scholarly journals A Selective TNFR2 Agonist Expands Host Treg Cells in Vivo to Protect from Acute Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1099-1099 ◽  
Author(s):  
Andreas Beilhack ◽  
Martin Chopra ◽  
Marlene Biehl ◽  
Martin Vaeth ◽  
Andreas Brandl ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Hematopoietic Stem ◽  
Peripheral Tissues ◽  
Host Disease ◽  
Graft Versus Host ◽  
Pre Treatment

Abstract Donor CD4+Foxp3+ regulatory T cells (Tregs) suppress graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) while maintaining the anti-tumoral effect of transplanted conventional T cells in preclinical mouse models. Current clinical study protocols with donor Tregs for treatment or prophylaxis of GVHD rely on their ex vivo expansion and infusion in high numbers. Here we present a fundamentally novel strategy for inhibiting GVHD that is based on the in vivo expansion of recipient Tregs prior to allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in Treg biology. To this end we constructed a recombinant nonameric TNFR2-specific agonist, mimicking the activity of murine membrane-bound TNF on TNFR2 without TNFR1 stimulation, thereby avoiding the inflammatory side effects observed with conventional TNF. In vitro, this TNFR2-agonist expanded natural Tregs from wild type but not from TNFR2 KO mice. Accordingly, a human variant of this TNFR2-specific agonist expanded human Tregsin vitro. In vivo treatment of healthy mice with the murine TNFR2-agonist significantly increased Treg numbers in secondary lymphoid organs and peripheral tissues, particularly in the gastrointestinal tract, a prime target of acute GVHD. Next, we pre-treated recipient mice with this novel TNFR2-agonist to expand host-type radiation resistant Tregs prior to of allo-HCT in two models across MHC barriers (C57BL/6, H-2b->Balb/c, H-2d and FVB/N, H-2q->C57BL/6, H-2b). TNFR2-agonist pre-treatment resulted in significantly prolonged survival and reduced GVHD severity when compared to TNFR2-deficient recipients or untreated allo-HCT recipients. This was accompanied by reduced donor T cell proliferation and infiltration into GVHD target organs as assessed by in vivo and ex vivo bioluminescence imaging, flow cytometry and immunofluorescence microscopy. While in vivo TNFR2-agonist pre-treatment protected allo-HCT recipients from GVHD, anti-tumor effects of transplanted T cells remained unaffected in two different murine B cell leukemia models. In vivo depletion of host derived Tregs completely abrogated the protective effect of TNFR2-agonist pre-treatment. Our study shows that the expansion of host Tregs by selective in vivo TNFR2-activation significantly improves the outcome after allo-HCT and results in prolonged tumor-free survival. Disclosures No relevant conflicts of interest to declare.

Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4+ T-cells

2013 ◽  
Vol 71 (11) ◽  
pp. 2135-2148 ◽  
Author(s):  
Stephan Fricke ◽  
Nadja Hilger ◽  
Christian Fricke ◽  
Uta Schönfelder ◽  
Gerhard Behre ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Graft Versus Leukemia Effect

scholarly journals In vivo dynamics of T cells and their interactions with dendritic cells in mouse cutaneous graft-versus-host disease

2019 ◽  
Vol 3 (14) ◽  
pp. 2082-2092
Author(s):  
Sarah Morin-Zorman ◽  
Christian Wysocki ◽  
Jieqing Zhu ◽  
Hongmei Li ◽  
Sylvain Zorman ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Cd4 Cells ◽  
Tcr Signaling ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Cd8 Cells ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (alloSCT). By static microscopy, cutaneous GVHD lesions contain a mix of T cells and myeloid cells. We used 2-photon intravital microscopy to investigate the dynamics of CD4+ and CD8+ T cells and donor dendritic cells (DCs) in cutaneous GVHD lesions in an MHC-matched, multiple minor histocompatibility antigen-mismatched (miHA) model. The majority of CD4 and CD8 cells were stationary, and few cells entered and stopped or were stopped and left the imaged volumes. CD8 cells made TCR:MHCI-dependent interactions with CD11c+ cells, as measured by the durations that CD8 cells contacted MHCI+ vs MHCI− DCs. The acute deletion of Langerin+CD103+ DCs, which were relatively rare, did not affect CD8 cell motility and DC contact times, indicating that Langerin−CD103− DCs provide stop signals to CD8 cells. CD4 cells, in contrast, had similar contact durations with MHCII+ and MHCII− DCs. However, CD4 motility rapidly increased after the infusion of an MHCII-blocking antibody, indicating that TCR signaling actively suppressed CD4 movements. Many CD4 cells still were stationary after anti-MHCII antibody infusion, suggesting CD4 cell heterogeneity within the lesion. These data support a model of local GVHD maintenance within target tissues.

Nanoparticle-Encapsulated Allogeneic T Cells Mitigate Graft-Versus-Host Disease but Retain Graft-Versus-Leukemia Activity

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3820-3820
Author(s):  
Lingling Zhang ◽  
Shuting Zhao ◽  
Steven M. Devine ◽  
Xiaoming He ◽  
Jianhua Yu
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Electrostatic Deposition ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) has curative potential for hematological malignancies, but is often associated with life-threatening complications including graft-versus-host disease (GVHD). The graft-versus-leukemia (GVL) activity which accompanies HSCT is responsible for eradication of tumor cells and prevention of relapse. GVHD and GVL are usually associated with each other and the separation of the two activities occurs in limited circumstances. In this study, we aimed to mitigate GVHD but retain GVL through transplantation of allogeneic T cells encapsulated with bio-degradable nanoparticle materials. For the above purpose, donor T cells were encapsulated with chitosan and alginate through layer-by-layer coating using electrostatic deposition. Encapsulated donor T cells were characterized in vitro, and their ability to inhibit GVHD and retain GVL was determined in vivo after being transplanted together with non-encapsulated donor bone marrow (BM) cells in a C57BL/6 → BALB/c HSCT mouse model. We found 85.7% of donor T cells were successfully encapsulated by the above method (Fig 1A). In vitro studies showed that the encapsulation did not change the phenotype of T cells as defined through the following parameters: size, viability, proliferation, antibody binding, cytokine secretion, and cytotoxicity of T cells (Fig. 1B and data not shown). Mice transplanted with encapsulated allogeneic T cells exhibited less severe acute GVHD and prolonged survival (Fig. 1 C-E). The mice showed a lower GVHD score, less liver damage, a smaller CD8/CD4 T cell ratio, and a higher number of donor BM-derived cells following transplantation with encapsulated donor T cells (Fig. 1 C-E and data not shown). When this GVHD model was combined with implantation of A20 lymphoma cells, GVL of encapsulated T cells was not compromised, while GVHD was still suppressed and the mouse survival also prolonged (Figure 2). In summary, nanoencapsulation of T cells with bio-degradable materials attenuated the severity of GVHD but retained GVL, presenting a novel and potentially safer and effective approach of allogeneic HSCT for future clinical application. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2649-2656 ◽  
Author(s):  
Vu H. Nguyen ◽  
Robert Zeiser ◽  
Daniel L. daSilva ◽  
Daisy S. Chang ◽  
Andreas Beilhack ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Lymphoid Organs ◽  
Allogeneic Bone ◽  
Major Barrier ◽  
Peripheral Tissues ◽  
Host Disease ◽  
Graft Versus Host

Abstract CD4+CD25+ regulatory T cells (Tregs) suppress immune responses to alloantigens. The in vivo circulation and tissue localization of Tregs during an adaptive immune response remain unclear. We noninvasively tracked luciferase-expressing Tregs over time in an allogeneic bone marrow transplant model and demonstrated colocalization with effector T cells and initial expansion in secondary lymphoid organs before migration into inflamed tissues. Inflammation induced by irradiation and the allogeneic setting provided crucial stimuli for early Treg expansion and migration, leading to parallel reduction of effector T-cell proliferation in lymphoid organs and peripheral tissues. Treg transplants conferred long-term protection from systemic inflammatory challenge consistent with Treg in vivo survival. Suppression occurred during multiple phases of inflammation, but is optimal in the initial phase, providing protection from graft-versus-host disease while maintaining the graft-versus-tumor effect even at physiologic doses of Tregs due to their in vivo expansion, hence overcoming a major barrier to potential clinical applications of Tregs given their rarity.

scholarly journals Attenuation of graft-versus-host disease and graft rejection by ex vivo immunotoxin elimination of alloreactive T cells in an H-2 haplotype disparate mouse combination

Blood ◽  
1994 ◽  
Vol 83 (1) ◽  
pp. 288-298 ◽  
Author(s):  
M Cavazzana-Calvo ◽  
JL Stephan ◽  
S Sarnacki ◽  
S Chevret ◽  
C Fromont ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Graft Rejection ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
In Vivo Model ◽  
Host Disease ◽  
Graft Versus Host

A mouse anti-interleukin-2 receptor A-chain-specific PC61-immunotoxin (PC61-IT) strongly inhibited a primary mixed lymphocyte culture and major histocompatibility complex (MHC)-restricted cytotoxicity. The allodepleted T cells retained their proliferative and cytotoxic capacities in response to third-party stimulation, showing that PC61-IT specifically deleted recipient antigen-specific T-cell clones from the donor mouse. The ability of this specific allodepletion to prevent graft-versus-host disease (GVHD) and graft rejection was investigated in vivo. IT-depleted, activated parental T lymphocytes (C3H/eB) were intravenously injected into lethally irradiated CDF1 mice. GVHD was evaluated after 6 days on the severity of gut lesions. PC61-IT-treated cells significantly reduced both donor T-cell infiltration and acceleration of epithelial renewal (a sensitive index of gut damage) as compared with those for the corresponding untreated controls. The effect of selective allo-depletion on prevention of GVHD and graft rejection was further studied after MHC-haploincompatible bone marrow (BM) transplantation. A significant increase in survival was observed in mice receiving 2 x 10(6) T-cell-depleted BM cells and 0.5 x 10(6) PC61-IT-treated T cells, because one-third were alive without GVHD (and with stable full or partial engraftment) after 100 days, whereas all the mice infused with BM and sham-treated T cells died within 80 days from GVHD, and all the mice infused with BM cells alone rejected grafts. Furthermore, specific tolerance in chimeras towards donor cells could be shown. These results as observed in an experimental in vivo model corroborate previous results obtained in vitro in humans and lead us to consider the use of this selective allodepletion in human BM transplant from donors other than identical familial siblings.

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

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Huihui Liu ◽  
Zhengyu Yu ◽  
Bo Tang ◽  
Shengchao Miao ◽  
Chenchen Qin ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Treg Cells ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). As a complex immunopathology, aGVHD depends on the recognition of host antigens by donor T cells and induces augmented response of alloreactive T cells. Despite considerable achievements in the treatment of aGVHD, it remains a major clinical problem for the patients undergoing allo-HSCT. Therefore, it is necessary to further illustrate new mechanisms and develop novel therapeutic strategies of aGVHD. Previously we reported LYG1 (Lysozyme G-like 1) as a novel classical secretory protein promoted antitumor function of T cell. In this study, the role of LYG1 in aGVHD was investigated. Firstly, we examined whether LYG1 affected the alloreactivity of CD4+ T cells in vitro by MLR assay and discovered that LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio. Then we confirmed these observations using a major MHC mismatched aGVHD model by transferring T cells sorting from WT B6 or Lyg1-/- mice with bone marrow cells from WT B6 mice into lethally irradiated BALB/c mice. The alloreactive CD4+ T cells and the proportions of Th1 cells decreased whereas the proportions of Treg cells increased in spleens and livers in mice receiving Lyg1-/- T cells. LYG1-deficient T cells attenuated aGVHD severity, inhibited the expression of CXCL9 and CXCL10 and restrained CD4+ T cells infiltrating in livers. Furthermore, administration of recombinant LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production. More importantly, LYG1 deficiency did not affect GVT (graft-versus-tumor) effects. In summary, we demonstrate LYG1 regulates aGVHD via modulating the alloreactivity of CD4+ T cells and differentiation of Th1/Treg cells. Our study indicates that LYG1 may be a novel target in aGVHD by mitigating aGVHD without impairing GVT function. The therapeutic effect of targeting LYG1 is required in future investigations. Funding This study was supported by grant from The National Natural Science Foundation of China (NSFC) (Grant Number 81600144) and grant from Research Foundation of Peking University First Hospital. Disclosures No relevant conflicts of interest to declare.

The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3493-3499 ◽  
Author(s):  
Patricia A. Taylor ◽  
Christopher J. Lees ◽  
Bruce R. Blazar
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cellular Therapy ◽  
Ex Vivo ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Host Disease ◽  
Graft Versus Host ◽  
In Vivo Animal Model

Immune regulatory CD4+CD25+ cells play a vital role in the induction and maintenance of self-tolerance and the prevention of autoimmunity. Recently, CD4+CD25+ cells have been shown to be required for the ex vivo induction of tolerance to alloantigen via costimulatory blockade and to inhibit allogeneic skin graft rejection. Data presented here demonstrate that CD4+CD25+ cells play an important role in graft-versus-host disease (GVHD) generation. Depletion of CD4+CD25+ cells from the donor T-cell inoculum or in vivo CD25-depletion of the recipient before transplantation resulted in increased GVHD mediated by CD4+or whole T cells in several strain combinations irrespective of the total body irradiation conditioning regime. The infusion of freshly purified donor CD4+CD25+ cells modestly inhibited GVHD when administered in equal numbers with whole CD4+ cells. Because CD4+CD25+ cells only account for 5% to 10% of the total CD4+ population, the administration of high numbers of fresh donor CD4+CD25+ cells may not be clinically practical. However, we found that large numbers of CD4+CD25+ cells can be obtained by ex vivo activation and expansion. Cultured CD4+CD25+ cells, administered in equal numbers with CD4+ T cells or CD25-depleted whole T cells, resulted in significant inhibition of rapidly lethal GVHD. To our knowledge, this study is the first to demonstrate that activated, cultured CD4+CD25+ cells can offer substantial protection in a relevant in vivo animal model of disease. These data have important ramifications for clinical bone marrow and solid organ transplantation. CD4+CD25+ cells warrant consideration as an exciting new modality of cellular therapy for the inhibition of undesirable autologous and allogeneic responses.

Regulatory T Cells Preserve Anti-Viral Immunity While Preventing Lethal Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5432-5432
Author(s):  
Thomas H. Winkler ◽  
Martina Seefried ◽  
Irena Kroeger ◽  
Petra Hoffmann ◽  
Matthias Edinger ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Viral Immunity ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cmv Reactivation

Abstract Graft-versus-host disease (GvHD) is a frequent and life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) and is therefore one of the main factors that limits the broad application of HSCT. Over the last decades, several studies have reported a clinical association between GvHD and reactivation of cytomegalovirus (CMV). Using a lethal murine GvHD model with major MHC mismatch (C57BL/6 -> Balb/c), we were able to demonstrate that recipients latently infected with murine CMV (MCMV) before transplantation showed recurrence of CMV infection concomitant with the manifestation of GvHD. Moreover, these preinfected recipients showed an accelerated mortality compared to recipients that were not preinfected. The therapeutic co-infusion of CD4+CD25+ regulatory T cells (Tregs) with conventional T cells (Tcons) prevented lethal GvHD in preinfected mice and, markedly reduced the recurrence of MCMV infection. Remarkably, these mice showed clearance of MCMV 5 weeks post transplantation in contrast to mice receiving only Tcons in which massive virus infection persisted. Enhanced reconstitution of T lymphocytes and establishment of an anti-MCMV antibody titer from donor B cells in these animals suggest that CD4+CD25+ Tregs do not interfere with an anti-viral response while suppressing Tcon-mediated GvHD. Therefore, our study revealed that the suppressive function of CD4+CD25+ Tregs is not affected by CMV reactivation and more importantly, that Tregs do not adversely affect the anti-viral immunity in the recipient. In sum, these results provide important information on the correlation of GvHD and CMV reactivation and underline the possible clinical benefit of Treg application in GvHD patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ex vivo fucosylation of third-party human regulatory T cells enhances anti–graft-versus-host disease potency in vivo

Blood ◽  
2015 ◽  
Vol 125 (9) ◽  
pp. 1502-1506 ◽  
Author(s):  
Simrit Parmar ◽  
Xiaoying Liu ◽  
Amer Najjar ◽  
Nina Shah ◽  
Hong Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Ex Vivo ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Dose ◽  
Key Points

Key Points Fucosylated Tregs persist for a longer time in vivo. Fucosylated Tregs are able to prevent GVHD at a lower cell dose compared with untreated Tregs.

Sign in / Sign up

Export Citation Format

Share Document