Publications by authors named "Moutuaata Moutuou"

7 Publications

  • Page 1 of 1

Modulating endothelial cells with EGFL7 to diminish aGVHD after allogeneic bone marrow transplantation in mice.

Blood Adv 2021 Oct 15. Epub 2021 Oct 15.

Hopital Maisonneuve-Rosemont, Canada.

Acute graft versus host (aGVHD) is the second cause of death after allogeneic-hematopoietic stem cell transplant (allo-HSCT) underscoring the need for novel therapies. Based on previous work that endothelial cell dysfunction is present in aGVHD and that epidermal growth factor-like domain 7 (EGFL7) plays a significant role in decreasing inflammation by repressing endothelial cell activation and T cell migration, we hypothesized that increasing EGFL7 levels after allo-HSCT will diminish the severity of aGVHD. Here, we show that treatment with recombinant EGFL7 (rEGFL7) in two different murine models of aGVHD decreases aGVHD severity and improves survival in recipient mice after allogeneic transplantation with respect to controls without affecting graft versus leukemia effect. Furthermore, we showed that rEGFL7 treatment results in higher thymocytes, T, B and dendritic cells in recipient mice after allo-HSCT. This study constitutes a proof of concept of the ability of rEGFL7 therapy to reduce GHVD severity and mortality after allo-HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2021005498DOI Listing
October 2021

Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on Antiproliferative and PP2A-Activating Functions.

Blood Cancer Discov 2020 Jul;1(1):48-67

Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom.

Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating long noncoding RNA that uncouples and limits function to cytostasis. Genetic and pharmacologic modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis and in patient-derived xenografts; hence, the importance of and PP2A activity for CML development and therapy.
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http://dx.doi.org/10.1158/0008-5472.BCD-19-0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510943PMC
July 2020

Studying Peripheral T Cell Homeostasis in Mice: A Concise Technical Review.

Methods Mol Biol 2020 ;2111:267-283

Division Immunologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.

For several years, it was believed that the thymus was entirely responsible for maintaining T cell homeostasis. Today, it is well-known that homeostatic peripheral mechanisms are essential in order to maintain T cell numbers and diversity constant in the periphery. Naïve and memory T cells require continual access to self-peptide MHC class I and II molecules and/or cytokines to survive in the periphery. Under normal conditions, homeostatic resources are low, and lymphocytes undergo very slow proliferation and survive. Following T cell depletion, the bioavailability of homeostatic resources is significantly increased, and T cell proliferation is dramatically augmented. The development of lymphopenic mouse models has helped our current understanding of factors involved in the regulation of peripheral T cell homeostasis. In this minireview, we will give a brief overview about basic techniques used to study peripheral T cell homeostasis in mice.
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http://dx.doi.org/10.1007/978-1-0716-0266-9_21DOI Listing
January 2021

IL-7 Is the Limiting Homeostatic Factor that Constrains Homeostatic Proliferation of CD8 T Cells after Allogeneic Stem Cell Transplantation and Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2019 04 19;25(4):648-655. Epub 2018 Dec 19.

Départment de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada; Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada. Electronic address:

Immune reconstitution after allogeneic hematopoietic stem cell transplantation relies primarily on homeostatic proliferation (HP) of mature T lymphocytes, but this process is typically impaired during graft-versus-host disease (GVHD). We previously showed that low IL-7 levels combined with lack of dendritic cell (DC) regeneration constrain CD4 T cell HP during GVHD. However, it is not clear whether these alterations to the peripheral CD4 T cell niche also contribute to impair CD8 T cell regeneration during GVHD. We found that IL-7 therapy was sufficient for restoring CD8 T cell HP in GVHD hosts while forcing DC regeneration with Flt3-L had only a modest effect on CD8 T cell HP in IL-7 treated mice. Using bone marrow chimeras, we showed that HP of naïve CD8 T cells is primarily regulated by MHC class I on radio-resistant stromal cells, yet optimal recovery of CD8 T cell counts still requires expression of MHC class I on both radio-resistant and radio-sensitive hematopoietic cells. Thus, IL-7 level is the primary limiting factor that constrains naïve CD8 T cell HP during GVHD, and accessibility of MHC class I on stromal cells explains how IL-7 therapy, as a single agent, can induce robust CD8 T cell HP in the absence of DCs.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.066DOI Listing
April 2019

Double-Negative T Cell Levels Correlate with Chronic Graft-versus-Host Disease Severity.

Biol Blood Marrow Transplant 2019 01 19;25(1):19-25. Epub 2018 Sep 19.

Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada; Department of Microbiology, Infection, and Immunology, University of Montreal, Montreal, Quebec, Canada. Electronic address:

Chronic graft-versus-host disease (cGVHD) is a major complication, affecting 50% to 80% of long-term survivors of allogeneic hematopoietic stem cell transplantation. Current cGVHD therapies are neither specific nor curative, and patients are typically maintained for several months to years under immunosuppressive regimens that are associated with important side effects and increased susceptibility to life-threatening infections. As a result, continued investigation into the pathology of the disease and the search for novel diagnostic and therapeutic strategies to treat cGVHD remains a high priority. We report that the cellular dynamics of various immune cell subsets are related to cGVHD onset and severity in a cohort of allogeneic hematopoietic stem cell transplantation recipients. We document a decrease in the proportion of CD45RO CD4CD8 (double-negative [DN]) T cells at the onset of cGVHD, a time at which serum levels of B cell activating factor and B cells are increased. We also find that DN T cell levels are correlated with cGVHD severity. Our present findings are in line with the view that activated DN T cells exhibit their immunoregulatory potential by eliminating B cells in vivo. Taken together, these findings suggest that maintaining elevated DN T cell numbers before the onset of cGVHD may prevent pathological B cell responses.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.008DOI Listing
January 2019

Restoring T Cell Homeostasis After Allogeneic Stem Cell Transplantation; Principal Limitations and Future Challenges.

Front Immunol 2018 18;9:1237. Epub 2018 Jun 18.

Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.

For several leukemia patients, allogeneic stem cell transplantation (allogeneic-SCT) is the unique therapeutic modality that could potentially cure their disease. Despite significant progress made in clinical management of allogeneic-SCT, acute graft-versus-host disease (aGVHD) and infectious complications remain the second and third cause of death after disease recurrence. Clinical options to restore immunocompetence after allogeneic-SCT are very limited as studies have raised awareness about the safety with regards to graft-versus-host disease (GVHD). Preclinical works are now focusing on strategies to improve thymic functions and to restore the peripheral niche that have been damaged by alloreactive T cells. In this mini review, we will provide a brief overview about the adverse effects of GVHD on the thymus and the peripheral niche and the resulting negative outcome on peripheral T cell homeostasis. Finally, we will discuss the potential relevance of coordinating our studies on thymic rejuvenation and improvement of the peripheral lymphoid niche to achieve optimal T cell regeneration in GVHD patients.
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http://dx.doi.org/10.3389/fimmu.2018.01237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015883PMC
August 2019

Homeostatic cytokines in immune reconstitution and graft-versus-host disease.

Cytokine 2016 06 1;82:24-32. Epub 2016 Feb 1.

Maisonneuve-Rosemont Research Center, Montreal, Quebec, Canada; Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, Quebec, Canada. Electronic address:

For numerous patients, allogeneic stem cell transplantation (SCT) is the only therapeutic option that could potentially cure their disease. Despite significant progress made in clinical management of allogeneic SCT, acute graft-versus-host disease (aGVHD) remains the second cause of death after disease recurrence. aGVHD is highly immunosuppressive and the adverse effect of allogeneic SCT on T cell regeneration is typically more important than the levels of immunosuppression normally seen after autologous SCT. In these patients, immune reconstitution often takes several years to occur and restoring immunocompetence after allogeneic SCT represents an important challenge, principally because clinical options are limited and current methods used to accelerate immune reconstitution are associated with increased GVHD. Interleukin-7 and IL-15 are both under clinical investigation and demonstrate the greatest potential on peripheral T cells regeneration in mice and humans. However, awareness has been raised about the use of IL-7 and IL-15 after allogeneic SCT with regards to potential adverse effects on aGVHD. In this review, we will discuss about recent progress made in lymphocyte regeneration, the critical role played by IL-7 and IL-15 in T cell homeostasis and how these cytokines could be used to improve immune reconstitution after allogeneic SCT.
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http://dx.doi.org/10.1016/j.cyto.2016.01.003DOI Listing
June 2016
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