scholarly journals Thymus Transplantation Plus Allogeneic Bone Marrow Transplantation Can Induce Strong Graft-Versus Leukemia Effects with Low Risk of Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5798-5798
Author(s):  
Yuming Zhang ◽  
Xiaoqing Feng ◽  
Cuiling Wu ◽  
Wenling Guo ◽  
Huiping Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Cd4 Cells ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Thymus Transplantation

Abstract Abstract: [Objective] Allogeneic bone marrow transplantation (allo-BMT) has been used for the treatment of refractory leukemia and donor lymphocyte infusion (DLI) was used for the purpose of graft versus leukemia (GVL) effects. However, DLI is associated with a risk of graft versus host disease (GVHD). Thus, new cellular-based methods are desired. In the present study, we performed thymus transplantation (TT) plus allo-BMT to explore it’s anti leukemia effects. [Methods] Recipient B6 mice (H-2b) bearing leukemia (EL-4 cells, H-2b) were irradiated 8 Gy. The next day, bone marrow cells from BALB/c mice (H-2d) were transplanted into the B6 mice. Simultaneously, DLI and thymus transplantation from the same donor were carried out. The survival period of the recipient B6 mice were examined, histological studies were performed in the liver, intestine, and the engrafted thymus from the recipients 4 weeks after the BMT. Surface markers on lymphocytes from the spleen were analyzed by 3-color fluorescence staining using a FACScan system to determine chimerism. [Results]. All mice treated with BMT showed fully donor-derived chimerism(H-2d). The survival rate in mice treated with BMT plus TT was significantly prolonged compared with those treated with BMT alone or BMT plus DLI. Histologically, both the cortex and medullar areas of the engrafted thymus under the renal capsule were clearly shown. Normal T-cell differentiation was also observed in the engrafted thymus. Microscopic founding of small intestine and liver in the BMT plus TT group indicated mild GVHD, whereas those treated with BMT plus DLI showed moderated to serious GVHD. The number of the CD4+ cells was significantly greater in the mice treated with BMT+TT compared with those with BMT alone or those with BMT + DLI. The percentage of FoxP3+ regulatory T cells among CD4+ cells was higher in the mice treated with BMT + TT comparable to those treated with BMT + DLI. The results for CD8+ T cells were similar to those for CD4+ cells. [Conclusion]. Allo-BMT combined with TT induces high thymopoiesis, and can elicit strong GVL effects with mild GVHD reaction. We thus found that donor-derived T cells play an important role in the treatment of leukemia. Also the details of the mechanisms are still unknown, one possibilities may be the continuous supplementation of T cells from the allogeneic thymus. The results of the present study suggest this strategy will become a new way for the treatment of refractory or relapse leukemia in human. Disclosures No relevant conflicts of interest to declare.

Human Mesenchymal Stem Cells Attenuate Graft-Versus-Host Disease and Maintain Graft-Versus-Leukemia in Murine Allogeneic Bone Marrow Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1907-1907 ◽  
Author(s):  
Jeffery J Auletta ◽  
Saada Eid ◽  
Matthew Keller ◽  
Leland Metheny ◽  
Rocio Guardia-Wolff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Graft Versus Leukemia

Abstract Abstract 1907 Defining in vivo effects and biodistribution of human bone marrow-derived mesenchymal stem cell (hMSCs) following allogeneic bone marrow transplantation (alloBMT) could impact the clinical utility of MSC therapy for the prevention and treatment of graft-versus-host disease (GvHD). Using an established model of murine alloBMT, we defined hMSC effects on GvHD and graft-versus-leukemia (GvL) activity. We first studied whether hMSC could modulate in vitro murine T-cell (TC) alloreactivity in mixed leukocyte cultures (MLCs). Specifically, hMSCs added to MLCs significantly reduced TC proliferation in a concentration-dependent manner distinct from human fibroblasts. In contrast to MLC cultures alone, MLCs containing hMSCs had significant reduction in TNFα, IFNγ, and IL-10 levels and higher levels of PGE2 and TGFβ1. Modulation in the inflammatory milieu was associated with changes in TC phenotypes, including more naïve and less activated TC surface marker expression (CD62L+CD69−) and the induction of CD4+CD25+FoxP3+ T-regulatory cells. To determine whether hMSCs could modulate in vivo mTC alloreactivity, irradiated recipient B6D2F1 (H-2bxd) mice were transplanted with allogeneic C57BL/6 (H-2b) BM and purified splenic TCs (B6→B6D2F1) and then were tail-vein injected with hMSC infusions (1 million per injection) on days one and four post-transplant. Syngeneic transplant recipients (B6D2F1→B6D2F1) were used as controls. hMSC-treated alloBMT mice had significantly prolonged survival and improved clinical GvHD scores, reduced splenic TC expansion and TNFα and IFNγ-producing TCs, and lower circulating TNFα and IFNγ levels versus untreated alloBMT mice. Bioluminescence imaging showed redistribution of labeled hMSCs from the lungs to abdominal organs within 72 hours following infusion. Importantly, GvHD target tissues (small and large bowel and liver) harvested from hMSC-treated alloBMT mice had significantly lower GvHD pathology scores than untreated alloBMT mice. We next determined the effects of hMSCs on GvL activity using the murine mastocytoma cell line, P815 (H-2d). TCs co-cultured with hMSCs maintained potent in vitro cytotoxic T-lymphocyte (CTL) activity comparable to untreated control CTLs. After challenge with P815 tumor cells, hMSCs-treated alloBMT mice had less severe GvHD, eradication of tumor burden, and improved leukemia-free survival compared to alloBMT control mice. Lastly, indomethacin (IM) added to MLC-hMSC co-cultures significantly reversed attenuation in both murine TC alloreactivity and surface activation expression. In addition, IM administered to hMSC-treated alloBMT mice reversed hMSC-associated survival advantage, suggesting that PGE2 in part mediates hMSC immunomodulatory effects. Together, our results show that hMSC infusions effectively attenuate GvHD and maintain GvL potency in alloBMT mice and reveal potential biomarkers and mechanisms of action underlying hMSC effects. Disclosures: Solchaga: Bimemetic Therapeutics: Employment. Cooke:Amgen: Provides experimental drug and central pharmacy support for 2 trials for which I am Co-PI.

Graft-Versus-Leukemia Effect and Graft-Versus-Host Disease Can Be Differentiated by Cytotoxic Mechanisms in a Murine Model of Allogeneic Bone Marrow Transplantation

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2738-2747 ◽  
Author(s):  
Nobuhiro Tsukada ◽  
Tetsuji Kobata ◽  
Yoshifusa Aizawa ◽  
Hideo Yagita ◽  
Ko Okumura
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Leukemia Cells ◽  
Allogeneic Bone ◽  
Wild Type ◽  
Graft Versus Host ◽  
Graft Versus Leukemia

Allogeneic bone marrow transplantation (allo-BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect. In the present study, we examined the contribution of cytotoxic effector mechanisms, which are mediated by tumor necrosis factor- (TNF-), Fas ligand (FasL), or perforin, to GVHD and GVL effect in a murine BMT model. Bone marrow cells plus spleen cells (BMS) from wild-type, FasL-defective, or perforin-deficient donors were transferred into lethally irradiated recipients in the parent (C57BL/6) to F1 (C57BL/6 × DBA/2) BMT model with or without prior inoculation of DBA/2 leukemia L1210 or P815 mast cytoma cells. The effect of anti–TNF- antibody administration was also examined. Whereas the defect or blockade of each cytotoxic pathway could ameliorate lethal acute GVHD, the GVL effect was differentially affected. The wild-type BMS recipients died of acute GVHD within 50 days without residual leukemia cells. The FasL-defective BMS recipients showed 60%< survival over 80 days without acute GVHD or residual leukemia cells. Administration of anti–TNF- antibody resulted in early leukemia relapse and the recipients died within 25 days with massive leukemia infiltration in the liver. The perforin-deficient BMS recipients died within 60 days with residual leukemia cells. These results suggest that blockade of the Fas/FasL pathway could be used for ameliorating GVHD without impairing GVL effect in allo-BMT.

Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2256-2265 ◽  
Author(s):  
Onder Alpdogan ◽  
Cornelius Schmaltz ◽  
Stephanie J. Muriglan ◽  
Barry J. Kappel ◽  
Miguel-Angel Perales ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Populations ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Allogeneic Bmt ◽  
Interleukin 7

Prolonged immunodeficiency after allogeneic bone marrow transplantation (BMT) causes significant morbidity and mortality from infection. This study examined in murine models the effects of interleukin-7 (IL-7) given to young and middle-aged (9-month-old) recipients of major histocompatibility complex (MHC)–matched or –mismatched allogeneic BMT. Although administration of IL-7 from day 0 to 14 after syngeneic BMT promoted lymphoid reconstitution, this regimen was ineffective after allogeneic BMT. However, IL-7 administration from day 14 (or 21) to 27 after allogeneic BMT accelerated restoration of the major lymphoid cell populations even in middle-aged recipients. This regimen significantly expanded donor-derived thymocytes and peripheral T cells, B-lineage cells in bone marrow and spleen, splenic natural killer (NK) cells, NK T cells, and monocytes and macrophages. Interestingly, although recipients treated with IL-7 had significant increases in CD4+ and CD8+ memory T-cell populations, increases in naive T cells were less profound. Most notable, however, were the observations that IL-7 treatment did not exacerbate graft-versus-host disease (GVHD) in recipients of an MHC-matched BMT, and would ameliorate GVHD in recipients of a MHC-mismatched BMT. Nonetheless, graft-versus-leukemia (GVL) activity (measured against 32Dp210 leukemia) remained intact. Although activated and memory CD4+ and CD8+ T cells normally express high levels of IL-7 receptor (IL-7R, CD127), activated and memory alloreactive donor-derived T cells from recipients of allogeneic BMT expressed little IL-7R. This might explain the failure of IL-7 administration to exacerbate GVHD. In conclusion, posttransplant IL-7 administration to recipients of an allogeneic BMT enhances lymphoid reconstitution without aggravating GVHD while preserving GVL.

scholarly journals Acute Renal Graft-Versus-Host Disease in a Murine Model of Allogeneic Bone Marrow Transplantation

2017 ◽  
Vol 26 (8) ◽  
pp. 1428-1440 ◽  
Author(s):  
Peter M. Schmid ◽  
Abdellatif Bouazzaoui ◽  
Karin Schmid ◽  
Christoph Birner ◽  
Christian Schach ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Renal Impairment ◽  
Adhesion Molecule ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Graft Versus Host

Acute kidney injury (AKI) is a very common complication after allogeneic bone marrow transplantation (BMT) and is associated with a poor prognosis. Generally, the kidneys are assumed to not be no direct targets of graft-versus-host disease (GvHD), and renal impairment is often attributed to several other factors occurring in the early phase after BMT. Our study aimed to prove the existence of renal GvHD in a fully major histocompatibility complex (MHC)-mismatched model of BALB/c mice conditioned and transplanted according to 2 different intensity protocols. Syngeneically transplanted and untreated animals served as controls. Four weeks after transplantation, allogeneic animals developed acute GvHD that was more pronounced in the high-intensity protocol (HIP) group than in the low-intensity protocol (LIP) group. Urea and creatinine as classic serum markers of renal function could not verify renal impairment 4 weeks after BMT. Creatinine levels were even reduced as a result of catabolic metabolism and loss of muscle mass due to acute GvHD. Proteinuria, albuminuria, and urinary N-acetyl-beta-d-glucosaminidase (NAG) levels were measured as additional renal markers before and after transplantation. Albuminuria and NAG were only significantly increased after allogeneic transplantation, correlating with disease severity between HIP and LIP animals. Histological investigations of the kidneys showed renal infiltration of T cells and macrophages with endarteriitis, interstitial nephritis, tubulitis, and glomerulitis. T cells consisted of CD4+, CD8+, and FoxP3+ cells. Renal expression analysis of allogeneic animals showed increases in indoleamine-2,3 dioxygenase (IDO), different cytokines (tumor necrosis factor α, interferon-γ, interleukin 1 α [IL-1α], IL-2, IL-6, and IL-10), and adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), resembling findings from other tissues in acute GvHD. In summary, our study supports the entity of renal GvHD with histological features suggestive of cell-mediated renal injury. Albuminuria and urinary NAG levels may serve as early markers of renal impairment.

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