RESUMO
Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.
Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunidade , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Nanotecnologia , Acetilmuramil-Alanil-Isoglutamina/metabolismo , Animais , Comportamento Animal , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Colesterol/metabolismo , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Imunidade/efeitos dos fármacos , Imunoterapia , Lipoproteínas HDL/metabolismo , Camundongos Endogâmicos C57BL , Primatas , Distribuição Tecidual/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
Assuntos
Restrição Calórica , Monócitos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Adulto , Animais , Antígenos Ly/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Quimiocina CCL2/deficiência , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Feminino , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , PPAR alfa/deficiência , PPAR alfa/genética , PPAR alfa/metabolismoRESUMO
The nuclear RNA exosome is an essential multi-subunit complex that controls RNA homeostasis. Congenital mutations in RNA exosome genes are associated with neurodegenerative diseases. Little is known about the role of the RNA exosome in the cellular response to pathogens. Here, using NGS and human and mouse genetics, we show that influenza A virus (IAV) ribogenesis and growth are suppressed by impaired RNA exosome activity. Mechanistically, the nuclear RNA exosome coordinates the initial steps of viral transcription with RNAPII at host promoters. The viral polymerase complex co-opts the nuclear RNA exosome complex and cellular RNAs en route to 3' end degradation. Exosome deficiency uncouples chromatin targeting of the viral polymerase complex and the formation of cellular:viral RNA hybrids, which are essential RNA intermediates that license transcription of antisense genomic viral RNAs. Our results suggest that evolutionary arms races have shaped the cellular RNA quality control machinery.
Assuntos
Interações Hospedeiro-Patógeno , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Influenza Humana/virologia , RNA Polimerase II/metabolismo , Células A549 , Animais , Imunoprecipitação da Cromatina , Exorribonucleases/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Exossomos/metabolismo , Humanos , Espectrometria de Massas , Camundongos , Mutação , Doenças Neurodegenerativas/virologia , Proteínas de Ligação a RNA/genética , Ribossomos/genética , Transcrição GênicaRESUMO
Macrophages have protective roles in immunity to pathogens, tissue development, homeostasis and repair following damage. Maladaptive immunity and inflammation provoke changes in macrophage function that are causative of disease. Despite a historical wealth of knowledge about macrophages, recent advances have revealed unknown aspects of their development and function. Following development, macrophages are activated by diverse signals. Such tissue microenvironmental signals together with epigenetic changes influence macrophage development, activation and functional diversity, with consequences in disease and homeostasis. We discuss here how recent discoveries in these areas have led to a multidimensional concept of macrophage ontogeny, activation and function. In connection with this, we also discuss how technical advances facilitate a new roadmap for the isolation and analysis of macrophages at high resolution.
Assuntos
Ativação de Macrófagos/imunologia , Macrófagos , Animais , HumanosAssuntos
Imunidade Adaptativa , Tolerância Imunológica , Imunidade Inata , Memória Imunológica , Imunidade Adaptativa/imunologia , Animais , Vacina BCG/imunologia , Diferenciação Celular , Humanos , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , VacinaçãoRESUMO
Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8+ T cell-mediated immunity and promoted tolerogenic CD4+ regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6-specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance.
Assuntos
Sobrevivência de Enxerto/imunologia , Terapia de Imunossupressão , Inflamação/imunologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Transplante de Órgãos , Aloenxertos , Animais , Biomarcadores , Proteína HMGB1/genética , Tolerância Imunológica , Imunidade Inata , Memória Imunológica , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Serina-Treonina Quinases TOR/metabolismo , Vimentina/genéticaRESUMO
A hallmark of autoimmunity in murine models of lupus is the formation of germinal centers (GCs) in lymphoid tissues where self-reactive B cells expand and differentiate. In the host response to foreign antigens, follicular dendritic cells (FDCs) maintain GCs through the uptake and cycling of complement-opsonized immune complexes. Here, we examined whether FDCs retain self-antigens and the impact of this process in autoantibody secretion in lupus. We found that FDCs took up and retained self-immune complexes composed of ribonucleotide proteins, autoantibody, and complement. This uptake, mediated through CD21, triggered endosomal TLR7 and led to the secretion of interferon (IFN) α via an IRF5-dependent pathway. Blocking of FDC secretion of IFN-α restored B cell tolerance and reduced the amount of GCs and pathogenic autoantibody. Thus, FDCs are a critical source of the IFN-α driving autoimmunity in this lupus model. This pathway is conserved in humans, suggesting that it may be a viable therapeutic target in systemic lupus erythematosus.
Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Células Dendríticas Foliculares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Autoantígenos/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Interferon-alfa/biossíntese , Interferon-alfa/imunologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Reação em Cadeia da Polimerase , Receptor 7 Toll-Like/imunologia , TranscriptomaRESUMO
Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic ß-amyloid (Aß)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
Assuntos
Apolipoproteínas E/metabolismo , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais , Transcriptoma , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apoptose/genética , Apoptose/imunologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Análise por Conglomerados , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Marcação de Genes , Humanos , Tolerância Imunológica , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/imunologia , Monócitos/imunologia , Monócitos/metabolismo , Doenças Neurodegenerativas/imunologia , Neurônios/metabolismo , Fagocitose/genética , Fagocitose/imunologia , Fenótipo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells (PBMCs) with pre- and post-transplantation serum of kidney transplant patients, and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor (TNF) and interleukin-6 (IL-6) cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected one week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity, rarely experienced graft loss. This suppressive effect of post-transplant serum is likely mediated, by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
RESUMO
BACKGROUND AIMS: There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)-hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA- memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment. METHODS: Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 106/kg CD45RA- memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2-specific response within the CD45RA- memory T cells and the most frequent human leukocyte antigen typing in the Spanish population. RESULTS: We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events. CONCLUSIONS: Adoptive cell therapy with off-the-shelf CD45RA- memory T cells containing SAR-CoV-2-specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia. TRIAL REGISTRATION: NCT04578210.
Assuntos
COVID-19 , Linfopenia , Humanos , SARS-CoV-2 , COVID-19/terapia , Células T de Memória , Resultado do Tratamento , Linfopenia/terapia , AntiviraisRESUMO
Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic.
Assuntos
Moléculas de Adesão Celular/metabolismo , Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Receptores de Superfície Celular/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular/genética , Células Cultivadas , Fatores de Transcrição Forkhead/metabolismo , Rejeição de Enxerto/etiologia , Tolerância Imunológica , Interleucina-10/metabolismo , Lectinas Tipo C/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Receptores de Superfície Celular/genética , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Tolerância ao Transplante , Regulação para CimaRESUMO
BACKGROUND: To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK). METHODS: We did a phase 2, open-label, randomised, controlled trial on adults aged 18-60 years, vaccinated with a single dose of ChAdOx1-S 8-12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing. FINDINGS: Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 BAU/mL (7371·53-8161·96) at day 14 (p<0·0001). IgG against trimeric spike protein increased from 98·40 BAU/mL (95% CI 85·69-112·99) to 3684·87 BAU/mL (3429·87-3958·83). The interventional:control ratio was 77·69 (95% CI 59·57-101·32) for RBD protein and 36·41 (29·31-45·23) for trimeric spike protein IgG. Reactions were mild (n=1210 [68%]) or moderate (n=530 [30%]), with injection site pain (n=395 [88%]), induration (n=159 [35%]), headache (n=199 [44%]), and myalgia (n=194 [43%]) the most commonly reported adverse events. No serious adverse events were reported. INTERPRETATION: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile. FUNDING: Instituto de Salud Carlos III. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.
Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Imunização Secundária , Imunogenicidade da Vacina/imunologia , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos , Adolescente , Adulto , Vacina BNT162 , COVID-19/epidemiologia , ChAdOx1 nCoV-19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espanha/epidemiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto JovemRESUMO
Consistent induction of donor-specific unresponsiveness in the absence of continuous immunosuppressive therapy and toxic effects remains a difficult task in clinical organ transplantation. Transplant immunologists have developed numerous experimental treatments that target antigen-presentation (signal 1), costimulation (signal 2), and cytokine production (signal 3) to establish transplantation tolerance. While promising results have been obtained using therapeutic approaches that predominantly target the adaptive immune response, the long-term graft survival rates remain suboptimal. This suggests the existence of unrecognized allograft rejection mechanisms that contribute to organ failure. We postulate that trained immunity stimulatory pathways are critical to the immune response that mediates graft loss. Trained immunity is a recently discovered functional program of the innate immune system, which is characterized by nonpermanent epigenetic and metabolic reprogramming of macrophages. Since trained macrophages upregulate costimulatory molecules (signal 2) and produce pro-inflammatory cytokines (signal 3), they contribute to potent graft reactive immune responses and organ transplant rejection. In this review, we summarize the detrimental effects of trained immunity in the context of organ transplantation and describe pathways that induce macrophage training associated with graft rejection.
Assuntos
Rejeição de Enxerto/prevenção & controle , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Macrófagos/imunologia , Transplante de Órgãos/métodos , Imunologia de Transplantes/imunologia , Tolerância ao Transplante/imunologia , Animais , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , HumanosRESUMO
Although much is known about the migration of T cells from blood to lymph nodes, less is known about the mechanisms regulating the migration of T cells from tissues into lymph nodes through afferent lymphatics. Here we investigated T cell egress from nonlymphoid tissues into afferent lymph in vivo and developed an experimental model to recapitulate this process in vitro. Agonism of sphingosine 1-phosphate receptor 1 inhibited the entry of tissue T cells into afferent lymphatics in homeostatic and inflammatory conditions and caused the arrest, mediated at least partially by interactions of the integrin LFA-1 with its ligand ICAM-1 and of the integrin VLA-4 with its ligand VCAM-1, of polarized T cells at the basal surface of lymphatic but not blood vessel endothelium. Thus, the increased sphingosine 1-phosphate present in inflamed peripheral tissues may induce T cell retention and suppress T cell egress.
Assuntos
Vasos Linfáticos/imunologia , Lisofosfolipídeos/metabolismo , Modelos Imunológicos , Receptores de Lisoesfingolipídeo/imunologia , Esfingosina/análogos & derivados , Linfócitos T/imunologia , Animais , Movimento Celular , Endotélio Linfático/imunologia , Cloridrato de Fingolimode , Homeostase , Inflamação/imunologia , Integrina alfa4beta1/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Linfonodos/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Propilenoglicóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Transdução de Sinais , Esfingosina/metabolismo , Esfingosina/farmacologia , Molécula 1 de Adesão de Célula Vascular/imunologiaRESUMO
Dendritic cells (DCs) are specialized cells of the innate immune system that are characterized by their ability to take up, process and present antigens (Ag) to effector T cells. They are derived from DC precursors produced in the bone marrow. Different DC subsets have been described according to lineage-specific transcription factors required for their development and function. Functionally, DCs are responsible for inducing Ag-specific immune responses that mediate organ transplant rejection. Consequently, to prevent anti-donor immune responses, therapeutic strategies have been directed toward the inhibition of DC activation. In addition however, an extensive body of preclinical research, using transplant models in rodents and nonhuman primates, has established a central role of DCs in the negative regulation of alloimmune responses. As a result, DCs have been employed as cell-based immunotherapy in early phase I/II clinical trials in organ transplantation. Together with in vivo targeting through use of myeloid cell-specific nanobiologics, DC manipulation represents a promising approach for the induction of transplantation tolerance. In this review, we summarize fundamental characteristics of DCs and their roles in promotion of central and peripheral tolerance. We also discuss their clinical application to promote improved long-term outcomes in organ transplantation.
Assuntos
Células Dendríticas/imunologia , Tolerância Imunológica , Transplante de Órgãos , Tolerância ao Transplante , Animais , Linfócitos TRESUMO
Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI.
Assuntos
Imunossupressores/uso terapêutico , Preservação de Órgãos , Transplante de Órgãos , Traumatismo por Reperfusão/prevenção & controle , Animais , Humanos , Traumatismo por Reperfusão/imunologiaRESUMO
Costimulatory blockade-induced murine cardiac allograft survival requires intragraft accumulation of CD11b+ Ly6Clo Ly6G- regulatory myeloid cells (Mregs) that expand regulatory T cells (Tregs) and suppress effector T cells (Teffs). We previously showed that C5a receptor (C5aR1) signaling on T cells activates Teffs and inhibits Tregs, but whether and/or how C5aR1 affects Mregs required for transplant survival is unknown. Although BALB/c hearts survived >60 days in anti-CD154 (MR1)-treated or cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig-treated wild-type (WT) recipients, they were rejected at ~30 days in MR1-treated or CTLA4-Ig-treated recipients selectively deficient in C5aR1 restricted to myeloid cells (C5ar1fl/fl xLysM-Cre). This accelerated rejection was associated with ~2-fold more donor-reactive T cells and ~40% less expansion of donor-reactive Tregs. Analysis of graft-infiltrating mononuclear cells on posttransplant day 6 revealed fewer Ly6Clo monocytes in C5ar1fl/fl xLysM-Cre recipients. Expression profiling of intragraft Ly6Clo monocytes showed that C5aR1 deficiency downregulated genes related to migration/locomotion without changes in genes associated with suppressive function. Cotransfer of C5ar1fl/fl and C5ar1fl/fl xLysM-Cre myeloid cells into MR1-treated allograft recipients resulted in less accumulation of C5ar1-/- cells within the allografts, and in vitro assays confirmed that Ly6Chi myeloid cells migrate to C5a/C5aR1-initiated signals. Together, our results newly link myeloid cell-expressed C5aR1 to intragraft accumulation of myeloid cells required for prolongation of heart transplant survival induced by costimulatory blockade.
Assuntos
Abatacepte/imunologia , Antígeno CTLA-4/imunologia , Movimento Celular , Sobrevivência de Enxerto , Transplante de Coração/métodos , Células Supressoras Mieloides/imunologia , Receptor da Anafilatoxina C5a/metabolismo , Abatacepte/química , Abatacepte/metabolismo , Aloenxertos , Animais , Antígeno CTLA-4/metabolismo , Rejeição de Enxerto , Cardiopatias/imunologia , Cardiopatias/terapia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Receptor da Anafilatoxina C5a/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologiaRESUMO
Myeloid cells play a pivotal role in regulating innate and adaptive immune responses. In inflammation, autoimmunity, and after transplantation, myeloid cells have contrasting roles: on the one hand they initiate the immune response, promoting activation and expansion of effector T-cells, and on the other, they counter-regulate inflammation, maintain tissue homeostasis, and promote tolerance. The latter activities are mediated by several myeloid cells including polymorphonuclear neutrophils, macrophages, myeloid-derived suppressor cells, and dendritic cells. Since these cells have been associated with immune suppression and tolerance, they will be further referred to as myeloid regulatory cells (MRCs). In recent years, MRCs have emerged as a therapeutic target or have been regarded as a potential cellular therapeutic product for tolerance induction. However, several open questions must be addressed to enable the therapeutic application of MRCs including: how do they function at the site of inflammation, how to best target these cells to modulate their activities, and how to isolate or to generate pure populations for adoptive cell therapies. In this review, we will give an overview of the current knowledge on MRCs in inflammation, autoimmunity, and transplantation. We will discuss current strategies to target MRCs and to exploit their tolerogenic potential as a cell-based therapy.
Assuntos
Autoimunidade , Homeostase , Tolerância Imunológica , Inflamação/etiologia , Inflamação/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Animais , Biomarcadores , Suscetibilidade a Doenças , Humanos , Imunomodulação , Imunofenotipagem , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Transplante de Órgãos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transplante HomólogoRESUMO
The colony-stimulating factor 1 (CSF1) regulates the differentiation and function of tissue macrophages and determines the outcome of the immune response. The molecular mechanisms behind CSF1-mediated macrophage development remain to be elucidated. Here we demonstrate that neutrophil-derived CSF1 controls macrophage polarization and proliferation, which is necessary for the induction of tolerance. Inhibiting neutrophil production of CSF1 or preventing macrophage proliferation, using targeted nanoparticles loaded with the cell cycle inhibitor simvastatin, abrogates the induction of tolerance. These results provide new mechanistic insights into the developmental requirements of tolerogenic macrophages and identify CSF1 producing neutrophils as critical regulators of the immunological response.