Effector T cells require fatty acid metabolism during murine graft-versus-host disease

Key Points T cells activated during GVHD increase their dependence upon fatty acid oxidation. This dependence is not observed following acute activation or during normal immune reconstitution, suggesting novel therapeutic targets.

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CD4+CD25+ Regulatory T Cells Enhance Immune Reconstitution Following Allogeneic Hematopoietic Cell Transplantation by Protecting Thymic and Lymphoid Compartments from Graft-Versus-Host Disease Damage without Impacting T Cell Repertoire Development.

Blood ◽

10.1182/blood.v108.11.70.70 ◽

2006 ◽

Vol 108 (11) ◽

pp. 70-70 ◽

Cited By ~ 2

Author(s):

Vu H. Nguyen ◽

Daisy Chang ◽

Sumana Shashidhar ◽

Michael Bachmann ◽

Christopher H. Contag ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Graft Versus Host Disease ◽

Immune Reconstitution ◽

Hematopoietic Cell Transplantation ◽

Effector T Cells ◽

T Cell Repertoire ◽

Cell Repertoire ◽

Graft Versus Host

Abstract Regulatory T cells (Treg) protect from acute graft-versus-host disease (GvHD) in murine models of major-MHC mismatched hematopoietic cell transplantation (HCT) presumably by dampening the proliferation of mature effector T cells. It is unclear whether the effect of Treg on effector T cells is a selective or nonselective process or if Treg regulate the process of intrathymic and peripheral T cell maturation and selection following HCT, particularly given the intrinsic link of GvHD and immune reconstitution. We previously showed that Treg improved the quantitative and functional lymphoid reconstitution in a murine model of HCT. In the current study, we hypothesize that Treg prevent thymic and lymphoid damage from GvHD, leading to enhanced lymphoid reconstitution. Lethally-irradiated adult thymectomized Balb/c (H2d) recipients were transplanted with wild-type FVB (H2q) T cell depleted bone marrow (TCD-BM) cells and CD4+/CD8+ cells (Tcon), the latter to induce GvHD, with or without donor Treg given at a 1:1 dose ratio with Tcon. At day 30, when all groups had reached full donor chimerism, transplant recipients were challenged with murine CMV (5×105 pfu/mouse) intraperitoneally. At day 90, survival for thymectomized groups with TCD-BM alone, with Tcon, or with Tcon+Treg was 78%, 0%, and 45%, respectively, compared to 100%, 0%, and 86% survival in their respective euthymic infected counterparts (p<0.05 for thymectomized vs euthymic Treg groups). Elispot for Interferon-γ showed CMV-specific donor responses in all infected groups. CMV viral titers in the liver and kidney 2 weeks after infection was lower in recipients that received Treg compared to animals that received Tcon alone. Compared to euthymic transplant controls, thymectomized animals had higher viral titers in the liver, lungs, and kidneys in all groups. Uninfected thymectomized mice in the respective groups served as controls to separate the effect of CMV infection and GvHD on survival. All animals, infected or uninfected, that received Treg had no evidence of clinical GvHD while animals that received Tcon alone had significant GvHD. In euthymic recipients, gross and histologic examination confirmed the general preservation of thymic integrity and architecture in animals that received Treg compared with smaller involuted thymuses partially replaced by adipose tissue in animals that received Tcon alone. T cell repertoire assessed by V-beta TCR screening with FACS analysis showed a polyclonal distribution in animals with or without Treg. Spectratyping at day 30 post-transplantation showed that Treg had no significant impact on the TCR repertoire diversity in animals which received Tcon. Based on survival of a subset of infected thymectomized animals that received Treg, we evaluated the impact of Treg on secondary lymphoid organs following HCT. Animals without transferred Treg had significant splenic and lymph node fibrosis and hypoplasia with a reduction in T cell numbers due to GvHD. Our findings indicate that Treg indirectly enhance immune reconstitution by protecting the thymic and secondary lymphoid compartments from GvHD damage, allowing the generation and peripheral expansion of lymphoid cells without impacting the diversity of T cell repertoire.

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

Blood ◽

10.1182/blood-2012-08-448977 ◽

2013 ◽

Vol 121 (18) ◽

pp. 3745-3758 ◽

Cited By ~ 136

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.

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

Blood ◽

10.1182/blood-2016-08-735886 ◽

2017 ◽

Vol 129 (20) ◽

pp. 2737-2748 ◽

Cited By ~ 17

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.

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Suicide gene therapy of graft-versus-host disease: immune reconstitution with transplanted mature T cells

Blood ◽

10.1182/blood.v98.7.2071 ◽

2001 ◽

Vol 98 (7) ◽

pp. 2071-2076 ◽

Cited By ~ 18

Author(s):

José L. Cohen ◽

Olivier Boyer ◽

David Klatzmann

Keyword(s):

Gene Therapy ◽

T Cells ◽

Immune System ◽

Graft Versus Host Disease ◽

Immune Reconstitution ◽

Suicide Gene ◽

Suicide Gene Therapy ◽

Allogeneic Hsct ◽

Graft Versus Host ◽

Donor T Cells

After allogeneic hematopoietic stem cell transplantation (HSCT), mature transplanted T cells play a major role in restoration of the immune system. However, they can also induce a life-threatening complication: graft-versus-host disease (GVHD). Suicide gene therapy of GVHD aims to selectively eliminate alloreactive T cells mediating GVHD while sparing nonalloreactive T cells that should contribute to immune reconstitution. It was demonstrated previously that treatment with ganciclovir (GCV) can control GVHD in mice by killing donor T cells engineered to express the thymidine kinase (TK) suicide gene. TK allows phosphorylation of nontoxic GCV into triphosphate GCV, which is selectively toxic for dividing cells. Thus, in the TK-GCV system, the specificity of cell killing depends on the cycling status of TK T cells rather than allogeneic recognition. This is a potential drawback because in recipients of lymphopenic allogeneic HSCT, alloreactive and homeostatic signals drive the proliferation of donor T cells. It is shown here that the onset of alloreactive T-cell division occurs earlier than that of nonalloreactive T cells, thus establishing a time frame for GCV administration. A 7-day GCV treatment initiated at the time of HSCT allowed efficient prevention of GVHD, while sparing a pool of nondividing donor TK T cells. These cells later expanded and contributed to the replenishment of the recipient immune system with a diversified T-cell receptor repertoire. These results provide a rationale for designing the therapeutic scheme when using TK-GCV suicide gene therapy in allogeneic HSCT.

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

Blood ◽

10.1182/blood.2019000396 ◽

2019 ◽

Vol 134 (23) ◽

pp. 2092-2106 ◽

Cited By ~ 4

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.

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Donor Lymphocytes Stimulated with CMV pp65 Gene Modified Dendritic Cells for Prophylaxis of CMV Following Allogeneic Haemopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.2989.2989 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2989-2989

Author(s):

Kenneth P. Micklethwaite ◽

Leighton E. Clancy ◽

Upinder Sandher ◽

Elizabeth Snape ◽

Kenneth Francis Bradstock ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Stem Cell ◽

Graft Versus Host Disease ◽

Immune Reconstitution ◽

Adverse Reactions ◽

Specific Lysis ◽

Graft Versus Host ◽

Haemopoietic Stem Cell ◽

Cmv Reactivation

Abstract Background: Cytomegalovirus (CMV) reactivation post-allogeneic haemopoietic stem cell transplant (HSCT) causes morbidity and mortality. Pharmacological therapy is limited by bone marrow suppression that can result in opportunistic infection. Adoptive transfer of ex-vivo generated CMV-specific T-cells has the potential to rapidly restore immunity, prevent CMV infection and circumvent the need for pharmacotherapy. Methods: We have recruited 18 patients into a trial of donor-derived CMV-specific T-cells generated using dendritic cells transduced with a fiber modified adenoviral vector encoding the immunodominant CMV matrix protein pp65. Thus far, 8 patients have received T-cells prophylactically starting at day 28 post-HSCT. Recipients were monitored for adverse reactions, CMV reactivation by polymerase chain reaction (PCR) and CMV-specific immune reconstitution. Results: 18 cultures have been completed with an 8.5–30 fold increase in total cell number (mean 2.1 × 108, range 0.8–5.1 × 108). Products consisted of T-cells (median 96.5%) displaying an effector memory phenotype (CD45RO+, CD62L−) and a predominance of CD8+ (14–90%) over CD4+ (2.5–57%) cells. All cultures exhibited negligible alloreactivity against recipient derived targets (0–3.6% specific lysis at E:T ratio of 20:1) but strong killing of CMV pp65 peptide pulsed targets (43–79% specific lysis at E:T 20:1). Killing was also observed against targets labeled with adenoviral antigens (2.7–12.5% lysis at E:T 20:1) demonstrating the bi-virus specificity of these cultures. In HLA-B7 and HLA-A2 donors, percentages of tetramer binding T-cells accounted for 3.2 to 40% of cells. Enrichment of cells recognizing known HLA-A24, B8 and B35 epitopes was not observed despite these cultures exhibiting strong cytotoxic activity against pp65 pulsed targets. Reasons for non-infusion include early death post-transplant (3 patients), failure of cultures to meet release criteria (2 patients), severe graft versus host disease (1 patient) and refusal (1 patient). 3 patients are currently awaiting infusion. Patients infused have been followed from 21 to 189 days post infusion. In 5 patients we have demonstrated rapid, polyepitope, CMV pp65-specific immune reconstitution using tetramer and ELISPOT analysis. CMV reactivation by PCR has occurred in 3 patients but none have progressed to CMV disease, suggesting the functional capacity of the cells to control viral reactivation. One patient received pharmacotherapy with valaciclovir while no other patients have required anti-viral antibiotics. There have been no infusion related adverse reactions. Graft versus host disease, non-CMV infections and other adverse events have not exceeded expected rates. Conclusions: Prophylactic adoptive transfer of CMV-specific T-cells is safe, hastens CMV-specific immune reconstitution and may reduce the need for anti-CMV pharmacotherapy in allogeneic HSCT recipients. Our data indicate the potential of specific cellular therapy to control opportunistic infections in severely immunosuppressed patients post-HSCT.

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Protection of the Intestinal Epithelium from Conditioning with R-spondin1 Ameliorates Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v112.11.66.66 ◽

2008 ◽

Vol 112 (11) ◽

pp. 66-66 ◽

Cited By ~ 2

Author(s):

Shuichiro Takashima ◽

Kazutoshi Aoyama ◽

Motoko Koyama ◽

Daigo Hashimoto ◽

Takeshi Oshima ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Large Bowel ◽

Immune Reconstitution ◽

Allogeneic Bone ◽

Gi Tract ◽

Host Disease ◽

Graft Versus Host ◽

Tract Damage

Abstract Damage to the gastrointestinal (GI) tract by pretransplant conditioning regimen plays a critical role in amplifying graft-versus-host disease (GVHD). Thus protection of the GI tract from conditioning may represent a novel approach to prevent GVHD. R-Spondin1 (R-Spo1) is a novel class of soluble activator for Wnt/□-catenin signaling, and has potent and specific proliferative effects on the intestinal crypt cells; injection of R-Spo1 protects mice from chemotherapy-induced intestinal mucositis. We therefore hypothesized that administration of R-Spo1 could modulate GVHD by reducing the GI tract damage and improve outcome of allogeneic bone marrow transplantation (BMT). Lethally irradiated B6D2F1 (H-2b/d) mice were injected with 5 × 106 BM and 2 × 106 T cells from MHC-mismatched B6 (H-2b) donors on day 0. Mice were intravenously injected with 200 μg of R-Spo1 or diluent from days −3 to −1 and +1 to +3 after BMT. In vivo labeling assay of mitotic cells with BrdU demonstrated that the proliferative index, as determined by the percentages of BrdU-positive cells among crypt epithelial cells, was significantly greater in the small intestine of R-Spo1 treated mice than controls 4 days after BMT (57% ± 3% vs 48% ± 1%, P<0.05). Analysis of the mesenteric lymph nodes and spleens on day +7 demonstrated significantly reduced expansion of donor T cells in R-Spo1 treated recipients in association with reduced serum levels of IFN-□ and TNF-□ on day +7 when compared to controls (Table). GVHD was severe in allogeneic controls, with 12.5% survival by day +40, whereas 62.5% of R-Spo1-treated animals survived this period (Table). Histopathologic examination of the small and large bowel and liver showed significantly reduced GVHD pathology in R-Spo1 treated animals than in controls (Table). A flowcytometric analysis of the spleen and thymus after BMT showed that administration of R-Spo1 did not impair donor cell engraftment and T and B cell immune reconstitution. We next evaluated the impact of R-Spo1 on graft-versus-leukemia (GVL) effects. BMT was performed similarly as above with the addition of 5 × 104 host-type P815 leukemia cells (H-2d). All recipients of T cell-depleted BM died from leukemia by day +20 after BMT, while no leukemia death was observed in R-Spo1 treated allogeneic animals. Overall, R-Spo1 treatment improved outcome of allogeneic BMT by reducing GVHD, while maintaining immune reconstitution and GVL effects. Thus, administration of R-Spo1 reduces the GI tract damage and suppresses donor T cell activation and systemic GVHD, supporting a hypothesis that the GI tract plays a major role in the amplification of systemic GVHD. Brief treatment with R-Spo1 may serve as an effective adjunct to clinical regimens of GVHD prophylaxis. Pathology Scores Group Survivals on day+40 (%) Small bowel Large bowel Liver INF □ (ng/ml) TNF □ (pg/ml) TCD: T cell-depleted BMT, +T: T cell-repleted BMT, ND: not detected Data are expressed as mean ± SD. *P<0.01 vs control, **P<0.05 vs control TCD diluent 100 2.4± 0.9 3.5± 1.0 0.3± 0.3 ND ND +T diluent 12.5 8.3± 2.7 7.3± 1.9 2.0± 0.8 6.0 ± 2.4 103.7 ± 9.9 +T R-Spo1 62.5* 3.4±1.9** 3.9± 0.3** 0.8± 0.7** 2.3 ± 1.5** 55.4 ± 6.6**

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Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

Blood ◽

10.1182/blood-2015-04-637587 ◽

2015 ◽

Vol 126 (4) ◽

pp. 546-557 ◽

Cited By ~ 28

Author(s):

Byung-Su Kim ◽

Hidekazu Nishikii ◽

Jeanette Baker ◽

Antonio Pierini ◽

Dominik Schneidawind ◽

...

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Host Disease ◽

Graft Versus Host ◽

Key Points

Key Points Donor treatment with agonistic DR3 antibody induces selective expansion of Tregs and reduced activation of conventional T cells. T cells from DR3 antibody–treated donors result in reduced acute GVHD and preserved GVT effects.

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Graft-Versus-Host Disease Is Defined By Tissue-Autonomous Regulation of Effector T Cells

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2015.11.348 ◽

2016 ◽

Vol 22 (3) ◽

pp. S58

Author(s):

Pedro Santos e Sousa ◽

Sophie Ward ◽

Cara Lomas ◽

Thomas Conlan ◽

Hannah Shorrock ◽

...

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Effector T Cells ◽

Host Disease ◽

Graft Versus Host ◽

Autonomous Regulation

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NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease

Blood ◽

10.1182/blood-2016-08-732636 ◽

2017 ◽

Vol 130 (5) ◽

pp. 606-618 ◽

Cited By ~ 37

Author(s):

Sara Mastaglio ◽

Pietro Genovese ◽

Zulma Magnani ◽

Eliana Ruggiero ◽

Elisa Landoni ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Graft Versus Host Disease ◽

Memory T Cells ◽

Central Memory ◽

Host Disease ◽

Graft Versus Host ◽

Central Memory T Cells ◽

Specific Tumor ◽

Key Points

Key Points TCR SE is a clinically feasible approach to rapidly produce highly performing and specific tumor reactive T cells. NY-ESO-1 TCR SE T cells kill multiple myeloma in the absence of off-target reactivity including alloreactivity.

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