Blood Res 2023; 58(2):
Published online June 30, 2023
https://doi.org/10.5045/br.2023.2022238
© The Korean Society of Hematology
Correspondence to : Jaebok Choi
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
E-mail: jchoi25@wustl.edu
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
TO THE EDITOR: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective and curative treatment for hematologic diseases. However, graft-versus-host disease (GvHD) is a major barrier to the success of allo-HSCT. Gastrointestinal (GI) tract is one of the frequently diagnosed GvHD target organs. Patients with GI-GvHD show poor prognosis and response rates to first-line corticosteroid treatment compared to those without GI-GvHD, indicating that GI-GvHD may be a major cause of non-relapse mortality [1]. Numerous studies demonstrated that GI-GvHD is associated with a significant change in the intestinal microbiota and antimicrobial functions of immune cells against pathogenic microorganisms after allo-HSCT [2-5]. In addition, a clinical study reported that patients undergoing donor fecal microbiota transplantation improved GvHD symptoms and survival rate at week 24 after transplantation by increasing intestinal microbial diversity, especially a microbial metabolite butyrate-producing
Our previous studies demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells reduced GvHD while preserving graft-versus-leukemia (GvL) effects [7-9]. In addition, we recently demonstrated for the first time that S100A9 is upregulated by IFNGR signaling blockade in both murine and human T cells and functions as a novel GvHD-suppressor effector molecule without compromising GvL effects of donor T cells [10]. We observed that mice transplanted with
We recently demonstrated that oral administration of murine recombinant S100A9 homodimers (mrS100A9) or S100A8/A9 heterodimers (mrS100A8/A9), both of which are functional forms of S100A9, suppresses GvHD in our mouse model of allo-HSCT [10]. Furthermore, S100A9 upregulation by in vivo administration of anti-human IFNGR antibodies significantly improves the overall survival of immune-deficient NOD/SCID/γcnull (NSG) mice transplanted with human peripheral blood mononuclear cells (PBMCs) [10]. In the current study, we examined if systemic administration of the recombinant proteins via intraperitoneal (i.p.) injection, which is a preferred route for therapeutic agents to avoid the GI tract, can also mitigate GvHD. Two independent allo-HSCT models were used; B6 to Balb/c murine GvHD model with mrS100A8/A9 proteins (Supplementary Fig. 2A) and human PBMCs to NSG mice with human recombinant S100A8/A9 proteins (hrS100A8/A9) (Supplementary Fig. 2B). We found that systemic administration (i.p.) of S100A8/A9 recombinant proteins failed to reduce GvHD in both GvHD models (Supplementary Fig. 2). These results further suggest that maximizing bioavailability or local effect of S100A9 in the GI tract is essential for GvHD reduction by modulating intestinal microbiota.
In this study, we report that mice transplanted with
JC is a Gabrielle's Angel Foundation for Cancer Research (GAFCR) Research Fellow and supported by Amy Strelzer Manasevit Research Program which is funded through Be The Match Foundation and the National Marrow Donor Program, Siteman Investment Program (supported by the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund, National Cancer Institute Cancer Center Support Grant, P30 CA091842, and Barnard Trust), St. Baldrick's Foundation, and Washington University SPORE in Leukemia (P50 CA171963).
No potential conflicts of interest relevant to this article were reported.
Blood Res 2023; 58(2): 105-111
Published online June 30, 2023 https://doi.org/10.5045/br.2023.2022238
Copyright © The Korean Society of Hematology.
Sena Kim, Sora Lim, Farnaz Razmkhah, Jaebok Choi
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Correspondence to:Jaebok Choi
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
E-mail: jchoi25@wustl.edu
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
TO THE EDITOR: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective and curative treatment for hematologic diseases. However, graft-versus-host disease (GvHD) is a major barrier to the success of allo-HSCT. Gastrointestinal (GI) tract is one of the frequently diagnosed GvHD target organs. Patients with GI-GvHD show poor prognosis and response rates to first-line corticosteroid treatment compared to those without GI-GvHD, indicating that GI-GvHD may be a major cause of non-relapse mortality [1]. Numerous studies demonstrated that GI-GvHD is associated with a significant change in the intestinal microbiota and antimicrobial functions of immune cells against pathogenic microorganisms after allo-HSCT [2-5]. In addition, a clinical study reported that patients undergoing donor fecal microbiota transplantation improved GvHD symptoms and survival rate at week 24 after transplantation by increasing intestinal microbial diversity, especially a microbial metabolite butyrate-producing
Our previous studies demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells reduced GvHD while preserving graft-versus-leukemia (GvL) effects [7-9]. In addition, we recently demonstrated for the first time that S100A9 is upregulated by IFNGR signaling blockade in both murine and human T cells and functions as a novel GvHD-suppressor effector molecule without compromising GvL effects of donor T cells [10]. We observed that mice transplanted with
We recently demonstrated that oral administration of murine recombinant S100A9 homodimers (mrS100A9) or S100A8/A9 heterodimers (mrS100A8/A9), both of which are functional forms of S100A9, suppresses GvHD in our mouse model of allo-HSCT [10]. Furthermore, S100A9 upregulation by in vivo administration of anti-human IFNGR antibodies significantly improves the overall survival of immune-deficient NOD/SCID/γcnull (NSG) mice transplanted with human peripheral blood mononuclear cells (PBMCs) [10]. In the current study, we examined if systemic administration of the recombinant proteins via intraperitoneal (i.p.) injection, which is a preferred route for therapeutic agents to avoid the GI tract, can also mitigate GvHD. Two independent allo-HSCT models were used; B6 to Balb/c murine GvHD model with mrS100A8/A9 proteins (Supplementary Fig. 2A) and human PBMCs to NSG mice with human recombinant S100A8/A9 proteins (hrS100A8/A9) (Supplementary Fig. 2B). We found that systemic administration (i.p.) of S100A8/A9 recombinant proteins failed to reduce GvHD in both GvHD models (Supplementary Fig. 2). These results further suggest that maximizing bioavailability or local effect of S100A9 in the GI tract is essential for GvHD reduction by modulating intestinal microbiota.
In this study, we report that mice transplanted with
JC is a Gabrielle's Angel Foundation for Cancer Research (GAFCR) Research Fellow and supported by Amy Strelzer Manasevit Research Program which is funded through Be The Match Foundation and the National Marrow Donor Program, Siteman Investment Program (supported by the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund, National Cancer Institute Cancer Center Support Grant, P30 CA091842, and Barnard Trust), St. Baldrick's Foundation, and Washington University SPORE in Leukemia (P50 CA171963).
No potential conflicts of interest relevant to this article were reported.