scholarly journals IL-12hi Rapamycin-Conditioned Dendritic Cells Mediate IFN-γ–Dependent Apoptosis of Alloreactive CD4+ T Cells In Vitro and Reduce Lethal Graft-Versus-Host Disease

2014 ◽  
Vol 20 (2) ◽  
pp. 192-201 ◽  
Author(s):  
Elizabeth O. Stenger ◽  
Brian R. Rosborough ◽  
Lisa R. Mathews ◽  
Huihui Ma ◽  
Markus Y. Mapara ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ

Inhibition of Graft-Versus-Host Disease (GVHD) by Histone Deacetylase Inhibitor (HDAC) SAHA Leads to Downregulation of STAT1 Activation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1311-1311
Author(s):  
Corinna Leng ◽  
Cuiling Li ◽  
Judy Ziegler ◽  
Anna Lokshin ◽  
Suzanne Lentzsch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Histone Deacetylase ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Ifn Γ

Abstract Histone deacetylase (HDAC) inhibitors have been shown to reduce development of graft versus host disease [GVHD] following allogeneic bone marrow transplantation [BMT]. Administration of the HDAC inhibitor suberonylanilide hydroxamic acid [SAHA] resulted in a significantly reduced GVHD-dependent mortality following fully MHC-mismatched allogeneic BMT. Median Survival Time (MST) for vehicle and SAHA-treated mice were 7.5 days and 38 days respectively. However, SAHA treatment did not affect T cell activation nor T cell expansion in vitro and in vivo as determined by MLR assays, phenotypic analysis of donor T cells with regard to expression of the CD25 activation antigen and calculation of donor CD4+ and CD8+ T cell numbers on days +3 and +6 post-BMT. Thus, SAHA treatment was not able to inhibit the strong upregulation of CD25 antigen on CD8+ T cells observed during induction of GVHD on days +3 and +6 post-BMT. We therefore focused on the effects of SAHA treatment on efferent immune effects including cytokine secretion and intracellular signaling events in vitro and in vivo following GVHD induction. SAHA treatment broadly inhibited lipopolysaccharide [LPS] and allo-antigen-induced cytokine/chemokine secretion in vitro like MIP-1-α, IP-10, IFN-γ, TNF-α and IL-6 and led also to a significant decrease in IFN-γ and TNF-α levels in vivo following induction of GVHD. Concomitantly, SAHA treatment inhibited phosphorylation of STAT1 and STAT3 in response to LPS and allo-activation in vitro. Furthermore, analysis of liver tissue and spleens from SAHA-treated animals with GVHD showed a significant decrease in phosphorylated STAT1. In contrast SAHA treatment had only moderate effects on p38 or ERK1,2 Mitogen-activated Protein Kinase (MAPK) pathway underscoring the relevance of the inhibition of the STAT1 pathway. In conclusion, GVHD is associated with a strong induction of phosphorylation of STAT1 in the liver and spleen and SAHA-dependent reduction of GVHD is associated with systemic and local inhibition of pSTAT1 and modulation of the inflammatory cytokine milieu during the efferent immune response.

Interleukin-2-Producing CD4+OX40+ T Cell as a Target for the Treatment of Chronic Graft-Versus-Host-Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1816-1816
Author(s):  
Takero Shindo ◽  
Takayuki Ishikawa ◽  
Akiko Fukunaga ◽  
Toshiyuki Hori ◽  
Takashi Uchiyama
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
Interleukin 2 ◽  
Host Disease ◽  
Effector Cells ◽  
Graft Versus Host ◽  
Ifn Γ

Abstract Chronic graft-versus-host-disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a serious complication, for which limited therapeutic approaches exist. Thymus-derived autoreactive as well as alloreactive T cells are shown to be involved in the development of chronic GVHD and CD4+ T cells are regarded to play a central role. OX40 (CD134) is known to play an important role in co-stimulation and survival elongation of CD4+ T cells, and murine models revealed that the interaction of OX40/OX40-ligand constitutes an essential parts in autoimmune and alloimmune responses. Since we showed that the increase of CD4+OX40+ T cells in peripheral blood of allo-HSCT recipients precedes the occurrence of chronic GVHD (Kotani A et al. Blood2001; 98: 3162–4), we have paid attention to the role of peripheral blood CD4+OX40+ T cells in the development of chronic GVHD. To further know the characteristics of peripheral blood CD4+OX40+ T cells from patients after allo-HSCT, we analyzed surface phenotype and the ability of cytokine production of CD4+ T cells from 25 allo-HSCT recipients. A majority of CD4+OX40+ T cells showed CD45RO+CD62L+CCR7+, while CD4+OX40− T cells were mainly CD45RO+CD62L−CCR7−. When stimulated with PMA and ionomycin, a significant part of CD4+OX40+ T cells produced interleukin-2 (IL-2). In contrast, a majority of CD4+OX40−HLA-DR+ T cells, the ratio of which also increased in peripheral blood of allo-HSCT recipients, produced interferon-γ (IFN-γ). Thus, the pattern of the expression of activation antigens on CD4+ T cells is a landmark of the potential to produce IL-2 or IFN-γ. When clinical data were combined, patients suffering from chronic GVHD showed increased ratio of IL-2-producing CD4+OX40+ T cells among CD4+ T cells (more than 10%). In fact, it correlates more closely (p=0.016) to the occurrence of chronic GVHD than the ratio of CD4+OX40+ T cells or that of IL-2-producing CD4+ T cells (p=0.06). Interestingly, the ratio of IFN-γ-producing CD4+ T cells does not correlate (p=0.95), suggesting that they do not contribute to the process of ongoing chronic GVHD. As CD4+OX40+ T cells share the characteristics of central memory T cells, we hypothesized that CD4+OX40+ T cells, which home secondary lymphoid organs, are stimulated with antigens and develop into effector cells, some of which induce chronic GVHD. Then we collected CD4+ T cells from recipients of allo-HSCT and sorted them into OX40+ and OX40− fractions. When sorted cells were stimulated with immobilized anti-CD3 and soluble anti-CD28 (CD3/28 stimulation), IL-2-producing cells were detected mainly in OX40+ fraction and IFN-γ-producing cells were abundantly and exclusively observed in OX40− fraction. When sorted cells were stimulated with CD3/28 for 48 hr, followed by 4-day cultivation with IL-2, OX40+ cells showed vigorous growth without reducing viability. In addition, re-stimulation with CD3/CD28 revealed that OX40+ cells produce a large amount of IFN-γ or IL-4. In this way, peripheral blood CD4+OX40+ T cells have potential to easily differenciate into effector cells, which may contribute to the development of chronic GVHD. The signaling from OX40 may also accelerate this process. Targeted therapy against IL2-producing CD4+OX40+ T cells may afford a breakthrough in the treatment of chronic GVHD.

Donor CD4+ T Cells That Possess Both Allo- and Autoreactivity in Transplants Mediate Chronic Graft Versus Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3555-3555
Author(s):  
Dongchang Zhao ◽  
Yu-Hong Chen ◽  
James Young ◽  
Elizabeth Shen ◽  
Tangsheng Yi ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Spleen Cells ◽  
Autoreactive T Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract Abstract 3555 Poster Board III-492 Chronic graft versus host disease (GVHD) is considered an autoimmune-like disease mediated by donor CD4+ T cells, but the role and origin of the autoreactive T cells remain controversial. Here, we report that, in a chronic GVHD model of MHC-matched DBA/2 (H-2d) donor to BALB/c (H-2d) host, donor spleen cells induced autoimmune-like chronic GVHD in thymectomized allogeneic BALB/c but not in syngeneic DBA/2 recipients. The spleen cells from the former but not the latter recipients induced autoimmune-like disease in the secondary DBA/2 recipients, indicating that autoreactive donor CD4+ T cells from transplants are expanded and contribute to chronic GVHD pathogenesis. In addition, we found that both auto- and alloreactive donor CD4+ T cells generated from primary chronic GVHD recipients via serial in vivo and in vitro expansion proliferated to donor and host DC stimulation and both induced autoimmune-like disease in syngeneic and allogeneic recipients. Furthermore, the clonal expansion and TCR spreading of the autoreactive T cells in chronic GVHD recipients were following the alloreactive T cells, as revealed by TCR-spectrum typing and skewing of TCR-CDR3 length; No dual TCR was expressed by the donor-type T cells with both allo- and autoreactivity; and the autoreactive hybridoma T clones proliferated to stimulation by both syngeneic and allogeneic DCs. Taken together, these results demonstrate that donor CD4+ T cells that possess both allo- and autoreactivity in transplants are expanded in recipients and contribute to chronic GVHD pathogenesis, and the allo- and autoreactivity of the donor T cells can be mediated by a single TCR. Disclosures: No relevant conflicts of interest to declare.

scholarly journals In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

2019 ◽  
Vol 25 (2) ◽  
pp. 204-215 ◽  
Author(s):  
Loïc Delens ◽  
Grégory Ehx ◽  
Joan Somja ◽  
Louise Vrancken ◽  
Ludovic Belle ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Host Disease ◽  
Graft Versus Host

scholarly journals IL-17 contributes to CD4-mediated graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 113 (4) ◽  
pp. 945-952 ◽  
Author(s):  
Lucy W. Kappel ◽  
Gabrielle L. Goldberg ◽  
Christopher G. King ◽  
David Y. Suh ◽  
Odette M. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
Proinflammatory Cytokines ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Interleukin 17 ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ

Abstract CD4+ interleukin-17 (IL-17)+ T cells (Th17 cells) have been implicated in allograft rejection of solid organs and several autoimmune diseases. However, the functional role of Th17 cells in the development of acute graft-versus-host disease (GVHD) has not been well-characterized. We detected significant numbers of alloreactive CD4+ donor T cells expressing IL-17, IL-17F, or IL-22 in the lymphoid organs of recipients of an allogeneic bone marrow transplant. We found no differences in GVHD mortality or graft-versus-tumor (GVT) activity between wild type (WT) and IL-17−/− T-cell recipients. However, upon transfer of murine IL-17−/− CD4+ T cells in an allogeneic BMT model, GVHD development was significantly delayed behind recipients of WT CD4+ T cells, yet overall GVHD mortality was unaffected. Moreover, recipients of IL-17−/− CD4+ T cells had significantly fewer Th1 cells during the early stages of GVHD. Furthermore, we observed a decrease in the number of IFN-γ–secreting macrophages and granulocytes and decreased production of proinflammatory cytokines (interferon [IFN]-γ, IL-4, and IL-6) in recipients of IL-17−/− CD4+ T cells. We conclude that IL-17 is dispensable for GVHD and GVT activity by whole T cells, but contributes to the early development of CD4-mediated GVHD by promoting production of proinflammatory cytokines.

scholarly journals Role of MMP-13 in Graft-Versus-Host Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1928-1928
Author(s):  
Hui-Hui Ma ◽  
Jing Fu ◽  
Suzanne Lentzsch ◽  
Markus Y Mapara
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Research Funding ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Matrix metalloproteinases (MMPs) have been initially recognized for their role in degradation of extracellular matrix (ECM) and collagen remodeling. However, MMPs have been shown to play a crucial role in inflammation, tumor cell invasion, adaptive and innate immunity. Acute and chronic Graft versus Host Disease (GVHD) are characterized by distinctive histopathological features involving tissue infiltration with donor cells, tissue damage and remodeling. We therefore hypothesized that GVHD-associated organ damage may involve MMPs. We have now identified a novel immunomodulatory function for MMP-13 (alternatively called collagenase-3)and have uncovered a previously unknown role of MMP-13 in regulating GVHD.To address the function of MMP-13 in GVHD we first assesed the effect of MMP-13 on alloresponses in vitro. Using fully Major Histocompatibility Complex (MHC)-mismatched standard mixed lymphocyte reaction we demonstated that antigen presentig cells (APC) from B6.MMP-13-/-(H2b) mice led to signifcantly enhanced antigen-driven activation and proliferation of Carboxyfluorescein succinimidyl ester (CFSE)-labeled Balb/c responder splenocytes. Thus, MMP-13 deficiency in either splenocytes or bone marrow-derived dendritic cells used as stimulators resulted in enhanced proliferation, activation and IFN-gproduction in the allo-reactive lymphocyte responders. Similarly, exogenous MMP13 reduced proliferation of responder T cells as determined tested by CFSEdilution (CFSEloof CD4+T cells from 62.3% decreased to 40.6%, CFSEloof CD8+T cells from 74.1% down to 47.9%). We next assessed the impact of MMP-13 in vivousing fully MHC-mismatched rodent acute GVHD models. To study the role of host-derived MMP-13 we induced GVHD in B6.MMP-13-/-or B6.WT recipient mice following lethal TBI (1075 rad) using splenic T cells from Balb/cdonors. We observed signifcantly accelerated GVHD-related mortality (Median Survival Time 7 vs. 47 days post-transplant, p<0.05) in MMP-13-deficient recipients. Most importantly, donor T cells expanded more vigorously in the secondary lymphoid organs (Spleen and mesenteric lymphnoodes) of MMP13-/-compared to wildtype recipient mice (e.g. spleen: absolute donor CD4+Tcells 1.5x104± 7.3 x 103 (WT) vs. 5.83 x104±1.65 x104[MMP-13-/-] and CD8+5.5 x104± 3.8 x104(WT) vs 3.4 x105±1.4 x105[MMP-13-/-], p<0.01). Enhanced donor lymphocyte expansion was further confirmed by bioluminescence imaging. To further delineate the underlying mechanisms, we analyzed the effects of MMP-13deficiency and exogenous MMP-13 on maturation of mouse bone marrow derived-dendritic cells (BMDC) and macrophages in vitro. We noted decreased expression of inhibitory molecules PD-L1 and PD-1H on GM-CSF/LPS cultured BMDC. Similarly, bone marrow-derived MMP-13-/-macrophages also showed reduced PD-L1 and PD-1H expression upon LPS stimulation when compared to their WT counterparts. In summary we posit that recipient myeloid cell-derived MMP-13 mitigates GVHD and limits donor T cell expansion. Further studies are warranted to determine how MMP-13 suppresses expansion of donor T cells and impacts Graft-versus-Leukemia responses. Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Proclara: Consultancy; BMS: Consultancy.

scholarly journals Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 114 (14) ◽  
pp. 3101-3112 ◽  
Author(s):  
Tangsheng Yi ◽  
Ying Chen ◽  
Lin Wang ◽  
Gong Du ◽  
Daniel Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Tissue Damage ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Tissue Specific ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ ◽  
Th17 Differentiation

In acute graft-versus-host disease (GVHD), naive donor CD4+ T cells recognize alloantigens on host antigen-presenting cells and differentiate into T helper (Th) subsets (Th1, Th2, and Th17 cells), but the role of Th subsets in GVHD pathogenesis is incompletely characterized. Here we report that, in an MHC-mismatched model of C57BL/6 donor to BALB/c recipient, WT donor CD4+ T cells predominantly differentiated into Th1 cells and preferentially mediated GVHD tissue damage in gut and liver. However, absence of interferon-γ (IFN-γ) in CD4+ T cells resulted in augmented Th2 and Th17 differentiation and exacerbated tissue damage in lung and skin; absence of both IL-4 and IFN-γ resulted in augmented Th17 differentiation and preferential, although not exclusive, tissue damage in skin; and absence of both IFN-γ and IL-17 led to further augmentation of Th2 differentiation and idiopathic pneumonia. The tissue-specific GVHD mediated by Th1, Th2, and Th17 cells was in part associated with their tissue-specific migration mediated by differential expression of chemokine receptors. Furthermore, lack of tissue expression of the IFN-γ–inducible B7-H1 played a critical role in augmenting the Th2-mediated idiopathic pneumonia. These results indicate donor CD4+ T cells can reciprocally differentiate into Th1, Th2, and Th17 cells that mediate organ-specific GVHD.

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.

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