scholarly journals Bendamustine with Total Body Irradiation Limits Murine Graft-versus-Host Disease in Part Through Effects on Myeloid-Derived Suppressor Cells

2019 ◽  
Vol 25 (3) ◽  
pp. 405-416 ◽  
Author(s):  
Jessica Stokes ◽  
Emely A. Hoffman ◽  
Megan S. Molina ◽  
Jelena Eremija ◽  
Nicolas Larmonier ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Total Body Irradiation ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Total Body

scholarly journals Bendamustine with Total Body Irradiation Limits Murine Graft-Versus-Host Disease in Part Via Myeloid-Derived Suppressor Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2040-2040 ◽  
Author(s):  
Emely Hoffman ◽  
Jessica Stokes ◽  
Megan Stanley Molina ◽  
Emmanuel Katsanis
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Total Body Irradiation ◽  
Conditioning Regimen ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Myeloablative Conditioning ◽  
Graft Versus Host ◽  
Total Body

Abstract Background GvHD remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An under-investigated strategy to reduce GvHD is the modification of the preparative conditioning regimen. Cyclophosphamide (CY) and total body irradiation (TBI) is a commonly utilized myeloablative conditioning regimen, but is associated with GvHD. Bendamustine (BEN) is an alkylating agent that has been applied recently in nonmyeloablative chemotherapy-based conditioning regimens, demonstrating reduced myelosuppression, transplant related mortality, and acute graft versus host disease (GvHD). We have recently published that BEN can effectively replace CY when given following murine haploidentical bone marrow transplantation. We therefore hypothesized that BEN can also have advantages over CY when given in conjunction with TBI as a myeloablative preparative regimen. Methods We used a major histocompatibility mismatched murine BMT model to evaluate GvHD following BEN-TBI and CY-TBI conditioning. BALB/c (H-2d) mice received equivalent doses of BEN or CY (based on maximum tolerated dose), followed by TBI (400 cGy) and infusion of bone marrow (BM) cells with splenocytes (SC) or purified T-cells from C57BL/6 (H-2b) mice. GvHD morbidity and mortality and engraftment were monitored and MDSC frequencies were assessed by flow cytometry and immunofluorescence. Results We demonstrate that BEN-TBI conditioning, while facilitating complete donor chimerism, results in significantly less GvHD and improved survival compared to CY-TBI. In BEN-TBI conditioned mice, suppressive CD11b+Gr-1high myeloid cells are increased in the blood, bone marrow (BM), and spleen, with no evident differences in suppressive function. The ratio of Gr-1+ cells to T-cells is significantly increased in BEN-TBI mice in the intestines. When Gr-1high cells are depleted prior to transplant, the beneficial effects of BEN-TBI are partially lost. Alternatively, administration of G-CSF, which promotes CD11b+Gr-1+ myeloid cell expansion, trends towards an increase in survival in BEN-TBI mice. Conclusions These findings indicate a potential role of granulocytic myeloid-derived suppressor cells (MDSCs) in the mechanism by which BEN allows engraftment with reduced GvHD. BEN-TBI conditioning reduces GvHD morbidity and mortality compared to CY-TBI and may present a safer alternative to CY-TBI as a myeloablative conditioning regimen in allogeneic HCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mechanism of Suppression Effect of Myeloid-Derived Suppressor Cells on Hyperacute Graft-Versus-Host Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5716-5716
Author(s):  
Yigeng Cao ◽  
Ming-Zhe Han ◽  
Peng Liu ◽  
Haiyan Gong ◽  
Haiyan Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Suppressor Cells ◽  
Cd8 T Cell ◽  
Large Sample Size ◽  
Myeloid Derived Suppressor Cells ◽  
Common Complication ◽  
Host Disease ◽  
Graft Versus Host

Abstract Allogeneic HSCT (allo-HSCT) is associated with serious side effects and its most common complication is graft-versus-host disease (GVHD). Hyperacute GVHD is a clinical syndrome that occurs within the first 14 days after allo-HSCT associated with significant morbidity and mortality. The large sample size of clinical study indicated that the incidence of hyperacute GVHD in patient who underwent an allo-HSCT was about 9%, but the pathological process and crucial factor of this complication have incompletely defined. Myeloid-derived suppressor cells (MDSCs) have been found that had a beneficial role in treatment of GVHD, on account of suppressing ability on alloreactive T-cell-response in vitro and in vivo. It was reported that reactive oxygen species (ROS) have been implicated in MDSCs-mediated T cell suppression and MDSCs from NOX2-deficient mice, chronic granulomatous disease (CGD) mice, failed to suppress T cell function. However, the investigation of whether and how MDSCs and ROS play in CGD mice receiving allo-HSCT is lacking. In our research, WT mice receiving allo-HSCT began to appear typical acute GVHD clinical manifestations in about 20 days and died within 30 days after transplantation, while CGD mice receiving allo-HSCT suddenly suffered from hyperacute GVHD at day 3 after allo-HSCT: performed continuous weight loss, demonstrated poor grooming and impairs movement with or without hunching or skin integrated and animals died within 2 days after onset of symptoms. Further study shown that the donor spleen derived T cells was indispensable for hyperacute GVHD of CGD mice after receiving allo-HSCT. T lymphocyte subsets and proportional change in bone marrow and spleen of each group were detected by flow cytommeter after transplantation. The percentage and absolute number of donor derived CD3+CD8+T cell from both BM and spleen of CGD were significant higher than that of WT mice received allo-HSCT. Moreover, cell size and expression of activation marker CD25, CD44, and CD69 of CD3+CD8+T cell from both BM and spleen of CGD mice were significant higher than that of WT mice. The killing ability of donor derived CD3+T cells was observed by the living cells workstation and it was obviously to see that allo-reactive T cells from CGD mice had stronger killing ability. The levels of different cytokines in serum of recipient mice were detected by protein chip at day 3 after allo-HSCT. Comparing to C57BL/6 mice, more than ten kinds of inflammatory factors, including IL-6, were increased in the serum of CGD mice, which indicated that the cytokine storm related to T cells might be occur during hyperacute GVHD. In addition, using this hyperacute mouse model, we revealed that application of ROS agonist, L-buthionine-S, R-sulfoximine (BSO), rescued the CGD mice receiving allo-HSCT from hyperacute GVHD. In General, this study pioneering established a stable murine model of hyperacute GVHD and proved that allo-reactive T cells massively activated and proliferated since ROS production defective MDSCs lose the ability of inhibiting T cell immune reaction and caused hyperacute GVHD. These data provided new insights into the pathogenesis of GVHD and may improve the clinical management of this common complication. Disclosures No relevant conflicts of interest to declare.

scholarly journals CD99-dependent expansion of myeloid-derived suppressor cells and attenuation of graft-versus-host disease

2012 ◽  
Vol 33 (3) ◽  
pp. 259-267 ◽  
Author(s):  
Hyo Jin Park ◽  
Dahye Byun ◽  
An Hi Lee ◽  
Ju Hyun Kim ◽  
Young Larn Ban ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Host Disease ◽  
Graft Versus Host

The Effect of the Order of Total Body Irradiation and Chemotherapy on Graft-Versus-Host Disease

2014 ◽  
Vol 36 (1) ◽  
pp. e9-e12 ◽  
Author(s):  
Motohiro Kato ◽  
Ryosuke Shiozawa ◽  
Katsuyoshi Koh ◽  
Yoshihisa Nagatoshi ◽  
Junko Takita ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Total Body Irradiation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Total Body
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