Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance

Morris, Edward S.; MacDonald, Kelli P. A.; Rowe, Vanessa; Johnson, Diana; Banovic, Tatjana; Clouston, Andrew D.; Hill, Geoffrey R.

doi:10.1182/blood-2003-08-2864

Cited by 119 publications

(112 citation statements)

References 53 publications

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…27,28 There are also data suggesting that GCSF-induced protection against acute GVHD may be mediated through NK cells 29 and recently it has been shown that CD4 þ T cells exposed to GCSF may acquire the properties of regulatory cells that can prevent GVHD. 30,31 The increased rates of chronic GVHD observed in our PBSC compared to BM recipients following identical nonmyeloablative conditioning are in keeping with several reports of a high incidence of chronic GVHD after myeloablative PBSCT. 3,5,23,32,33 Possible explanations for the increased incidence of chronic GVHD following PBSCT include the larger numbers of CD34 þ cells and T cells in the infused inoculum [34][35][36][37][38] and the skewed cytokine profile, namely polarization of donor T cells toward a Th2 phenotype.…”

Section: Discussionsupporting

confidence: 71%

Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen

Dey

Shaffer

Yee

et al. 2007

Bone Marrow Transplant

View full text Add to dashboard Cite

This is the first study to examine the outcomes in 54 patients with hematologic malignancies who received an HLA-matched related donor bone marrow (BM, n ¼ 42) or GCSF-mobilized peripheral blood stem cells (PBSC, n ¼ 12) following identical nonmyeloablative conditioning with the intention of induction of mixed chimerism (MC) followed by prophylactic donor leukocyte infusion (pDLI) to convert MC to full donor chimerism (FDC) and capture a graft-versus-tumor effect without clinical graft-versushost disease (GVHD). Neutrophil and platelet recovery were faster and transfusion requirement was less in PBSC recipients (Po0.05). A total of 48% of BMT recipients achieved FDC with a median conversion time of 84 days, including 13 following pDLI. In contrast, 83% (P ¼ 0.04) in the PBSC group had spontaneous FDC at a median of 14 days, precluding the administration of pDLI. There was no significant difference in the incidences of acute or chronic GVHD, though the rates of chronic GVHD were considerably higher in PBSC group than in the BM group (6/7, 86% vs 10/24, 42%). CD4 and CD8 T-cell recovery was faster in PBSC recipients. In PBSC recipients, a higher number of CD34 þ cells was associated with increased rates of severe, grade III-IV acute GVHD.

show abstract

Section: Discussionsupporting

confidence: 71%

Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen

Dey

Shaffer

Yee

et al. 2007

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…Further evidence in favor of a role for G-CSF in the promotion of Treg cell differentiation stems from studies in mice demonstrating that treatment with pegylated G-CSF augments the generation of IL-10-producing Treg cells and promotes transplantation tolerance (36). Pegylated G-CSF-mediated protection from graft-vs-host disease (GVHD) was crucially dependent on IL-10 production by T cells.…”

Section: Induction Of Treg Cells By G-csfmentioning

confidence: 99%

Granulocyte Colony-Stimulating Factor: A Novel Mediator of T Cell Tolerance

Rutella

Zavala

Danese

et al. 2005

The Journal of Immunology

201

154

View full text Add to dashboard Cite

In recent years, several investigators have unraveled a previously unrecognized role for G-CSF in the regulation of T cell and dendritic cell functions. The experimental evidence in favor of G-CSF-mediated immune regulation includes the ability to switch T cell cytokine secretion profile to Th2 responses and the promotion of regulatory T cell and tolerogenic dendritic cell differentiation. Interestingly, G-CSF is beneficial in animals for the prevention and/or treatment of immune-mediated diseases, e.g., graft-vs-host disease, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and diabetes, suggesting a potential role in human autoimmune diseases. This review summarizes the growing body of evidence that supports a critical role for G-CSF as a novel mediator of T cell tolerance.

show abstract

“…19 Animals with severe clinical GVHD (scores Ն 6) were killed according to ethical guidelines, and the day of death was deemed to be the following day, as previously described. 12,16,17,20 Statistics Survival curves were plotted using Kaplan-Meier estimates and compared by log-rank analysis. The Mann Whitney U test was used for the statistical analysis of cytokine data and clinical scores.…”

mentioning

confidence: 99%

Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD

MacDonald

Kuns

Rowe

et al. 2007

Blood

Self Cite

View full text Add to dashboard Cite

IntroductionAllogeneic bone marrow transplantation (BMT) is the definitive curative therapy for the majority of hematologic malignancies and severe immunodeficiencies. The major complication of allogeneic BMT remains graft-versus-host disease (GVHD) in which the skin, gastrointestinal tract, and liver are preferentially damaged by the transplanted donor immune system. The therapeutic potential of BMT relates to the graft-versus-leukemia (GVL) effect, which eradicates host malignancy after BMT and is mediated by donor T and natural killer cells. 1 GVHD occurs in the majority (50%-70%) of recipients and is largely responsible for the high rate of mortality associated with allogeneic BMT. There is thus a pressing need for new treatment approaches to both prevent and treat GVHD, ideally without inhibiting GVL.The complex interactions resulting in the generation of T-cellmediated alloimmune responses depend on antigen presentation, cognate interactions between donor T cells and antigen-presenting cells (APCs), and the concomitant production of soluble and membrane-bound costimulatory molecules by APCs and T cells (reviewed in Morris et al 2 ). The initiation of GVHD absolutely depends on the presence of mature donor T cells in the graft. 2 Thus, although TLR signaling undoubtedly contributes to the activation of APCs early after transplantation, 3 it is likely that donor T cells provide the most critical signal. In this regard, the CD40-CD40L pathway appears to be of major importance, as demonstrated by the induction of tolerance following disruption of this receptor-ligand interaction. 4 The subsequent molecular mechanisms controlling APC function in tolerance and immunity are poorly defined. The NF-kB/Rel family of proteins include 5 subunits: c-Rel, RelA, RelB, NF-kB1, and NF-kB2, which form homodimers or heterodimers. At steady state, most of these proteins are inactive within the cytoplasm, bound by inhibitory IkB proteins. Activation by the classical pathway within a broad range of cells (including APCs and T cells) occurs as a result of a variety of membrane signals, including TNF, IL-1, and Toll receptors, that allow nuclear import of c-Rel and RelA heterodimers with subsequent transcriptional activation of inflammatory proteins. Activation by the alternative pathway within APCs is the result of lymphocyte interactions and signaling through the lymphotoxin-␤ receptor, BAFF receptor or CD40, resulting in nuclear import of p52/RelB heterodimers and transcriptional activation of characterized and uncharacterized proteins that result in maturation and antigenpresenting activity within professional APCs. [5][6][7] Because APCs are known to be critical for the initiation and maintenance of GVHD 8,9 and their activation occurs rapidly after transplantation, 10 we hypothesized that maintaining host APCs in a state of RelB inactivity during conditioning would promote the induction of peripheral tolerance after allogeneic stem cell transplantation (SCT). We found that the lack of RelB within either host or donor APCs l...

show abstract

Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance

Cited by 119 publications

References 53 publications

Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen

Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen

Granulocyte Colony-Stimulating Factor: A Novel Mediator of T Cell Tolerance

Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD

Contact Info

Product

Resources

About