Graft-versus-host disease (GvHD) remains a major complication after allogeneic hematopoietic cell transplantation (HCT). Recent literature demonstrates a potential benefit of human mesenchymal stromal cells (MSC) for the treatment of refractory GvHD; however, the optimal dose remains uncertain. We set out to develop an animal model that can be used to study the effect of MSC on GvHD.
A GvHD mouse model was established by transplanting C3H/he donor bone marrow (BM) cells and spleen cells into lethally irradiated BALB/c recipient mice. MSC were obtained from C3H/he mice and the C3H/10T1/2 murine MSC line.
The mRNA expression of Foxp3 in regional lymph nodes (LN) localized with T cells was markedly increased by the addition of C3H10T1/2 cells in a real-time polymerase chain reaction (PCR). Using a mixed lymphocyte reaction, we determined the optimal splenocyte proliferation inhibition dose (MSC:splenocyte ratios 1:2 and 1:1). Three different C3H10T1/2 cell doses (low, 0.5 × 106, intermediate, 1 × 106, and high, 2 × 106) with a consistent splenocyte dose (1 × 106) were evaluated for their therapeutic potential in an in vivo GvHD model. The clinical and histologic GvHD score and Kaplan–Meier survival rate were improved after MSC transplantation, and these results demonstrated a dose-dependent inhibition.
We conclude that MSC inhibit GvHD in a dose-dependent manner in this mouse model and this model can be used to study the effects of MSC on GvHD.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Cytotherapy
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Management of infections complicating allogeneic hematopoietic stem cell transplantation.Semin Hematol. 2009; 46: 289-312
- Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+CD25+ regulatory T cells.Hepatobiliary Pancreat Dis Int. 2008; 7: 608-614
- Immune modulation and chronic graft-versus-host disease.Bone Marrow Transplant. 2008; 42: S66-9
- Shared biology of GVHD and GVT effects: potential methods of separation.Crit Rev Oncol Hematol. 2006; 57: 225-244
- Graft-versus-leukemia effects of transplantation and donor lymphocytes.Blood. 2008; 112: 4371-4383
- Immunobiology of allogeneic hematopoietic stem cell transplantation.Annu Rev Immunol. 2007; 25: 139-170
- Human mesenchymal stem cells modulate allogeneic immune cell responses.Blood. 2005; 105: 1815-1822
- Pharmaceutical and cellular strategies in prophylaxis and treatment of graft-versus-host disease.Curr Pharm Des. 2009; 15: 1974-1997
- Mixed chimerism and transplantation tolerance.Annu Rev Med. 2001; 52: 353-370
- Mechanisms of and perspectives on the mesenchymal stem cell in immunotherapy.J Lab Clin Med. 2004; 143: 284-291
- Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells.Gene Expr. 2007; 13: 217-226
- The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function.Cell Immunol. 2008; 251: 131-136
- Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children.Bone Marrow Transplant. 2001; 27: 777-783
- In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets.Blood. 2005; 106: 1113-1122
- CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation.Nat Med. 2003; 9: 1144-1150
- Kinetics of Th1/Th2 cytokines and lymphocyte subsets to predict chronic GVHD after Allo-SCT: results of a prospective study.Bone Marrow Transplant. 2009; 44: 729-737
- Interleukin 12 is associated with reduced relapse without increased incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant. 2005; 11: 1014-1021
- Effectiveness of rotor off fraction in allogeneic murine bone marrow transplantation with complete disparity of major histocompatibility.Exp Hematol. 1999; 27: 1219-1225
- An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation. I. The roles of minor H antigens and endotoxin.Blood. 1996; 88: 3230-3239
- Prevention of graft-versus-host disease by intra-bone marrow injection of donor T cells.Stem Cells. 2007; 25: 1595-1601
- Irradiation of the skin and systemic graft-versus-host disease synergize to produce cutaneous lesions.Am J Pathol. 1994; 144: 883-888
- Bone-marrow transplantation (second of two parts).N Engl J Med. 1975; 292: 895-902
- Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation.J Clin Invest. 1998; 101: 1835-1842
- Human adipose-derived mesenchymal stem cells reduce inflammatory and T-cell responses and induce regulatory T cells in vitro in rheumatoid arthritis.Ann Rheum Dis. 2010; 69: 241-248
- Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells.J Immunol. 2008; 181: 3933-3946
- Mesenchymal cells recruit and regulate T regulatory cells.Exp Hematol. 2008; 36: 309-318
- Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells.Clin Exp Immunol. 2007; 149: 353-363
- Mechanisms of T regulatory cell function.Autoimmun Rev. 2008; 7: 370-375
- Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism.Stem Cells. 2007; 25: 2025-2032
- Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation.Immunol Lett. 2008; 115: 50-58
- Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.Nat Med. 2009; 15: 42-49
- Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6.Cytotherapy. 2009; 11: 570-583
- Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease.Leukemia. 2007; 21: 1992-1999
- Coblockade of the LFA1:ICAM and CD28/ CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts.Blood. 1995; 85: 2607-2618
Accepted: November 20, 2009
Received: August 11, 2009
© 2010 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.