scholarly journals Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Makoto Nakamura ◽  
Yusuke Meguri ◽  
Shuntaro Ikegawa ◽  
Takumi Kondo ◽  
Yuichi Sumii ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell Subsets ◽  
Inkt Cells ◽  
Early Recovery ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Reduced Dose ◽  
Graft Versus Leukemia ◽  
Novel Strategy

AbstractPosttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient’s condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

Immunotherapy ◽  
2009 ◽  
Vol 1 (4) ◽  
pp. 599-621
Author(s):  
Jian-Ming Li ◽  
Cynthia R Giver ◽  
Ying Lu ◽  
Mohammad S Hossain ◽  
Mojtaba Akhtari ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Graft Versus Leukemia

Routine methods to maximize the graft-versus-leukemia (GvL) activity of allogeneic hematopoietic stem cell transplantation (HSCT) without the detrimental effects of graft-versus-host disease (GvHD) are lacking. Depletion or inhibition of alloreactive T cells is partially effective in preventing GvHD, but usually leads to decreased GvL activity. The current model for the pathophysiology of acute GvHD describes a series of immune pathways that lead to activation of donor T cells and inflammatory cytokines responsible for tissue damage in acute GvHD. This model does not account for how allotransplant can lead to GvL effects without GvHD, or how the initial activation of donor immune cells may lead to counter-regulatory effects that limit GvHD. In this review, we will summarize new findings that support a more complex model for the initiation of GvHD and GvL activities in allogeneic HSCT, and discuss the potential of novel strategies to enhance GvL activity of the transplant.

T Cell Toll-Like Receptors Play a Critical Role in Graft-Versus-Host Disease and Graft-Versus-Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 63-63 ◽  
Author(s):  
Masanori Kadowaki ◽  
Kazutoshi Aoyama ◽  
Motoko Koyama ◽  
Yukimi Sakoda ◽  
Kiyoshi Takeda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Critical Role ◽  
Tlr Signaling ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor Cells

Abstract Graft-versus-host disease (GVHD), the major complication of allogeneic hematopoietic stem cell transplantation, is mediated by donor T cells recognizing host alloantigens expressed on antigen-presenting cells (APCs). Total body irradiation (TBI) activates and damages host tissue, produces inflammatory cytokines and damage-associated molecular patterns, and allows translocation of microbial products into the systemic circulation. It has been assumed that these products bind to toll-like receptors (TLRs) on APCs and monocytes/macrophages, activate inflammatory pathways, and further amplify GVHD. On the other hand, TLRs are also expressed on T cells but their roles in the adoptive T cell response remain to be investigated in vivo. TLR signals are mediated by both MyD88-dependent and independent TRIF protein pathways. We evaluated the role of T cell TLR signaling in T cell alloreactivity in a mouse model of allogeneic bone marrow transplantation using mice with defective TLR signaling induced by deletions of the TLR adaptor proteins TRIF and MyD88 (TRIF/MyD88 DKO mice); in these mice, the TLR-dependent signaling pathway was eliminated. Lethally irradiated B6D2F1 mice were injected with 2 × 106 T cells from wild-type (wt) or TRIF/MyD88 DKO mice together with 5 × 106 T cell-depleted bone marrow (TCD-BM) from wt or DKO mice. Morbidity and mortality of GVHD was significantly less in recipients of TRIF/MyD88 DKO T cells than in recipients of wt T cells, irrespective of donor bone marrow type (Table). Reduction of GVHD was not seen in recipients of MyD88−/− T cells or TRIF−/− T cells, suggesting that inhibition of signaling through TRIF or MyD88 alone in donor cells is not sufficient to reduce GVHD. Histopathologic examination of the small intestine, liver, and skin showed significantly reduced GVHD pathology in recipients of DKO T cells (Table). Thus, effects of TLR signaling in donor cells on GVHD primarily reside in the T cell compartment of the donor graft, not in donor accessory cells. In recipients of TRIF/MyD88 DKO T cells, reduction of GVHD was associated with impairment of donor T cell expansion and production of TNF-□ and IFN-□. In marked contrast though, TRIF/MyD88 DKO T cells were activated equally to wt T cells in unirradiated B6D2F1 mice after adoptive transfer, thus activation of DKO T cells was impaired only in recipient mice heavily pretreated with TBI. These results suggest that T cell TLR signaling provides critical co-stimulation for T cells in an inflamed environment. T cell TLR signaling was also required for optimal graft-versus-leukemia activity. These results challenge the current paradigm that TLR functions are primarily attributable to their role in APCs and monocytes/macrophages in GVHD, and reveal a previously unrecognized critical role for T cell TLRs in inducing GVHD and GVL after hematopoietic stem cell transplantation. Pathological scores T BM Survivals(%) Clinical scores Serum IFN □ (ng/ml) Liver Intestine Skin *P<0.05 vs wt, ND; not detected syn syn 100 0.2±0.2* ND 1.0±0.6 1.0±0.0 0.0±0.0 wt wt 27 6.2±0.9 4.3±1.2 18.3±2.3 16.7±3.0 1.7±0.8 wt DKO 25 5.5±0.8 DKO wt 100* 1.8±0.4* 0.4±0.1* 7.9±1.0* 10.9±1.7 0.1±0.1* DKO DKO 88* 2.2±0.4*

scholarly journals IFN-γ and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 1075-1085 ◽  
Author(s):  
Ying Lu ◽  
Cynthia R. Giver ◽  
Akshay Sharma ◽  
Jian Ming Li ◽  
Katarzyna A. Darlak ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells ◽  
Ifn Γ

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) can eradicate chemorefractory leukemia through the graft-versus-leukemia (GVL) activity of donor T cells. However, the clinical success of allo-HSCT is limited by the graft-versus-host disease (GVHD) activity of donor T cells. We have reported previously that donor bone marrow precursors of plasmacytoid dendritic cells (pre-pDCs) can activate donor T cells toward T-helper 1 immune polarization in murine allogeneic HSCT. To optimize the GVL activity of these activated donor T cells and limit their graft versus host activity, we engineered the cellular constituents of an allogeneic hematopoietic stem cell graft with highly purified hematopoietic stem cells, T cells, and pre-pDCs and studied their GVL and GVHD activities in a murine model of allogeneic HSCT. Transplanted donor pre-pDCs expanded in vivo for 2 weeks after transplant, and they markedly augmented the activation and GVL activity of donor T cells while attenuating their GVHD activity, leading to an improved therapeutic index. Bidirectional signaling between donor T cells and donor pDCs with IFN-γ synthesis by donor T cells inducing indoleamine 2,3-dioxygenase synthesis by donor pDCs limited GVHD by altering the balance between donor T-reg and inflammatory T cells. Manipulating the content of donor DC precursors in allogeneic HSCT is a novel method to optimize the balance between GVL and GVHD.

The role of B cells in the pathogenesis of graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 114 (24) ◽  
pp. 4919-4927 ◽  
Author(s):  
Alexander Shimabukuro-Vornhagen ◽  
Michael J. Hallek ◽  
Rainer F. Storb ◽  
Michael S. von Bergwelt-Baildon
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
B Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Graft Versus Host Reaction ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Abstract Allogeneic hematopoietic stem cell transplantation is an established treatment modality for malignant and nonmalignant hematologic diseases. Acute and chronic graft-versus-host diseases (GVHDs) are a major cause of morbidity and mortality after allogeneic stem cell transplantation. T cells have been identified as key players in the graft-versus-host reaction and, therefore, most established drugs used against GVHD target T cells. Despite our knowledge on the pathogenesis of the GVH reaction, success of established therapies for prevention and treatment of GHVD is unsatisfactory. Recently, animal and human studies demonstrated that B cells are involved in the immunopathophysiology of acute and chronic GVHD. Early phase clinical trials of B-cell depletion with rituximab have shown beneficial effects on both acute and chronic GVHD. This review summarizes the current experimental and clinical evidence for the involvement of B cells in the pathogenesis of acute and chronic GVHD and discusses the clinical implications for the management of patients undergoing allogeneic stem cell transplantation.

scholarly journals Exosomes Released From Human Bone Marrow–Derived Mesenchymal Stem Cell Attenuate Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Ke-Liang Li ◽  
Jin-Yan Li ◽  
Gui-Ling Xie ◽  
Xiao-Yan Ma
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Clinical Score ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Acute Graft

ObjectiveMesenchymal stromal cell–derived exosomes have been applied for the treatment of several immune diseases. This study aimed to explore the effect of human bone marrow–derived mesenchymal stem cell (hBMSC)–derived exosomes on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).MethodshBMSC were cultured, and the culture supernatants were then collected to prepare exosomes using total exosome isolation reagent from Invitrogen. Mouse aGVHD model was established by allogeneic cell transplantation and injected with hBMSC-derived exosomes (Msc-exo) via tail vein. Exosomes from human fibroblast (Fib-exo) were used as the treatment control. The effects of Msc-exo on dendritic cells, CD4+, and CD8+ T cells in aGVHD mice were analyzed through flow cytometry. The impact on inflammatory cytokines was tested by ELISA. Besides, the body weight, survival rate, and clinical score of treated mice were monitored.ResultsMsc-exo were successfully prepared. aGVHD mice injected with Msc-exo led to 7–8-fold increase of the CD8α+ conventional dendritic cells (cDCs) and CD11b+ cDCs compared with the controls. In addition, Msc-exo altered the T help and Treg subpopulation, and decreased the cytotoxicity and proliferation of cytotoxic T cells to favor inflammatory inhibition in aGVHD mice. Mice that received Msc-exo exhibited decreased weight loss and reduced aGVHD clinical score in a time-dependent manner as well as reduced lethality compared with Fib-exo treated or untreated control. Furthermore, the levels of IL-2, TNF-α, and IFN-γ were decreased, as well as the level of IL-10 was increased after Msc-exo treatment in vivo and in vitro.ConclusionhBMSC-derived exosomes could attenuate aGVHD damage and promote the survival of aGVHD mice by regulating the DC and T-cell subpopulation and function, and lead to inhibited inflammatory response in aGVHD mice.

scholarly journals Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245232
Author(s):  
Kiyomi Mashima ◽  
Iekuni Oh ◽  
Ken Fujiwara ◽  
Junko Izawa ◽  
Norihito Takayama ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Graft Versus Leukemia ◽  
Graft Versus Leukemia Effect

Graft-versus-host disease is a major complication after allogeneic hematopoietic stem cell transplantation for hematological malignancies. Immunosuppressive drugs, such as anti-thymocyte globulin, alemtuzumab, and post-transplant cyclophosphamide, have been used to prevent graft-versus-host disease in HLA-mismatched haploidentical hematopoietic stem cell transplantation. Here, we investigated whether these drugs could ameliorate graft-versus-host disease without diminishing the graft-versus-leukemia effect by using a xenogeneic transplanted graft-versus-host disease/graft-versus-leukemia model. Anti-thymocyte globulin treatment diminished graft-versus-host disease symptoms, completely depleted the infiltration of inflammatory cells in the liver and intestine, and led to prolonged survival. By contrast, improvement after post-transplant cyclophosphamide treatment remained minimal. Alemtuzumab treatment modestly prolonged survival despite an apparent decrease of Tregs. In the graft-versus-leukemia model, 1.5 to 2.0 mg/kg of anti-thymocyte globulin and 0.6 to 0.9 mg/kg of alemtuzumab reduced graft-versus-host disease with minimal loss of graft-versus-leukemia effect. Mice treated with 400 mg/kg of post-transplant cyclophosphamide did not develop graft-versus-host disease or leukemia, but it was difficult to evaluate the graft-versus-leukemia effect due to the sensitivity of A20 cells to cyclophosphamide. Although the current settings provide narrow optimal therapeutic windows, further studies are warranted to maximize the benefits of each immunosuppressant.

scholarly journals Prior Use of Mogamulizumab to Allogenic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-Versus-Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1940-1940 ◽  
Author(s):  
Takeshi Sugio ◽  
Koji Kato ◽  
Takatoshi Aoki ◽  
Takanori Ota ◽  
Noriyuki Saito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Research Funding ◽  
Acute Gvhd ◽  
Cell Lymphoma ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Abstract [Introduction] Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma (PTCL) with a dismal prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment in ATL patients. Mogamulizumab, a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, is a novel immunotherapeutic agent, effective in treating patients with PTCL such as ATL, PTCL-not specified, and cutaneous T-cell lymphoma. However, in allo-HSCT setting, we should be careful to use mogamulizumab because CCR4 is expressed in regulatory T cells: The mogamulizumab treatment may accelerate GVHD by eradicating regulatory T cells in allo-HSCT patients. Here, we retrospectively analyzed the effect of mogamulizumab on GVHD development in ATL patients treated with mogamulizumab prior to allo-HSCT. [Patients and Methods] Data from the Fukuoka Bone Marrow Transplantation Group were retrospectively analyzed after the approval of mogamulizumab use in Japan. [Results] A total of 24 patients with ATL received mogamulizumab prior to allo-HSCT between April 2012 and April 2015 in our group. The median age at allo-HSCT was 58.5 years (range, 32-72). The median intervals from the last administration of mogamulizumab to allo-HSCT were 25 days (range, 9-126). The median total dose of mogamulizumab was 3 mg/kg (range, 1-8 mg/kg). After treatment with mogamulizumab, 18 patients (75%) had achieved in remission (CR in 4 patients and PR in 14) at allo-HSCT. Ten patients received unrelated bone marrow, 5 received related peripheral blood, and 9 received cord blood as stem cell sources. Eleven patients were treated with full-intensity conditioning and 13 received reduced-intensity conditioning. Graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitors (cyclosporine or tacrolimus) with short-term methotrexate in 14 patients and mycophenolate mofetil in 9. The cumulative incidence (CI) of acute GVHD at 100 days was 66.6% in grade 2-4 and 33.3% in grade 3-4. The involved organs of acute GVHD were skin in 14 patients, gut in 10, and liver in 4. Among 14 patients who developed grade 2-4 acute GVHD, 5 had severe fluid retention such as pleural effusion or ascites associated with GVHD. Chronic GVHD was observed in 6 patients, and 5 of them were extensive disease. The CI of transplant-related mortality (TRM) and relapse at 1-year were 53.2% (95%CI, 29.3-72.3%) and 29.6% (95%CI, 12.6-48.9%), respectively. The leading cause of death was GVHD (n = 7). The 1-year overall survival and progression-free survival were 19.2% (95%CI, 5.7-38.8%) and 17.2% (95%CI, 4.9-35.7%), respectively. [Discussion] Use of mogamulizumab prior to transplantation in allo-HSCT patients has a merit to decrease the burden of ATL cells. However, it was associated with an increase of TRM due to severe GVHD. Although most of ATL patients achieved better disease status at allo-HSCT through mogamulizumab and the survival rate was expected to be 50% based on the previous data, the survival in the present study was ~20%. These data suggest that mogamulizumab administered before transplantation may have retained until an early phase of post-transplantation, and the donor or host-derived regulatory T cells might be eliminated, allowing the GVHD T-cell clone to expand. Since mogalizumab is a potent anti-ATL agent, we need to develop new treatment protocols integrating mogalizumab at a suitable dose or administration timing, to minimize the unwanted GVHD development in future studies. Disclosures Akashi: Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

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