scholarly journals In vitro polyclonal activation of conventional T cells with a CD28 superagonist protects mice from acute graft versus host disease

2015 ◽  
Vol 45 (7) ◽  
pp. 1997-2007 ◽  
Author(s):  
Niklas Beyersdorf ◽  
Sandra Werner ◽  
Nelli Wolf ◽  
Thomas Hünig ◽  
Thomas Kerkau
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Polyclonal Activation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Modulation of acute graft-versus-host disease and chimerism after adoptive transfer of in vitro-expanded invariant Vα14 natural killer T cells

2006 ◽  
Vol 106 (1) ◽  
pp. 82-90 ◽  
Author(s):  
Masaki Kuwatani ◽  
Yoshinori Ikarashi ◽  
Akira Iizuka ◽  
Chihiro Kawakami ◽  
Gary Quinn ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Graft Versus Host Disease ◽  
Adoptive Transfer ◽  
Natural Killer T Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Killer T Cells ◽  
Acute Graft

G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 734-739 ◽  
Author(s):  
Anke Franzke ◽  
Wenji Piao ◽  
Jörg Lauber ◽  
Patricia Gatzlaff ◽  
Christian Könecke ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Autoimmune Diseases ◽  
Graft Versus Host Disease ◽  
Bone Marrow Failure ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Results from experimental models, in vitro studies, and clinical data indicate that granulocyte colony-stimulating factor (G-CSF) stimulation alters T-cell function and induces Th2 immune responses. The immune modulatory effect of G-CSF on T cells results in an unexpected low incidence of acute graft-versus-host disease in peripheral stem cell transplantation. However, the underlying mechanism for the reduced reactivity and/or alloreactivity of T cells upon G-CSF treatment is still unknown. In contrast to the general belief that G-CSF acts exclusively on T cells via monocytes and dendritic cells, our results clearly show the expression of the G-CSF receptor in class I– and II– restricted T cells at the single-cell level both in vivo and in vitro. Kinetic studies demonstrate the induction and functional activity of the G-CSF receptor in T cells upon G-CSF exposure. Expression profiling of T cells from G-CSF–treated stem cell donors allowed identification of several immune modulatory genes, which are regulated upon G-CSF administration in vivo (eg, LFA1-α, ISGF3-γ) and that are likely responsible for the reduced reactivity and/or alloreactivity. Most importantly, the induction of GATA-3, the master transcription factor for a Th2 immune response, could be demonstrated in T cells upon G-CSF treatment in vivo accompanied by an increase of spontaneous interleukin-4 secretion. Hence, G-CSF is a strong immune regulator of T cells and a promising therapeutic tool in acute graft-versus-host disease as well as in conditions associated with Th1/Th2 imbalance, such as bone marrow failure syndromes and autoimmune diseases.

Deleterious Roles of the KIR Ligand Mismatch on Acute Graft Versus Host Disease in Unmanipulated HLA-Mismatched/Haploidentical Blood and Marrow Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2874-2874
Author(s):  
Xiao Jun Huang ◽  
Xiang Yu Zhao ◽  
Dai Hong Liu ◽  
Kai Yan Liu ◽  
Lan Ping Xu ◽  
...  
Keyword(s):  
T Cells ◽  
Multivariate Analysis ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Blood And Marrow Transplantation ◽  
Acute Graft

Abstract The beneficial effect of KIR ligand mismatch with a very low incidence of rejection, acute graft versus host disease (aGVHD), and leukemia relapse had been demonstrated by Perugia’s group in the Haploidentical mismatched Hematopoitic cell transplantation (HCT) with extensive T cells depletion in vitro. However, many analytical results of the haploidentical and unrelated mismatched transplantation appeared to be inconsistent with Perugia’s work. The disputes in the inconsistent roles of KIR ligand mismatch seem to be caused by the different transplant protocols with different extent of T cells depletion in vitro or in vivo. In recent years, we successfully established a novel protocol—conditioning including antithymocyte globulin followed by un-manipulated HLA-mismatched/haploidentical blood and marrow transplantation, which can achieve comparable outcomes to HLA-identical sibling transplantation. Following the contradictory results about the KIR ligand mismatch in the haploidentical related and mismatched unrelated HCT, we have evaluated the roles of the KIR ligand mismatch in 94 leukemia patients undergoing unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation. Multivariate analysis showed that both KIR ligand mismatch (HR 2.833, CI, 1.286–6.241, p=0.01) and doses of T cells (HR 3.059, CI, 1.292–7.246, p=0.011) were independent risk factors causing the acute graft versus host disease (aGVHD). In addition, compared to patients without KIR ligand mismatch, KIR ligand mismatch worsened the adverse effect of ‘high’ dose T cells (>1.48×108/kg) on aGVHD (100% vs 63.3%, p=0.036), and increased the incidence of aGVHD in patients with HLA-C mismatch (80% vs 57.4, p=0.056). Since multivariate analysis demonstrated that high risk leukemia is the only predictor for TRM, relapse and OS, we further analyzed the effect of KIR ligand mismatch on prognosis in standard and high risk patients. The differences in TRM (50% vs 7.6%, p=0.005) and OS (50% vs 88.4%, p=0.014) between patients with and without KIR ligand mismatch were most striking for standard risk. Therefore we conclude that due to the presence of large dose T cells in the allograft, the alloreactivity of NK cells had been inhibited and KIR ligand mismatch directed alloreactive T cells played crucial roles in our model.

Efficient Treatment of Murine Acute Graft-Versus-Host Disease with In Vitro Expanded CD4+CD25+ Regulatory T Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2987-2987
Author(s):  
Tina J Boeld ◽  
Kristina Doser ◽  
Corinna Lang-Schwarz ◽  
Elisabeth Huber ◽  
Reinhard Andreesen ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Treg Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Abstract 2987 Acute graft-versus-host disease (GVHD) is a frequent complication after allogeneic bone marrow transplantation (BMT). We previously showed that the adoptive transfer of donor-type CD4+CD25+ regulatory T cells (Treg) at the time of BMT prevents acute GVHD in murine models. However, the therapeutic potential of donor-derived Treg cells for the treatment of established acute GVHD has not yet been examined in detail. In analogy to potential clinical applications we now tested the capacity of in vitro expanded Treg cells to ameliorate acute GVHD after haploidentical BMT (BALB/c→CB6F1). CD4+CD25highCD62L+ Treg cells were purified by FACS and stimulated polyclonally using anti-CD3/CD28-coated beads. Cells expanded on average 130±19-fold (n=7) within 2 wks and maintained high levels of FoxP3 expression (96, 8±0, 8% FoxP3+ cells; n=7) as well as potent immunosuppressive activity in vitro. For the induction of acute GVHD CB6F1 recipients were lethally irradiated and transplanted with 2.5×106 BM cells in combination with 5×106 splenocytes. All animals developed severe GVHD by d11, as revealed by an increase of the GVHD severity score (2.3±0.4 in GVHD animals vs 0±0 in BM controls, p<0.001, n=1–11) and by histological analyses of the gut (score: 7.8±0.4 for the GVHD group vs 0.2±0.2 for BM controls, p =0.046, n=3). When animals with acute GVHD were treated with 5×106 expanded CD4+CD25highCD62L+ Treg cells on d11 after BMT, they initially developed progressive GVHD comparable to non-treated GVHD animals, as indicated by weight loss and an increase of the GVHD score. However from d44 post BMT onwards, Treg-treated GVHD animals regained body weight (d44: 75±3% vs 67±2% of initial weight; p <0.05; n=9–10) and their clinical GVHD score (d44: 6±0 vs 4.3±0.4; p <0.05; n=9–10) decreased. While all non-treated GVHD animals succumbed to disease by d67 after transplantation, 50% of Treg-treated GVHD animals survived for at least 100d (p =0, 002; n=16–21). As immune reconstitution and in particular reconstitution of the lymphocyte compartment is impaired in animals with GVHD, we analyzed the effect of Treg therapy on the reconstitution of the lymphoid and myeloid compartment. At d21 after BMT spleen and BM of non-treated as well as Treg-treated GVHD animals were completely lymphopenic as compared to control mice and both organs contained exceptionally high numbers of granulocytes. Unlike non-treated GVHD animals, however, Treg-treated recipients by d60 showed a recovery of the lymphocyte compartment in spleen (10±2.6×106 T cells and 23.5±12.5×106 B cells in Treg-treated vs 3.0±0.6×106 T cells and 1.5±0.4×106 B cells in non-treated GVHD animals vs 26.25±2.6×106 T cells and 63.9±9.1×106 B cells in BM controls) and BM (0.7±0.1×106 T cells and 8.6±4×106 B cells in Treg-treated vs 0.3±0.01×106 T cells and 0.7±0.4 ×106 B cells in non-treated GVHD animals vs 0.4±0.03×106 T cells and 11.2±0.6×106 B cells in BM controls), while the number of granulocytes decreased constantly. Successful treatment with Treg cells was finally accompanied by a reconstitution of the lymphatic system comparable to control mice. Furthermore, successfully treated mice showed only mild histological signs of gut GVHD at d100 that was significantly lower then those in non-treated GVHD animals with end-stage disease (score: 4.2±1 vs 9.9±1.5 in treated vs non-treated animals, p =0.006, n=4–6). Taken together, these results indicate that in vitro expanded natural Treg cells may not only be effective for the prevention, but also for the treatment of acute GVHD after allogeneic BMT. Disclosures: No relevant conflicts of interest to declare.

Superagonistic CD28 stimulation of allogeneic T cells protects from acute graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4575-4582 ◽  
Author(s):  
Niklas Beyersdorf ◽  
Xin Ding ◽  
Thomas Hünig ◽  
Thomas Kerkau
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Hematologic Malignancies ◽  
Therapeutic Window ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft ◽  
Stimulation Of

Abstract Acute graft-versus-host disease (aGVHD) often precludes successful immunotherapy of hematologic malignancies with allogeneic T cells. Therefore, we investigated the effect of immunomodulatory superagonistic anti-CD28 monoclonal antibodies (CD28-SA) on the capacity of allogeneic T cells to mediate both aGVHD and the protective graft-versus-tumor (GVT) response. In vivo pretreatment of donor C57BL/6 mice or short-term in vitro culture of donor lymph node cells with a CD28-SA efficiently protected BALB/c recipient mice from aGVHD. This protection strongly relied on the presence of CD28-SA–activated CD4+ CD25+ Foxp3+ regulatory T cells in the donor T-cell inoculum. With respect to the GVT response, CD28-SA–prestimulated T cells were still as potent in clearing lymphoma cells as were T cells without CD28-SA preactivation. Taken together, our data suggest that CD28-SA stimulation of bulk leukocyte cultures in vitro markedly increases the therapeutic window for adoptive immunotherapy with allogeneic T cells in vivo.

scholarly journals LYG1 Deficiency Attenuates the Severity of Acute Graft-Versus-Host Disease via Skewing Allogeneic T Cells Polarization Towards Treg Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Huihui Liu ◽  
Zhengyu Yu ◽  
Bo Tang ◽  
Shengchao Miao ◽  
Chenchen Qin ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Foxp3 Expression ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ ◽  
Acute Graft

Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation. The mechanism involves the recognition of host antigens by donor-derived T cells which induces augmented response of alloreactive T cells. In this study, we characterized the role of a previously identified novel classical secretory protein with antitumor function-LYG1 (Lysozyme G-like 1), in aGVHD. LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio in vitro by MLR assay. By using major MHC mismatched aGVHD model, LYG1 deficiency in donor T cells or CD4+ T cells attenuated aGVHD severity, inhibited CD4+ T cells activation and IFN-γ expression, promoted FoxP3 expression, suppressed CXCL9 and CXCL10 expression, restrained allogeneic CD4+ T cells infiltrating in target organs. The function of LYG1 in aGVHD was also confirmed using haploidentical transplant model. Furthermore, administration of recombinant human LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production and inhibiting FoxP3 expression. The effect of rhLYG1 could partially be abrogated with the absence of IFN-γ. Furthermore, LYG1 deficiency in donor T cells preserved graft-versus-tumor response. In summary, our results indicate LYG1 regulates aGVHD by the alloreactivity of CD4+ T cells and the balance of Th1 and Treg differentiation of allogeneic CD4+ T cells, targeting LYG1 maybe a novel therapeutic strategy for preventing aGVHD.

scholarly journals Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

2002 ◽  
Vol 196 (3) ◽  
pp. 389-399 ◽  
Author(s):  
Petra Hoffmann ◽  
Joerg Ermann ◽  
Matthias Edinger ◽  
C. Garrison Fathman ◽  
Samuel Strober
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Treg Cells ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Type ◽  
Acute Graft

Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4+CD25+ regulatory T (Treg) cells have recently been shown to suppress proliferative responses of CD4+CD25− T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD. Here we show that CD4+CD25+ T cells isolated from the spleen or BM of donor C57BL/6 (H-2b) mice that have not been tolerized are still potent inhibitors of the alloresponse in vitro and of lethal aGVHD induced by C57BL/6 CD4+CD25− T cells in irradiated BALB/c (H-2d) hosts in vivo. The addition of the CD4+CD25+ Treg cells at a 1:1 ratio with responder/inducer CD4+CD25− T cells resulted in a &gt;90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD. This protective effect depended in part on the ability of the transferred CD4+CD25+ T cells to secrete interleukin 10 and occurred if the Treg cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4+CD25+ Treg and conventional CD4+CD25− T cells can determine the outcome of aGVHD.

scholarly journals Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3+ T Cell through Modulation of CD11b+ Cell Function

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Jianbo Wu ◽  
Jian Gu ◽  
Shun Zhou ◽  
Hao Lu ◽  
Yunjie Lu ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cell Function ◽  
Host Disease ◽  
Graft Versus Host ◽  
Forkhead Box ◽  
Viable Approach ◽  
Necrosis Factor ◽  
Acute Graft

Transfer of splenocytes isolated from B6 mice into normal B6D2F1 mice induces acute graft-versus-host disease (aGVHD), resulting in the expansion of donor cytotoxic T lymphocytes that eliminate recipient B cells. The cytokine IL-22, secreted by Th1 cells, Th17 cells, and innate immune cells, is structurally related to IL-10. To investigate the association between IL-22 and aGVHD, an anti-mouse IL-22 antibody (IL-22Ab) was used to ablate IL-22 activity in a mouse aGVHD model. Administration of IL-22Ab significantly reduced the progression of aGVHD in B6D2F1 recipients of B6 grafts. IL-22Ab treatment also decreased the percentage of interferon-γ+ and tumor necrosis factor-α+ T cells but increased the number of forkhead box p3+ regulatory T cells (Tregs). In the presence of Tregs and donor CD11b+ cells, IL-22Ab protected against aGVHD. In vitro Treg induction was more efficient when CD4+CD25− T cells differentiated in the presence of CD11b+ cells obtained from IL-22Ab-treated GVHD mice, compared with cocultured untreated control cells. Finally, IL-22Ab modulated the expression of cytokines and costimulatory molecules in CD11b+ cells in aGVHD mice. We therefore conclude that IL-22Ab administration represents a viable approach for treating aGVHD.

scholarly journals Compound a Increases Cell Infiltration in Target Organs of Acute Graft-versus-Host Disease (aGVHD) in a Mouse Model

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4237
Author(s):  
Abdellatif Bouazzaoui ◽  
Ahmed A. H. Abdellatif ◽  
Faisal A. Al-Allaf ◽  
Neda M. Bogari ◽  
Mohiuddin M. Taher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Cell Infiltration ◽  
Compound A ◽  
Host Disease ◽  
Graft Versus Host ◽  
Target Organs ◽  
Acute Graft

Systemic steroids are used to treat acute graft-versus-host disease (aGVHD) caused by allogenic bone marrow transplantation (allo-BMT); however, their prolonged use results in complications. Hence, new agents for treating aGVHD are required. Recently, a new compound A (CpdA), with anti-inflammatory activity and reduced side effects compared to steroids, has been identified. Here, we aimed to determine whether CpdA can improve the outcome of aGVHD when administered after transplantation in a mouse model (C57BL/6 in B6D2F1). After conditioning with 9Gy total body irradiation, mice were infused with bone marrow (BM) cells and splenocytes from either syngeneic (B6D2F1) or allogeneic (C57BL/6) donors. The animals were subsequently treated (3 days/week) with 7.5 mg/kg CpdA from day +15 to day +28; the controls received 0.9% NaCl. Thereafter, the incidence and severity of aGVHD in aGVHD target organs were analyzed. Survival and clinical scores did not differ significantly; however, CpdA-treated animals showed high cell infiltration in the target organs. In bulk mixed lymphocyte reactions, CpdA treatment reduced the cell proliferation and expression of inflammatory cytokines and chemokines compared to controls, whereas levels of TNF, IL-23, chemokines, and chemokine receptors increased. CpdA significantly reduced proliferation in vitro but increased T cell infiltration in target organs.

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