regeneration and a major challenge of SC-based regenerative therapy constitutes exvivo expansion of the primitive cell compartment. The aim of this study was to investigate the ex-vivo expansion potential of UCB-derived HPCs and the ability of these expanded cells to migrate to the site of damage and improve ventricular function in a rodent model of myocardial infarction (MI). Methods and Results:UCB-derived HPCs, defined by coexpression of CD133 and CD34, were expanded using various cytokine combinations. MI was induced by left anterior descending artery ligation in nude rats. Cells were injected intravenously 2 days after infarction. The combination of SC factor, thrombopoietin, flt3-ligand and interleukin-6 was found to be the most effective for inducing proliferation of HPCs. The migratory capacity of expanded HPCs was similar to that of non-expanded HPCs and improvement of ejection fraction was significant in both groups, with a relative increase of >60%.Conclusions: UCB-derived HPCs can be reproducibly expanded ex-vivo and retain their potential to improve cardiac function post-MI. (Circ J 2010; 74: 188 - 194)

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Ex vivo expansion of long‐term culture initiating marrow cells by IL‐10, SCF, and IL‐3

Cited by 9 publications

References 41 publications

Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation

Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation

Rapid Establishment of Long-Term Culture-Initiating Cells of Donor Origin After Nonmyeloablative Allogeneic Hematopoietic Stem-Cell Transplantation, and Significant Prognostic Impact of Donor T-Cell Chimerism on Stable Engraftment and Progression-Free Survival

Ex-Vivo Expanded Umbilical Cord Blood Stem Cells Retain Capacity for Myocardial Regeneration

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