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Novel regulatory therapies for prevention of Graft-versus-host disease.

Leventhal J, Huang Y, Xu H, Goode I, Ildstad ST - BMC Med (2012)

Bottom Line: Unfortunately, elimination of donor-derived T cells impairs stem cell engraftment, and delays immunologic reconstitution, rendering the recipient susceptible to post-transplant infections and disease relapse, with potentially lethal consequences.In addition, advances in the design of cytoreductive conditioning regimens to selectively target graft-versus-host disease-inducing donor-derived T cells that have improved the safety of allogeneic stem cell transplantation are reviewed.Finally, we discuss advances in our understanding of the tolerogenic facilitating cell population, a phenotypically and functionally distinct population of bone marrow-derived cells which promote hematopoietic stem cell engraftment while reducing the risk of graft-versus-host disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, USA.

ABSTRACT
Graft-versus-host disease is one of the major transplant-related complications in allogeneic hematopoietic stem cell transplantation. Continued efforts have been made to prevent the occurrence of severe graft-versus-host disease by eliminating or suppressing donor-derived effector T cells. Conventional immunosuppression does not adequately prevent graft-versus-host disease, especially in mismatched transplants. Unfortunately, elimination of donor-derived T cells impairs stem cell engraftment, and delays immunologic reconstitution, rendering the recipient susceptible to post-transplant infections and disease relapse, with potentially lethal consequences. In this review, we discuss the role of dynamic immune regulation in controlling graft-versus-host disease, and how cell-based therapies are being developed using regulatory T cells and other tolerogenic cells for the prevention and treatment of graft-versus-host disease. In addition, advances in the design of cytoreductive conditioning regimens to selectively target graft-versus-host disease-inducing donor-derived T cells that have improved the safety of allogeneic stem cell transplantation are reviewed. Finally, we discuss advances in our understanding of the tolerogenic facilitating cell population, a phenotypically and functionally distinct population of bone marrow-derived cells which promote hematopoietic stem cell engraftment while reducing the risk of graft-versus-host disease.

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CD8+/TCR- facilitating cells. Flow cytometric analysis of bone marrow FC stained with CD8α phycoerythrin, αβ-TCR fluorescein isothiocyanate, and γδ-TCR fluorescein isothiocyanate mAb. (A) FC comprised approximately 0.4% (range, 0.04% to 0.62%) of the total bone marrow and less than 1.6% of cells in the lymphoid gate. (B) The majority of cells in the FC are CD11c+/B220+/CD11b- p-preDC. FC: facilitating cells; p-preDC: plasmacytoid precursor dendritic cells; TCR: T cell receptor.
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Figure 1: CD8+/TCR- facilitating cells. Flow cytometric analysis of bone marrow FC stained with CD8α phycoerythrin, αβ-TCR fluorescein isothiocyanate, and γδ-TCR fluorescein isothiocyanate mAb. (A) FC comprised approximately 0.4% (range, 0.04% to 0.62%) of the total bone marrow and less than 1.6% of cells in the lymphoid gate. (B) The majority of cells in the FC are CD11c+/B220+/CD11b- p-preDC. FC: facilitating cells; p-preDC: plasmacytoid precursor dendritic cells; TCR: T cell receptor.

Mentions: In light of the fact that FC function is distinct from that demonstrated by bone-marrow-derived mature T cells, much research has gone into identifying the resident cell subpopulations that constitute this rare facilitating population. Previous studies have shown that the CD8+/TCR- FC population shares phenotypic characteristics with CD8α plasmacytoid precursor dendritic cells (p-preDC) and that total FC are heterogeneous in morphology [45]. A comprehensive assessment of FC surface markers using flow cytometric analysis of sorted FC populations by Fugier-Vivier et al. [46] revealed a broad heterogeneity in subpopulations with facilitating potential. The majority of CD8+/TCR- FC were positive for CD11c+ (65% to 70%) and B220+ (75% to 88%) expression. While only 15% of the B220+ population was composed of B cells, 55% co-expressed CD11c (CD11c+/B220+), suggestive of a dendritic cell component. Further analysis into this CD11c+ dendritic subset revealed that a p-preDC phenotype (CD11dim/B220+/CD11b-) is the predominant cell type (93% to 95%) within this CD11c+ subset (Figure 1). The functionality of this p-preDC-like subset of FC has been assessed by transplanting these cells with HSC into ablated murine allogeneic recipients. The co-transplantation of p-preDC rescues allogeneic recipients from radiation aplasia, significantly enhancing alloengraftment and survival compared with ablated recipients that received HSC alone. However, facilitation by this p-preDC component alone was inferior to that observed when the entire FC population was utilized. This observation suggests that the p-pre DC subset is necessary, but not sufficient, for HSC facilitation and cannot fully replace the total FC population. Other elegant studies by Taylor et al. indicate that CD3e expression by FC and the association of CD3e with TCRβ chain and a novel 33 kDa protein termed FCp33 is critical for the HSC engraftment enhancing properties of FC [47].


Novel regulatory therapies for prevention of Graft-versus-host disease.

Leventhal J, Huang Y, Xu H, Goode I, Ildstad ST - BMC Med (2012)

CD8+/TCR- facilitating cells. Flow cytometric analysis of bone marrow FC stained with CD8α phycoerythrin, αβ-TCR fluorescein isothiocyanate, and γδ-TCR fluorescein isothiocyanate mAb. (A) FC comprised approximately 0.4% (range, 0.04% to 0.62%) of the total bone marrow and less than 1.6% of cells in the lymphoid gate. (B) The majority of cells in the FC are CD11c+/B220+/CD11b- p-preDC. FC: facilitating cells; p-preDC: plasmacytoid precursor dendritic cells; TCR: T cell receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3361491&req=5

Figure 1: CD8+/TCR- facilitating cells. Flow cytometric analysis of bone marrow FC stained with CD8α phycoerythrin, αβ-TCR fluorescein isothiocyanate, and γδ-TCR fluorescein isothiocyanate mAb. (A) FC comprised approximately 0.4% (range, 0.04% to 0.62%) of the total bone marrow and less than 1.6% of cells in the lymphoid gate. (B) The majority of cells in the FC are CD11c+/B220+/CD11b- p-preDC. FC: facilitating cells; p-preDC: plasmacytoid precursor dendritic cells; TCR: T cell receptor.
Mentions: In light of the fact that FC function is distinct from that demonstrated by bone-marrow-derived mature T cells, much research has gone into identifying the resident cell subpopulations that constitute this rare facilitating population. Previous studies have shown that the CD8+/TCR- FC population shares phenotypic characteristics with CD8α plasmacytoid precursor dendritic cells (p-preDC) and that total FC are heterogeneous in morphology [45]. A comprehensive assessment of FC surface markers using flow cytometric analysis of sorted FC populations by Fugier-Vivier et al. [46] revealed a broad heterogeneity in subpopulations with facilitating potential. The majority of CD8+/TCR- FC were positive for CD11c+ (65% to 70%) and B220+ (75% to 88%) expression. While only 15% of the B220+ population was composed of B cells, 55% co-expressed CD11c (CD11c+/B220+), suggestive of a dendritic cell component. Further analysis into this CD11c+ dendritic subset revealed that a p-preDC phenotype (CD11dim/B220+/CD11b-) is the predominant cell type (93% to 95%) within this CD11c+ subset (Figure 1). The functionality of this p-preDC-like subset of FC has been assessed by transplanting these cells with HSC into ablated murine allogeneic recipients. The co-transplantation of p-preDC rescues allogeneic recipients from radiation aplasia, significantly enhancing alloengraftment and survival compared with ablated recipients that received HSC alone. However, facilitation by this p-preDC component alone was inferior to that observed when the entire FC population was utilized. This observation suggests that the p-pre DC subset is necessary, but not sufficient, for HSC facilitation and cannot fully replace the total FC population. Other elegant studies by Taylor et al. indicate that CD3e expression by FC and the association of CD3e with TCRβ chain and a novel 33 kDa protein termed FCp33 is critical for the HSC engraftment enhancing properties of FC [47].

Bottom Line: Unfortunately, elimination of donor-derived T cells impairs stem cell engraftment, and delays immunologic reconstitution, rendering the recipient susceptible to post-transplant infections and disease relapse, with potentially lethal consequences.In addition, advances in the design of cytoreductive conditioning regimens to selectively target graft-versus-host disease-inducing donor-derived T cells that have improved the safety of allogeneic stem cell transplantation are reviewed.Finally, we discuss advances in our understanding of the tolerogenic facilitating cell population, a phenotypically and functionally distinct population of bone marrow-derived cells which promote hematopoietic stem cell engraftment while reducing the risk of graft-versus-host disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, USA.

ABSTRACT
Graft-versus-host disease is one of the major transplant-related complications in allogeneic hematopoietic stem cell transplantation. Continued efforts have been made to prevent the occurrence of severe graft-versus-host disease by eliminating or suppressing donor-derived effector T cells. Conventional immunosuppression does not adequately prevent graft-versus-host disease, especially in mismatched transplants. Unfortunately, elimination of donor-derived T cells impairs stem cell engraftment, and delays immunologic reconstitution, rendering the recipient susceptible to post-transplant infections and disease relapse, with potentially lethal consequences. In this review, we discuss the role of dynamic immune regulation in controlling graft-versus-host disease, and how cell-based therapies are being developed using regulatory T cells and other tolerogenic cells for the prevention and treatment of graft-versus-host disease. In addition, advances in the design of cytoreductive conditioning regimens to selectively target graft-versus-host disease-inducing donor-derived T cells that have improved the safety of allogeneic stem cell transplantation are reviewed. Finally, we discuss advances in our understanding of the tolerogenic facilitating cell population, a phenotypically and functionally distinct population of bone marrow-derived cells which promote hematopoietic stem cell engraftment while reducing the risk of graft-versus-host disease.

Show MeSH
Related in: MedlinePlus