Timing of neutrophil tissue repopulation predicts restoration of innate immune protection in a murine bone marrow transplantation model

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2821-2826 ◽  
Author(s):  
Chrisovalantou Cheretakis ◽  
Roland Leung ◽  
Chun Xiang Sun ◽  
Yigal Dror ◽  
Michael Glogauer
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Fluorescent Protein ◽  
Innate Immune ◽  
Bacterial Killing ◽  
Murine Bone Marrow ◽  
Susceptibility To Infection ◽  
Oral Rinse

Abstract It has been suggested that neutrophil tissue repopulation following bone marrow transplantation (BMT) serves as an earlier and more relevant marker of susceptibility to infection than circulating neutrophil counts. In a previous study using an oral rinse protocol, we found that oral neutrophil recovery always preceded blood neutrophil engraftment and that the day of oral neutrophil detection served as a predictor of patient susceptibility to infection after BMT. Consequently, we have developed and validated a mouse BMT model which uses bone marrow transplants containing enhanced green fluorescent protein-expressing neutrophils to follow neutrophil tissue repopulation after BMT. Using this in vivo cell migration model, we assessed the significance of neutrophil tissue recruitment kinetics with neutrophil functionality and in vivo bacterial killing after BMT. Using the animal model, we have demonstrated that protection against bacterial infection is conferred at the time of neutrophil tissue delivery, which always occurs before neutrophils are detected in the blood. We therefore conclude that neutrophil tissue recovery is an early measure of the restoration of cellular innate immune function after BMT. This model will help us better understand the factors regulating neutrophil recruitment to the tissues.

FLT3-ITD Cooperates with MOZ-TIF2 in Leukemogenesis in a Murine Bone Marrow Transplantation Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1427-1427
Author(s):  
Winnie F. Tam ◽  
Jennifer Rocnik ◽  
Sarah Wojiski ◽  
Kenji Deguchi ◽  
Rachel Okabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Transformation Model ◽  
Hematopoietic Progenitors ◽  
Murine Bone Marrow ◽  
Transplantation Assay ◽  
Transplantation Model

Abstract MOZ-TIF2 is expressed as a consequence of the chromosomal inversion inv(8)(p11q13) and is associated with AML FAB subtypes M4 and M5. Mice transplanted with MOZ-TIF2 succumb to monoclonal or oligoclonal leukemias with a long median disease latency, indicating that cooperating mutations are required for MOZ-TIF2 mediated leukemogenesis. The presence of a FLT3-ITD mutation in a patient with inv(8)(p11q13) has previously been reported, suggesting FLT3-ITD as a candidate cooperating mutation. Here we report that FLT3-ITD functionally cooperates with MOZ-TIF2 in co-transduction experiments in both a serial replating and murine bone marrow transplantation assay to induce AML that is transplantable to secondary recipients. At limit dilution, both MOZ-TIF2 and FLT3-ITD retroviruses are present, demonstrating cooperative effect. Moreover, tyrosine to phenylalanine mutations of FLT3-ITD residues 589 and 591, which we have previously reported to abrogate Stat5 signaling, also abolish the ability of FLT3-ITD to cooperate with MOZ-TIF2 both in vivo and in vitro. Furthermore, a constitutively active Stat5 mutant supports factor independent serial replating activity of MOZ-TIF2 in vitro. These data suggest a multi-step transformation model in which constitutive downstream Stat5 signaling by FLT3-ITD cooperates with MOZ-TIF2 in AML induction, and indicate that FLT3-ITD potentiates the properties of self-renewal in hematopoietic progenitors through activation of STAT5.

scholarly journals Persistence of myeloid progenitor cells expressing BCR-ABL mRNA after allogeneic bone marrow transplantation for chronic myelogenous leukemia

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2109-2114
Author(s):  
G Pichert ◽  
EP Alyea ◽  
RJ Soiffer ◽  
DC Roy ◽  
J Ritz
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Progenitor Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Myeloid Differentiation ◽  
Allogeneic Bone

Previous studies have shown that tumor-specific bcr-abl mRNA can often be detected by polymerase chain reaction. (PCR) for months to years after allogeneic bone marrow transplantation (BMT) for chronic myelocytic leukemia (CML). Nevertheless, the presence of bcr-abl mRNA by itself does not invariably predict for clinical relapse post-BMT. This has led to the hypothesis that bcr-abl mRNA might be expressed in cells that have lost either proliferative or myeloid differentiation potential. To directly characterize the cells detected by PCR in patients with CML after allogeneic BMT, we first identified five individuals in whom PCR-positive cells could be detected at multiple times post-BMT. Bone marrow samples from these individuals were cultured in vitro and single erythroid, granulocytic, and macrophage colonies, each containing 50 to 100 cells, were examined for the presence of bcr-abl mRNA by PCR. PCR-positive myeloid colonies could be detected in four of five individuals in marrow samples obtained 5 to 56 months post-BMT. Overall, 7 of 135 progenitor cell colonies (5.2%) were found to be PCR-positive. The expression of bcr-abl mRNA appeared to be equally distributed among committed erythroid, macrophage, and granulocyte progenitors. These patients have now been followed-up for an additional 20 to 33 months from the time of progenitor cell PCR analysis but only one of these individuals has been found to have cytogenetic evidence of recurrent Ph+ cells. These results show that long-term persistence of PCR-detectable bcr-abl mRNA after allogeneic BMT can be caused by the persistence of CML-derived clonogenic myeloid precursors that have survived the BMT preparative regimen. These cells continue to have both proliferative and myeloid differentiation capacity in vitro. Nevertheless, these PCR-positive cells do not appear to either expand or differentiate in vivo for prolonged periods, suggesting the presence of mechanisms for suppression of residual clonogenic leukemia cells in vivo.

scholarly journals Chediak-Higashi syndrome: reversal of increased susceptibility to infection by bone marrow transplantation

Blood ◽  
1976 ◽  
Vol 47 (4) ◽  
pp. 555-559
Author(s):  
JA Kazmierowski ◽  
RJ Elin ◽  
HY Reynolds ◽  
WA Durbin ◽  
SM Wolff
Keyword(s):  
Bone Marrow ◽  
Candida Albicans ◽  
Bone Marrow Transplantation ◽  
Human Disease ◽  
Marrow Transplantation ◽  
Normal Bone Marrow ◽  
Susceptibility To Infection ◽  
Normal Bone ◽  
Chediak Higashi Syndrome ◽  
Increased Susceptibility

Transplantation of normal bone marrow to mice with the Chediak-Higashi syndrome (CHS) resulted in normal granulopoiesis and a reversal of their increased susceptibility to challenge with intravenous Candida albicans. These findings suggest that (1) the leukocyte defect in CHS can be reversed by marrow transplantation and (2) the mechanism for increased susceptibility to infection in these animals is due to a bone- marrow-derived cellular defect. Because of similarities between murine and human CHS, bone marrow transplantation might be considered as a mode of therapy in selected cases of the human disease.

scholarly journals Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5898-5908 ◽  
Author(s):  
Renee J. Robb ◽  
Katie E. Lineburg ◽  
Rachel D. Kuns ◽  
Yana A. Wilson ◽  
Neil C. Raffelt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Regulatory T Cells ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Class I ◽  
Allogeneic Bone ◽  
Mesenteric Lymph Nodes

Abstract FoxP3+ confers suppressive properties and is confined to regulatory T cells (Treg) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4+ Treg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8+ population of FoxP3+ Treg that convert from CD8+ conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8+ Treg undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4+FoxP3+ population and is more potent in exerting class I–restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8+FoxP3+ Treg are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8+FoxP3+ Treg thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I–restricted T-cell responses after bone marrow transplantation.

scholarly journals Gamma-interferon and tumor necrosis factor production after bone marrow transplantation is augmented by exposure to marrow fibroblasts infected with cytomegalovirus

Blood ◽  
1990 ◽  
Vol 76 (5) ◽  
pp. 1046-1053 ◽  
Author(s):  
AS Duncombe ◽  
A Meager ◽  
HG Prentice ◽  
JE Grundy ◽  
HE Heslop ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Tumor Necrosis Factor ◽  
Marrow Transplantation ◽  
Tumor Necrosis ◽  
Gamma Interferon ◽  
Cmv Infection ◽  
Necrosis Factor

Abstract After bone marrow transplantation (BMT), mortality from viral infections such as cytomegalovirus (CMV) remains high. Gamma-Interferon (gamma IFN) and tumor necrosis factor (TNF) are produced constitutively after BMT and have anti-viral properties. To study the effects of these cytokines on CMV interaction with host cells, we have used patient marrow fibroblasts since marrow stroma is a target for CMV infection correlating with myelosuppression in vivo. Both gamma IFN and TNF are constitutively produced by recipient CD3+ and CD16+ lymphocytes, but not by their marrow fibroblasts. Secretion by peripheral blood mononuclear cells is increased if they are cultured with host fibroblasts infected with CMV in vitro and the levels of gamma IFN and TNF produced are within the range that protects fresh fibroblasts from CMV infection. Constitutive secretion of cytokines by lymphocytes declines by 8 weeks after BMT, a time when the risk of CMV disease increases sharply. The in vitro phenomenon that we have described needs to be evaluated in correlative studies on individual BMT recipients to determine whether such a cytokine-mediated defense mechanism against CMV may operate in vivo.

scholarly journals Recovery of contact hypersensitivity responses following murine bone marrow transplantation: comparison of gamma-irradiation and busulfan as preparative marrow-ablative agents

Blood ◽  
1987 ◽  
Vol 70 (6) ◽  
pp. 1910-1920 ◽  
Author(s):  
WE Samlowski ◽  
CL Crump
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Gamma Irradiation ◽  
Immune Function ◽  
Marrow Transplantation ◽  
Contact Hypersensitivity ◽  
Whole Body ◽  
Tissue Specific ◽  
Murine Bone Marrow ◽  
Specific Localization

Abstract Bone marrow transplantation (BMT) is often followed by significant morbidity and mortality due to protracted immunodeficiency. We have hypothesized that the bone marrow-ablative regimen may delay the recovery of normal immune function following transplantation by impairing the interaction of host endothelial cells with circulating graft-derived lymphocytes. This report compares the relative effects of busulfan (an alkylating drug) and gamma-irradiation on the tissue- specific localization potential of lymphocytes and the eventual recovery of immune function within syngeneic murine transplant recipients. Localization of normal lymphocytes into peripheral lymph nodes of irradiated BMT recipients was markedly less (less than 50%) than in busulfan-treated or normal mice over the first 2 months post- BMT. This finding correlated with irradiation-induced endothelial cell edema and microvascular occlusions within lymphocyte-receptive areas of the nodal microvasculature. The effect of both preparative regimens on the recovery of contact hypersensitivity (CHS) was also analyzed. This response recovered more quickly (between 1 and 2 months) in busulfan- pretreated animals. Further experiments demonstrated that the decrease in CHS responsiveness appeared, in part, related to a depression in the capacity of lymphocytes to localize into skin sites of antigen deposition within irradiated mice. The impairment of tissue-specific lymphocyte localization may represent a novel mechanism by which whole body irradiation can contribute to delayed immunologic reconstitution following bone marrow transplantation.

scholarly journals Chediak-Higashi syndrome: reversal of increased susceptibility to infection by bone marrow transplantation

Blood ◽  
1976 ◽  
Vol 47 (4) ◽  
pp. 555-559 ◽  
Author(s):  
JA Kazmierowski ◽  
RJ Elin ◽  
HY Reynolds ◽  
WA Durbin ◽  
SM Wolff
Keyword(s):  
Bone Marrow ◽  
Candida Albicans ◽  
Bone Marrow Transplantation ◽  
Human Disease ◽  
Marrow Transplantation ◽  
Normal Bone Marrow ◽  
Susceptibility To Infection ◽  
Normal Bone ◽  
Chediak Higashi Syndrome ◽  
Increased Susceptibility

Abstract Transplantation of normal bone marrow to mice with the Chediak-Higashi syndrome (CHS) resulted in normal granulopoiesis and a reversal of their increased susceptibility to challenge with intravenous Candida albicans. These findings suggest that (1) the leukocyte defect in CHS can be reversed by marrow transplantation and (2) the mechanism for increased susceptibility to infection in these animals is due to a bone- marrow-derived cellular defect. Because of similarities between murine and human CHS, bone marrow transplantation might be considered as a mode of therapy in selected cases of the human disease.

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