Cotransplantation of Marrow Stromal Cells May Prevent Lethal Graft-versus-Host Disease in Major Histocompatibility Complex Mismatched Murine Hematopoietic Stem Cell Transplantation
Received: 01 July 2004 Revised: 06 August 2004 Accepted: 10 August 2004 DOI:
Cite this article as: Chung, N.G., Jeong, D.C., Park, S.J. et al. Int J Hematol (2004) 80: 370. doi:10.1532/IJH97.A30409 Abstract
Marrow stromal cells (MSC) produce a microenvironment supporting hematopoiesis and may contribute immune tolerance because of low immunogenicity and the suppressive effect of alloreactivity. We investigated whether cotransplantation of MSC could prevent lethal graft-versus-host disease (GVHD) in major histocompatibility complex mismatched allogeneic murine hematopoietic stem cell transplantation (HSCT) using female BALB/c (H-2
d, recipient) and C3H/He (H-2 k, donor) mice. MSC were obtained from C3H/He bone marrow cells (BMC). MSC and irradiated BALB/c splenocytes (SP) were cocultured with C3H/He SP or BMC. Nonirradiated MSC did not inhibit the proliferation of alloantigen-stimulated BMC and SP. However, irradiated MSC suppressed the proliferation of alloantigen-stimulated SP at a level comparable with that of immunosuppressive agents, and the suppression by MSC was reversed to a significant degree by interleukin 2. Lethally irradiated BALB/c mice received transplants of donor cells according to the following experimental groups (group A, BMC only; group B, BMC and SP; group C, BMC, SP, and MSC; group D, BMC and MSC). The survival rate in group D was higher than in the other groups (P =.0057), and the clinical GVHD scores and serum levels of interferon-γ were low in group D. Our results suggest that cotransplantation of MSC in HSCT prevents lethal GVHD, possibly by immune modulation. Key words Marrow stromal cell Allogeneic hematopoietic stem cell transplantation Cell proliferation assay Interferon-γ References
Martin PJ, Hansen JA, Storb R,Thomas ED. Human marrow transplantation: an immunological perspective.
Beatty PG, Hansen JA, Longton GM, et al. Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies.
Ikehara S. A new concept of stem cell disorders and their new therapy.
J Hematother Stem Cell Res.
Starzl TE, Murase N, Thomson AW, Trucco M, Rao A. Immunity and tolerance are related, and governed by antigen migration and localization.
Nikolic B, Sykes M. Bone marrow chimerism and transplantation tolerance.
Curr Opin Immunol.
Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues.
Almeida-Porada G, Flake AW, Glimp HA, Zanjani ED. Cotrans- plantation of stroma results in enhancement of engraftment and early expression of donor hematopoietic stem cells in utero.
Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow- derived mesenchymal stem cell (MSCs) and stromal cells.
J Cell Physiol.
Noveli EM, Buyaner D, Chopra RK, et al. Human mesenchymal stem cells can enhance human CD34+ cell repopulating of NOD/ SCID mice [abstract].
Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.
Horwitz EM, Gordon PL, Koo WK, et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone.
Proc Natl Acad Sci USA
Pereira RF, Halford KW, O’Hara MD, et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice.
Proc Natl Acad Sci USA
Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli.
Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.
Jeong DC, Han CW, Jin JY, et al. Effectiveness of rotor off fraction in allogeneic murine bone marrow transplantation with complete disparity of major histocompatibility.
Cooke KR, Kobzik L, Martin TR, et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation, I: the roles of minor H antigens and endotoxin.
. 1996; 88:3230–3239.
Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide.
Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.
Le Blanc K,Tammik L, Sundberg B, Haynesworth SE, Ringdén O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex.
Scand J Immunol.
Fan TX, Hisha H, Jin TN, et al. Successful allogeneic bone marrow transplantation (BMT) by injection of bone marrow cells via portal vein: stromal cells as BMT-facilitating cells.
Gurevitch O, Prigozhina TB, Pugatsch T, Slavin S. Transplantation of allogeneic or xenogeneic bone marrow within the donor stromal microenvironment.
Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxy- genase-mediated tryptophan degradation.
Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and management.
Lazarus H, Curtin P, Devine S, et al. Role of mesenchymal stem cells (MSC) in allogeneic transplantation: early phase I clinical results [abstract].
Frassoni F, Labopin M, Bacigalupo A, et al. Expanded mesenchymal stem cells (MSC), co-infused with HLA identical hemopoietic stem cell transplants, reduce acute and chronic graft-versus-host disease: a matched pair analysis [abstract].
Bone Marrow Transplant. 2002;29:S2.
Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.
Imamura M, Hashino S, Kobayashi H, et al. Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease.
Bone Marrow Transplant
Ferrara JL, Cooke KR, Pan L, Krenger W. The immunopathophysiology of acute graft-versus-host-disease.
van der Meer A, Wissink WM, Schattenberg AV, Joosten I. Interferon-γ- based mixed lymphocyte culture as a selection tool for allogeneic bone marrow donors other than identical siblings.
Br J Haematol.
Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals.
PubMed CrossRef Copyright information
© The Japanese Society of Hematology 2004