scholarly journals IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling

Blood ◽  
2019 ◽  
Vol 134 (23) ◽  
pp. 2092-2106 ◽  
Author(s):  
Andrew N. Wilkinson ◽  
Karshing Chang ◽  
Rachel D. Kuns ◽  
Andrea S. Henden ◽  
Simone A. Minnie ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points ◽  
Donor T Cells ◽  
Principal Source

Key Points DCs are the principal source of IL-6 dysregulation after alloSCT. IL-6–dependent GVHD is driven by classical signaling of IL-6R on donor T cells but is regulated by trans signaling.

scholarly journals Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease

2015 ◽  
Vol 212 (8) ◽  
pp. 1303-1321 ◽  
Author(s):  
Motoko Koyama ◽  
Melody Cheong ◽  
Kate A. Markey ◽  
Kate H. Gartlan ◽  
Rachel D. Kuns ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Gi Tract ◽  
Mesenteric Lymph Nodes ◽  
Host Disease ◽  
Graft Versus Host ◽  
Glycation End Products ◽  
Donor T Cells ◽  
Antigen Presenting

The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103+CD11b− dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC–mediated indirect alloantigen presentation and cytokine secretion within the GI tract.

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 Siglec-G–CD24 axis controls the severity of graft-versus-host disease in mice

Blood ◽  
2014 ◽  
Vol 123 (22) ◽  
pp. 3512-3523 ◽  
Author(s):  
Tomomi Toubai ◽  
Guoqing Hou ◽  
Nathan Mathewson ◽  
Chen Liu ◽  
Ying Wang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
Fusion Protein ◽  
Graft Versus Host Disease ◽  
Negative Regulator ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points ◽  
Donor T Cells

Key Points Demonstrates a role for negative regulator of innate immunity, Siglec-G, in controlling GVHD. Shows that enhancing the interaction between host Siglec-G and CD24 on donor T cells with a novel CD24 fusion protein mitigates GVHD.

Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation

Blood ◽  
2013 ◽  
Vol 121 (18) ◽  
pp. 3745-3758 ◽  
Author(s):  
Emily Blyth ◽  
Leighton Clancy ◽  
Renee Simms ◽  
Chun K. K. Ma ◽  
Jane Burgess ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Organ Damage ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points

Key Points Infusion of CMV-specific T cells early posttransplant does not increase acute or chronic graft-versus-host disease. CMV-specific T cells early posttransplant reduce the need for pharmacotherapy without increased rates of CMV-related organ damage.

Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanised mouse model

Immunology ◽  
2021 ◽  
Author(s):  
Sam Raj Adhikary ◽  
Peter Cuthbertson ◽  
Leigh Nicholson ◽  
Katrina M. Bird ◽  
Chloe Sligar ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Donor T Cells

scholarly journals Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice

Blood ◽  
2017 ◽  
Vol 129 (20) ◽  
pp. 2737-2748 ◽  
Author(s):  
Qingrong Huang ◽  
Shan He ◽  
Yuanyuan Tian ◽  
Yuting Gu ◽  
Pan Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Stability ◽  
Graft Versus Host Disease ◽  
Hsp90 Inhibition ◽  
Host Disease ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Graft Versus Leukemia ◽  
Key Points ◽  
And Function

Key Points Ezh2 requires Hsp90 to maintain Ezh2 protein stability and function in alloreactive T cells. Pharmacological inhibition of Hsp90 destabilizes Ezh2 protein in alloreactive T cells and reduces GVHD but preserves graft-versus-leukemia effects.

Selective Depletion of Alloreacting CD25+ Cells from Stem Cell Allografts Can Reduce Acute Graft-Versus-Host Disease Following Matched Related Donor Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 426-426
Author(s):  
Scott R. Solomon ◽  
Thao Tran ◽  
Charles S. Carter ◽  
Nancy Hensel ◽  
Laura Wisch ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Donor T Cells ◽  
Related Donor

Abstract Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplant (SCT), especially in older patients. We previously showed that host-reactive donor T cells are selectively depleted (SD) from an allograft ex vivo, following a short co-culture of donor cells with irradiated T cell stimulators from the recipient and subsequent treatment with an anti-CD25 immunotoxin. We report a pilot study to test the hypothesis that GVHD could be decreased in a cohort of elderly patients receiving SD allografts from HLA-identical sibling donors. Sixteen patients, median age 65 years (range 51–73), with advanced hematologic malignancies were transplanted following reduced-intensity conditioning with fludarabine and either cyclophosphamide (n=5), melphalan (n=5), or busulfan (n=6). Cyclosporine was used as the only additional GVHD prophylaxis. SD allografts contained a median CD34 dose of 4.5x106/kg (range 3.5–7.3) and an SD CD3 dose of 1.0x108/kg (range 0.2–1.5). Fifteen patients achieved sustained engraftment. The helper T lymphocyte precursor (HTLp) frequency assay demonstrated depletion of host-reactive donor T cells in 9/11 cases tested from a mean of 1/182,089 to 1/822,354 (mean 5.5-fold depletion), while third party responses were conserved. Kaplan-Meier estimates of probability of grade II-IV and grade III-IV acute GVHD were lower than those seen in a historical control group of patients receiving cyclosporine alone for GVHD prophylaxis (35±13% vs. 57±10%, p=0.34) and (7±6% vs. 38±6%, p=0.05), respectively. Of note, the two patients who developed visceral (gut ± liver) GVHD showed ineffective allodepletion by HTLp (figure). Chronic GVHD occurred in five of 14 evaluable patients. At a median follow-up of 212 days (range 60 – 690), seven of sixteen patients remain alive and in remission. Relapse deaths occurred in four patients (refractory AML [2], therapy-related MDS [1], and CMML [1]). Non-relapse mortality in this high-risk cohort of patients included graft failure [1], GVHD [2], infection [1], and myocardial infarction [1]. In summary, CD25-directed allodepletion of stem cell allografts can reduce clinically relevant acute GVHD following matched related donor transplantation. Figure Figure

Resting B Cells Suppress CD8+ T Cell Function and Prevent the Induction of Graft Versus Host Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3111-3111
Author(s):  
David S. Ritchie ◽  
Victoria Watt
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cell ◽  
Regulatory Function ◽  
In Vivo Models ◽  
Host Disease ◽  
Graft Versus Host

Abstract B cells have been variously shown to induce direct tolerance of antigen specific CD8+ T cells, induce T cell anergy via TGF-b production, down regulate IL-12 production by dendritic cells (DC) and influence Th1/Th2 differentiation via the production of regulatory cytokines. Through these mechanisms, B cells can exert a regulatory function in in vivo models of T cell immunity including, experimental autoimmune encephalitis (EAE) and rheumatoid arthritis (RA). Recently, B cells have been shown to be essential in the prevention of effector T cell differentiation in a model of autoimmunity. We have previously shown that resting B cells inhibited tumor protection induced by dendritic cells vaccination. Inhibition of DC immunity by B cells was independent of presentation of major histocompatibility molecule (MHC) class-I bound tumor antigen but dependent on the expression of class-II MHC. Furthermore the inhibitory effect of B cells was lost if the B cells were activated by CD40L or if CD4+/CD25+ regulatory T cells (Treg) were depleted. These studies have been further extended to examine the role of resting B cells on the induction and severity of graft versus host disease (GVHD) induced in a major MHC mismatch model. We have found that mice transplanted with B cell depleted marrow revealed more rapid CD8+ T cell engraftment, higher IL-2 and IFN-γ production, more severe GVHD and shorter survival. Conversely, those who received additional resting B cells at the time of marrow infusion were substantially protected from GVHD. These findings indicate that resting B cells may regulate T cell activation, in part via the suppressive effects of Treg, but also through their important role in T cell homeostasis. Resting B cells may therefore limit the efficacy of DC based immunotherapy or alternatively be used therapeutically to limit CD8+ T cell autoimmunity including GVHD.

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