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| Open AccessAntiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment
Viral infection is a common risk for immune-compromised individuals, particularly pediatric patients receiving hematopoietic stem cell transplants. Here the authors report a phase II trial testing adoptive transfer of third party, virus-specific T cells on the feasibility, safety, clinical responses, as well as homeostasis of antiviral immunity in the recipients.
- Michael D. Keller
- , Patrick J. Hanley
- & Michael A. Pulsipher
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| Open AccessHLA class I peptide polymorphisms contribute to class II DQβ0603:DQα0103 antibody specificity
Bead-based assays to assess the donor-specific antibody profile of solid organ transplant patients often produce discordant results relative to cell-based alternatives. In this study, the authors demonstrate that, for some MHC class-II-specific antibodies, discordance can be attributed to recognition of the MHC class-I-derived peptides bound to MHC class-II molecules.
- N. Remi Shih
- , Thoa Nong
- & Jar-How Lee
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| Open AccessDefining a TCF1-expressing progenitor allogeneic CD8+ T cell subset in acute graft-versus-host disease
Graft-versus-host disease (GvHD) is mediated by activated T cells. Here the authors study mouse models of allogeneic and xenogeneic GvHD, and define T cell factor-1 (TCF1)+ and TCF1- T cell subsets with distinct functions and differentiation pathways that participate in GvHD pathogenesis.
- Solhwi Lee
- , Kunhee Lee
- & Se Jin Im
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| Open AccessTranscriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection
Although long-term kidney allograft failure is broadly classified as T cell- or antibody-mediated, this dichotomy is not always apparent in all patients, highlighting the need for improved allograft tissue characterisation. Here, the authors use single-cell RNA sequencing and multiplex imaging for transcriptomic and spatial profiling of allograft tissue from patients experiencing different degrees of rejection severity.
- Baptiste Lamarthée
- , Jasper Callemeyn
- & Maarten Naesens
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| Open AccessBiased IL-2 signals induce Foxp3-rich pulmonary lymphoid structures and facilitate long-term lung allograft acceptance in mice
IL-2/anti-IL-2 antibody complexes have been shown to facilitate the process of graft acceptance in transplantation. Here the authors use a mouse allograft model to show that IL-2 complexes promote graft acceptance and formation of inducible lymphoid structures containing Treg cells in transplanted lungs.
- Yoshito Yamada
- , Tuan Thanh Nguyen
- & Onur Boyman
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| Open AccessImplantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats
Islet transplantation for type 1 diabetes management is hindered by the life-long need for immunosuppressive medications. Here, the authors report an islet encapsulation device with local anti-rejection drug release that achieves long-term diabetes reversal in male rats and reduces drug-related toxicity.
- Jesus Paez-Mayorga
- , Jocelyn Nikita Campa-Carranza
- & Alessandro Grattoni
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| Open AccessHTLV-1 infection of donor-derived T cells might promote acute graft-versus-host disease following liver transplantation
Acute graft versus host disease is a rare but deadly complication following liver transplantation. Author show here, upon screening a large cohort of liver transplanted patients and detailed immune phenotyping of samples from the 7 affected individuals and appropriate controls, that human T cell lymphotropic virus type I infection of donor immune cells appear to correlate with the occurrence of acute graft versus host disease.
- Chuan Shen
- , Yiyang Li
- & Qiang Xia
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Article
| Open AccessEndowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing
Host versus graft reaction is a major impediment to CAR-T cell immune therapy in allogeneic settings. Authors show here that CAR-T cells, engineered to be deficient in MHC I expression but to express the NK inhibitor HLA-E, are resistant to destruction by both T and NK cells of the host.
- Sumin Jo
- , Shipra Das
- & Julien Valton
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| Open AccessEx vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis
Human regulatory B (Breg) cells have been difficult to study due to their scarcity and heterogeneity. Here the authors expand human B cells to exert immunosuppressive function in vitro and in vivo, and to implicate the TIM-1/STAT3 axis for the regulation of their homoeostasis and function.
- S. Shankar
- , J. Stolp
- & K. J. Wood
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Article
| Open AccessTransient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction
Chimeric antigen receptor engineering in T cells has been shown to be of great potential therapeutic benefit in a range of immune pathologies, although the functionality of such cell therapies can be limited due to tonic signalling and the induction of dysfunction. Here the authors show transient inhibition of mTOR can rescue their 41-BB-CAR-Tregs from tonic signalling-induced dysfunction.
- Baptiste Lamarthée
- , Armance Marchal
- & Julien Zuber
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| Open AccessC3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates
Donor-specific antibodies in sensitized recipients may cause kidney transplant rejection. Here the authors show that complement component C3 inhibition prolongs graft survival by inhibiting T and B cell proliferation/activation and hence tissue injury, despite antibody levels remaining unaffected.
- Robin Schmitz
- , Zachary W. Fitch
- & Stuart J. Knechtle
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| Open AccessT cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect
In hematopoietic stem cell transplants, T cells mediate graft-versus-leukemia (GVL), but GVL can fail leading to leukemia relapse. Here the authors use a mouse model in which T cells target the minor histocompatibility antigen H60 to show how this can occur, characterize the CD8+ T cell response and demonstrate how anti-CD40 antibody therapy improves GVL.
- Meng Zhou
- , Faruk Sacirbegovic
- & Warren D. Shlomchik
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| Open AccessCaspase-11 signaling enhances graft-versus-host disease
An increasing number of inflammatory pathologies is associated with IL-1 production downstream of caspases 1 and 11. Here the authors show that graft-versus-host-disease (GvHD) is diminished in mice with genetic or pharmacological ablation of caspase-11, and provide mechanistic insights into the signals leading to caspase-11 activation in GvHD.
- Yanyan Lu
- , Ran Meng
- & Ben Lu
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| Open AccessLong-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes
Injection of donor apoptotic cells induces graft tolerance in mice. Here the authors combine this approach with short immunosuppressive therapy to achieve long-term tolerance to allogeneic islets and restoration of normoglycemia in diabetic nonhuman primates, and delineate cellular and molecular correlates of tolerance induction.
- Amar Singh
- , Sabarinathan Ramachandran
- & Bernhard J. Hering
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| Open AccessBone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT
Allogeneic hematopoietic cell transplantation is the standard treatment of acute myeloid leukemia, but many patients relapse. Here the authors show increased markers of exhaustion and cancer antigen specificity within bone marrow-residing memory T cells precede and potentially predict the relapse.
- Maddalena Noviello
- , Francesco Manfredi
- & Chiara Bonini
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| Open AccessA late B lymphocyte action in dysfunctional tissue repair following kidney injury and transplantation
Allograft can induces local chronic inflammation, but how this feeds back to regulating late immunity is still not clear. Here the authors show, by charactering B cell transcriptome landscape dynamic in human allografts and in mouse kidneys transitioning from acute to chronic injury, that late B cell activation is associated with renal dysfunction and inflammation.
- Pietro E. Cippà
- , Jing Liu
- & Andrew P. McMahon
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| Open AccessDefining the structural basis for human alloantibody binding to human leukocyte antigen allele HLA-A*11:01
Anti-human leukocyte antigen (HLA) antibodies are important mediators of alloresponses, but structural insights on antibody:HLA interaction are still lacking. Here the authors provide a 2.4 Å structure of antibody:HLA complex, and also analyse HLA features important for other HLA-interacting molecules, to enhance our understanding of alloimmunity.
- Yue Gu
- , Yee Hwa Wong
- & Paul A. MacAry
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| Open AccessHematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation
Transplantation of allogeneic bone marrow helps establish chimerism that may induce tolerance to tissue grafts. Here the authors show that a CD117-antibody-drug-conjugate helps precondition the recipients for inducing mixed chimerism and allo-tolerance without clear adverse effects or the need for chronic immune suppression.
- Zhanzhuo Li
- , Agnieszka Czechowicz
- & Philip M. Murphy
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| Open AccessEvidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation
Allogeneic hematopoietic cell transplantation (allo-HCT) has led to the cure of HIV in one individual, but the underlying mechanisms are unclear. Here, the authors present a model of allo-HCT in SHIV-infected nonhuman primates and show that the SHIV reservoir persists in multiple tissues early after transplantation.
- Lucrezia Colonna
- , Christopher W. Peterson
- & Leslie S. Kean
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| Open AccessTIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity
Regulatory macrophages (Mreg) can directly suppress T effector cell responses. Here the authors show that human Mreg also elicit TIGIT+ regulatory T cells by integrating multiple differentiation signals, and that donor Mreg-induced recipient Tregs may promote kidney transplant acceptance in patients.
- Paloma Riquelme
- , Jan Haarer
- & James A. Hutchinson
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Article
| Open AccessTRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut
Gut-homing and colonization of T cells are important for maintaining local immune homoeostasis and protective immunity. Here the authors show that the kinase activity of TRPM7 regulates Th17 differentiation and T cell alloreactivity in the gut by modulating SMAD2 activation and CD103 expression in T cells
- Andrea Romagnani
- , Valentina Vettore
- & Susanna Zierler
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| Open AccessAllogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes
Rhesus macaques are not ideal for studying response to allogeneic hematopoietic stem cell transplant (allo-HSCT) owing to complex MHC genetics that prevent full MHC-matching. Here the authors show that inbred Mauritian-origin cynomolgus macaques are a superior preclinical model of allogeneic stem cell transplantation that mimics diverse clinical outcomes of human allo-HSCT.
- Benjamin J. Burwitz
- , Helen L. Wu
- & Jonah B. Sacha
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| Open AccessExtrafollicular CD4+ T-B interactions are sufficient for inducing autoimmune-like chronic graft-versus-host disease
Chronic graft-versus-host disease (cGVHD) is mediated by specific CD4 and B cells, but the relative contribution of extrafollicular and germinal centre (GC) T-B interaction is unclear. Here the authors show that the extrafollicular expansion of a specific CD4 T subset is sufficient for inducing cGVHD while GC is dispensable.
- Ruishu Deng
- , Christian Hurtz
- & Defu Zeng
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| Open AccessRegulation of T cell alloimmunity by PI3Kγ and PI3Kδ
Phosphatidylinositol-3-kinases (PI3K) γ and δ are key regulators of T cell signaling. Here the author show, using mouse heart allograft transplantation models, that PI3Kγ or PI3Kδ deficiency prolongs graft survival, but selective inhibition of PI3Kγ or PI3Kδ reveals alternative transplant survival outcomes post CTLA4-Ig treatment.
- Mayuko Uehara
- , Martina M. McGrath
- & Reza Abdi
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| Open AccessMHC matching improves engraftment of iPSC-derived neurons in non-human primates
Major histocompatibility complex (MHC) matching improves graft survival rates after organ transplantation. Here the authors show that in macaques, MHC-matched iPSC-derived neurons provide better engraftment in the brain, with a lower immune response and higher survival of the transplanted neurons.
- Asuka Morizane
- , Tetsuhiro Kikuchi
- & Jun Takahashi
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| Open AccessActivated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells
Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.
- Satish Ranjan
- , Alexander Goihl
- & Berend Isermann
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| Open AccessEx vivo pretreatment of human vessels with siRNA nanoparticles provides protein silencing in endothelial cells
The use of gene silencing techniques in the treatment of post-transplantation host rejection is not long lasting and can have systemic effects. Here, the authors utilize a nanocarrier for siRNA for treatment of arteries ex vivo prior to implantation subsequently attenuating immune reaction in vivo.
- Jiajia Cui
- , Lingfeng Qin
- & W. Mark Saltzman
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| Open AccessGraft-infiltrating host dendritic cells play a key role in organ transplant rejection
Blocking T cell activation in organ transplantation is important to prevent rejection. Here the authors show that unconventional monocyte-derived host dendritic cells enter allogeneic grafts to amplify the T cell response outside lymph nodes.
- Quan Zhuang
- , Quan Liu
- & Adrian E. Morelli