Study of Relieving Graft-versus-Host Disease by Blocking CD137-CD137 Ligand Costimulatory Pathway in Vitro
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Engagement of the TCR without appropriate costimulation will result in the inability of T-cells to respond to the alloantigen as described earlier. We made a further investigation into the effect of relieving graft-versus-host disease (GVHD) and its mechanism in mice by blocking CD137-CD137L pathway in vitro. Responder cells (spleen cells) from BALB/C donor mice (H-2d) were incubated with stimulator cells (spleen cells) from C57BL/6 recipient mice (H-2b),with or without anti-CD137L monoclonal antibodies (MoAbs). Donor bone marrow cells plus mixed lymphocyte culture (MLC) T-cells were transplanted into lethally irradiated C57BL/6 mice. C57BL/6 mice were divided into 3 groups: group A (allogeneic bone marrow transplantation control group), group B (cyclosporine + methotrexate group), and group C (donor T-cells were treated with anti-CD137L MoAbs). The percentage of CD3+CD4+ and CD3+CD8+ T-cells were detected by flow cytometry, and the levels of cytokines (IFN-γ, interleukin [IL]-2, IL-10, IL-4) by reverse-transcriptase polymerase chain reaction.The incidence of GVHD in group C was 70%, while the incidence of GVHD was 100% in group A and group B. The survival rate of group C was higher than that of group A and B, and the median survival time was longer than that of group A and B(P < .01). Clinical symptoms and histological signs of GVHD in group C were the mildest among all 3 groups. The percentage of CD3 +CD8 + T-cells in group C was lower than that in group A and B(P < .01). The levels of IFN-γ in group C were markedly lower than those in group A and B(P < .01), and the levels of IL-10 in group C were significantly higher than those in group A and B(P < .01).The results suggest that treatment of donor T-cells by anti-CD137L MoAbs in vitro may relieve GVHD, thereby improve the survival time and survival rate of recipient mice, which might be related to the increased TH1 cytokine (IFN-γ) and decreased TH2 cytokine (IL-10) as well as the reduced CD3 +CD8 + T-cells.
- Yanada M, Emi N, Naoe T, et al. Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors a nationwide survey conducted in Japan.Bone Marrow Transplant. 2004; 34:331–337. CrossRef
- Lee SJ, Klein SP, Barrett AJ, et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse.Blood. 2002;100:406–414. CrossRef
- Socie G, Loiseau P,Tamouza R, et al. Both genetic and clinical factor predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.Transplantation. 2001;72:699–706. CrossRef
- Goodwin RG, Din WS, Davis-Smith T, et al. Molecular cloning of a ligand for the inducible T cell gene 4–1BB:a member of an emerging family of cytokines with homology to tumor necrosis factor.Eur J Immunol. 1993;23:2631–2641. CrossRef
- Schrwarz H, Valbracht J, Tuckwell J, et al. ILA, the human 4–1BB homologue, is inducible in lymphoid and other cell lineages.Blood. 1995;85:1043–1052.
- Hurtado J, Kim K, Pollok,et al. Potential role of 4–1BB in T cell activation: comparison with the costimulatory molecule CD28.J Immunol. 1995;155:3360–3367.
- Lee HW, Park SJ, Choi BK, et al. 4-1BB promotes the survival of CD8+T lymphocytes by increasing expression of Bcl-xL and Bfl-l.J Immunol. 2002;169:4882–4888.
- Lee HW, Nam KD, Seo SK, et al. 4-1BB cross-linking enhances the survival and cell cycle progression of CD4 T lymphocytes.Cell Immunol. 2003;223:143–150. CrossRef
- Tan JT, Ha J, Cho HR, et al. Analysis of expression and function of the costimulatory molecule 4–1BB in alloimmune responses.Transplantation. 2000;70:175–183.
- Ketheesan N, Hirst RG. Cytokine gene expression in innately susceptible BALB/C mice and relatively resistant C57BL/6 mice during infection with virulent Burkholderia pseudomallei.Infect Immun. 2000;68:2034–2042. CrossRef
- Schonrich G, Kalinke U, Momburg F, et al. Down-regulation of cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction.Cell. 1991;65:293–304. CrossRef
- Markees TG, Nancy EP, Randolph JN, et al. Ponged survival of mouse skin allograft and antibody to CD40 ligand.Transplantation. 1997;64:329–335. CrossRef
- Ferrara JL, Levg R, Chao NJ. Pathophysiologic mechanisms of acute graft-versus-host disease.Bid Blood Marrow Transplant. 1999;5:347–356. CrossRef
- Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype.N Engl J Med. 1998;339:1186–1193. CrossRef
- Martin PJ, Rowley SD, Anasetti C, et al. A phase I-II clinical trial to evaluate removal of CD4 cells and partial depletion of CD8 cells from donor marrow for HLA-mismatched unrelated recipients.Blood. 1999;94:2192–2199.
- Storb R, Deeg HJ, Pepe M, et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft versus host disease in patients given HLA-identical marrow grafts for leukemia: long term follow up of a controlled trial.Blood. 1989;73:1729–1734.
- Nozawa K, Ohata J, Sakurai J, et al. Preferential blockade of CD8(+) T cell responses by administration of anti-CD137 ligand monoclonal antibody results in differential effect on development of murine acute and chronic graft-versus-host diseases.J Immunol. 2001;167:4981–4986.
- Pollok KE, Kim YJ, Zhou Z, et al. Inducible T cell antigen 4–1BB. Analysis of expression and function.J Immunol. 1993;150:771–781.
- Cannons JL, Lau P, Ghumman B, et al. 4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy.J Immunol. 2001;167:1313–1324.
- Kim YJ, Mantel PL, June CH, et al. 4-1BB costimulation promotes human T cell adhesion to fibronectin.Cell Immunol. 1999; 192:13–23. CrossRef
- Tan JT, Whitmire JK, Ahmed R. 4-1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T cell responses.J Immunol. 1999;163:4859–4868.
- Myers L, Takahashi C, Mittler RS, et al. Effector CD8 T cells possess suppressor function after 4–1BB and Toll-like receptor triggering.Proc Natl Acad Sci U S A. 2003;100:5348–5354. CrossRef
- Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.J Immunol. 1986;136:2348–2357.
- Jadus MR, Peck AB. Lethal murine graft-versus-host disease in the absence of detectable cytoxic T lymphocytes.Transplantation. 1983;36:281–289. CrossRef
- Malkovsky M, Brenner MK, Hunt R, et al. T cell-depletion of allogeneic bone marrow prevents acceleration of graft-versus-host disease induced by exogenous interleukin-2.Cell Immunol. 1986; 103:476–480. CrossRef
- Szebeni J, Wang MG, Pearson DA, et al. IL-2 inhibits early increases in serum γ-interferon levels associated with graft-versus-host-disease.Transplantation. 1994;58:1385–1393. CrossRef
- Wang MG, Szebeni J, Pearson DA, et al. Inhibition of graft-versus-host disease by interleukin-2 treatment is associated with altered cytokine production by expanded graft-versus-host-reactive CD4 + helper cells.Transplantation. 1995;60:481–490. CrossRef
- Velardi A, Vareae P, Terenzi A, et al. Lymphokine production by T-cell clones after human bone marrow transplantation.Blood. 1989;74:1665–1672.
- Zeller JC, Panoskaltisis-Mortari A, Murphy WJ, et al. Induction of CD4 + T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-β.J Immunol. 1999;163:3684–3691.
- Boussiotis VA, Chen ZM, Zeller JC, et al. Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-β-treated alloreactive T cells that do not induce graft-versus-host disease.Blood. 2001;97:565–571. CrossRef
- Study of Relieving Graft-versus-Host Disease by Blocking CD137-CD137 Ligand Costimulatory Pathway in Vitro
International Journal of Hematology
Volume 86, Issue 1 , pp 84-90
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- Bone marrow transplantation
- Graft-versus-host disease
- Anti-CD137L MoAbs
- Immune tolerance
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