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Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.
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Enfermedad Injerto contra Huésped , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/microbiología , Animales , Ratones , Ratones Endogámicos C57BL , Linfocitos T CD4-Positivos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Microbiota/inmunología , Selección Clonal Mediada por Antígenos , Trasplante Homólogo , Teorema de Bayes , Trasplante de Células Madre/efectos adversos , Ratones Endogámicos BALB C , Microbioma Gastrointestinal/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy.
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Antígenos CD28 , Redes Reguladoras de Genes , Factor 2 Asociado a Receptor de TNF/genética , Factor 2 Asociado a Receptor de TNF/metabolismo , Antígenos CD28/metabolismo , Transducción de Señal , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Ligando CD27/genética , Ligando CD27/metabolismo , Linfocitos T CD8-positivosRESUMEN
BACKGROUND: Equine-assisted services (EAS) involves the use of horses within therapy, learning or horsemanship sessions and has been used with military veterans suffering from post-traumatic stress disorder (PTSD). This study systematically reviewed existing research on the use of EAS in the treatment of PTSD in military veterans and evaluated its effectiveness. METHODS: A systematic review was performed, in May 2023, with searches and data extraction carried out from three separate databases (PubMed, JSTOR and Science Direct) related to testing the effect of EAS on PTSD outcomes in veterans. A risk of bias assessment of included studies was conducted and meta-analysis of outcomes performed when two or more studies reported the same outcomes. Other effects of EAS on veterans' health were also discussed. RESULTS: A total of 13 studies were identified based on our inclusion and exclusion criteria with 11 originating from the US and the remaining two from Australia and Israel. There were 344 participants amongst all of the studies with a mean age of 47 years and a male:female ratio of 19:6. Eight out of the 13 studies reported PTSD scores, as measured by either PTSD Checklist for DSM-5 (PCL-5) or PCL-Veteran/-Military versions (PCL-V/-M), and results suggested a reduction in PTSD score after EAS treatment of 22.6%. A meta-analysis confirmed that EAS favored a significantly lower PTSD score after treatment, with a mean difference of 12.46, 95% CI [9.03,15.88], p < 0.00001. However, only one study had low risk of bias whilst all the rest of the studies had some concerns to high risk of bias. CONCLUSIONS: EAS appeared to have a positive influence on PTSD symptoms in military veterans, significantly reducing PTSD severity scores. Other benefits of EAS may be peer support, social integration, learning new skills and bonding. However, the results of this systematic review must be interpreted with caution as almost all of the studies were of low quality. Therefore, further rigorous research is required with larger participants to be able to draw conclusions about the benefits of EAS on PTSD severity.
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Terapía Asistida por Caballos , Trastornos por Estrés Postraumático , Veteranos , Animales , Femenino , Humanos , Masculino , Terapía Asistida por Caballos/métodos , Caballos , Trastornos por Estrés Postraumático/terapia , Trastornos por Estrés Postraumático/psicología , Veteranos/psicología , Persona de Mediana EdadRESUMEN
Traumatic injury to the brain and spinal cord (neurotrauma) is a common event across populations and often causes profound and irreversible disability. Pathophysiological responses to trauma exacerbate the damage of an index injury, propagating the loss of function that the central nervous system (CNS) cannot repair after the initial event is resolved. The way in which function is lost after injury is the consequence of a complex array of mechanisms that continue in the chronic phase post-injury to prevent effective neural repair. This review summarises the events after traumatic brain injury (TBI) and spinal cord injury (SCI), comprising a description of current clinical management strategies, a summary of known cellular and molecular mechanisms of secondary damage and their role in the prevention of repair. A discussion of current and emerging approaches to promote neuroregeneration after CNS injury is presented. The barriers to promoting repair after neurotrauma are across pathways and cell types and occur on a molecular and system level. This presents a challenge to traditional molecular pharmacological approaches to targeting single molecular pathways. It is suggested that novel approaches targeting multiple mechanisms or using combinatorial therapies may yield the sought-after recovery for future patients.
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BACKGROUND: The paucity of tumor-specific targets for chimeric antigen receptor (CAR) T-cell therapy of solid tumors necessitates careful preclinical evaluation of the therapeutic window for candidate antigens. Human epidermal growth factor receptor 2 (HER2) is an attractive candidate for CAR T-cell therapy in humans but has the potential for eliciting on-target off-tumor toxicity. We developed an immunocompetent tumor model of CAR T-cell therapy targeting murine HER2 (mHER2) and examined the effect of CAR affinity, T-cell dose, and lymphodepletion on safety and efficacy. METHODS: Antibodies specific for mHER2 were generated, screened for affinity and specificity, tested for immunohistochemical staining of HER2 on normal tissues, and used for HER2-targeted CAR design. CAR candidates were evaluated for T-cell surface expression and the ability to induce T-cell proliferation, cytokine production, and cytotoxicity when transduced T cells were co-cultured with mHER2+ tumor cells in vitro. Safety and efficacy of various HER2 CARs was evaluated in two tumor models and normal non-tumor-bearing mice. RESULTS: Mice express HER2 in the same epithelial tissues as humans, rendering these tissues vulnerable to recognition by systemically administered HER2 CAR T cells. CAR T cells designed with single-chain variable fragment (scFvs) that have high-affinity for HER2 infiltrated and caused toxicity to normal HER2-positive tissues but exhibited poor infiltration into tumors and antitumor activity. In contrast, CAR T cells designed with an scFv with low-affinity for HER2 infiltrated HER2-positive tumors and controlled tumor growth without toxicity. Toxicity mediated by high-affinity CAR T cells was independent of tumor burden and correlated with proliferation of CAR T cells post infusion. CONCLUSIONS: Our findings illustrate the disadvantage of high-affinity CARs for targets such as HER2 that are expressed on normal tissues. The use of low-affinity HER2 CARs can safely regress tumors identifying a potential path for therapy of solid tumors that exhibit high levels of HER2.
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Inmunoterapia Adoptiva , Linfocitos T , Ratones , Humanos , Animales , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Ratones EndogámicosRESUMEN
BACKGROUND: Diversion of cerebrospinal fluid (CSF) is a common neurosurgical procedure for control of intracranial pressure (ICP) in the acute phase after traumatic brain injury (TBI), where medical management is insufficient. CSF can be drained via an external ventricular drain (EVD) or, in selected patients, via a lumbar (external lumbar drain [ELD]) drainage catheter. Considerable variability exists in neurosurgical practice on their use. METHODS: A retrospective service evaluation was completed for patients receiving CSF diversion for ICP control after TBI, from April 2015 to August 2021. Patients were included whom fulfilled local criteria deeming them suitable for either ELD/EVD. Data were extracted from patient notes, including ICP values pre/postdrain insertion and safety data including infection or clinically/radiologically diagnosed tonsillar herniation. RESULTS: Forty-one patients were retrospectively identified (ELD = 30 and EVD = 11). All patients had parenchymal ICP monitoring. Both modalities affected statistically significant decreases in ICP, with relative reductions at 1, 6, and 24 hour pre/postdrainage (at 24-hour ELD P < 0.0001, EVD P < 0.01). Similar rates of ICP control failure, blockage and leak occurred in both groups. A greater proportion of patients with EVD were treated for CSF infection than with ELD. One event of clinical tonsillar herniation is reported, which may have been in part attributable to ELD overdrainage, but which did not result in adverse outcome. CONCLUSIONS: The data presented demonstrate that EVD and ELD can be successful in ICP control after TBI, with ELD limited to carefully selected patients with strict drainage protocols. The findings support prospective study to formally determine the relative risk-benefit profiles of CSF drainage modalities in TBI.
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Lesiones Traumáticas del Encéfalo , Hipertensión Intracraneal , Humanos , Estudios Retrospectivos , Encefalocele , Estudios Prospectivos , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/cirugía , Hipertensión Intracraneal/etiología , Hipertensión Intracraneal/cirugía , Drenaje/métodos , Presión IntracranealRESUMEN
Traumatic brain injury (TBI) is a significant global health problem, for which no disease-modifying therapeutics are currently available to improve survival and outcomes. Current neuromonitoring modalities are unable to reflect the complex and changing pathophysiological processes of the acute changes that occur after TBI. Raman spectroscopy (RS) is a powerful, label-free, optical tool which can provide detailed biochemical data in vivo. A systematic review of the literature is presented of available evidence for the use of RS in TBI. Seven research studies met the inclusion/exclusion criteria with all studies being performed in pre-clinical models. None of the studies reported the in vivo application of RS, with spectral acquisition performed ex vivo and one performed in vitro. Four further studies were included that related to the use of RS in analogous brain injury models, and a further five utilised RS in ex vivo biofluid studies for diagnosis or monitoring of TBI. RS is identified as a potential means to identify injury severity and metabolic dysfunction which may hold translational value. In relation to the available evidence, the translational potentials and barriers are discussed. This systematic review supports the further translational development of RS in TBI to fully ascertain its potential for enhancing patient care.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Lesiones Traumáticas del Encéfalo/diagnóstico , Humanos , Espectrometría RamanRESUMEN
Considerable variation exists in the clinical practice of cerebrospinal fluid diversion for medically refractory intracranial hypertension in patients with acute traumatic brain injury (TBI), which is achievable via lumbar or ventricular drainage. This systematic review sought to compile the available evidence for the efficacy and safety of the use of lumbar drains for intracranial pressure (ICP) control. A systematic review of the literature was performed with the search and data extraction performed by two reviewers independently in duplicate. Nine independent studies were identified, enrolling 230 patients, 159 with TBI. Efficacy for ICP control was observed across all studies, with immediate and sustained effect, reducing medical therapy requirements. Lumbar drainage with medical therapy appears effective when used alone and as an adjunct to ventricular drainage. Safety reporting varied in quality. Clinical or radiological incidents of cerebral herniation (with an unclear relationship to lumbar drainage) were observed in 14/230 patients resulting in one incident of morbidity without adverse patient outcome. The available data is generally poor in quality and volume, but supportive of the efficacy of lumbar drainage for ICP control. Few reports of adverse outcomes are suggestive of, but are insufficient to confirm, the safety of use in the appropriate patient and clinical setting. Further large prospective observational studies are required to generate sufficient support of an acceptable safety profile.
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Introduction Diversion of cerebrospinal fluid (CSF) in a traumatic brain injury (TBI) is an established means for achieving control of intracranial pressure (ICP), aimed at improving intracranial homeostasis. The literature and anecdotal reports suggest a variation in practice between neurosurgical centres internationally, with current guidelines advocating ventricular drainage over lumbar drainage. We sought to establish the current neurosurgical practice in the United Kingdom regarding the methods of ICP control in TBI. Methods A 20-point survey was distributed electronically to British and Irish neurosurgeons after ratification by the Society of British Neurological Surgeons. Questions were directed at the clinician's opinion and experience of lumbar drain usage in patients with TBI: frequency, rationale, and experience of complications. Questions on lumbar drain usage in neurovascular patients were asked for practice comparison. Results Thirty-six responses from 21 neurosurgical centres were returned. Twenty-three per cent (23%) of responders reported using lumbar drains for refractory ICP in TBI patients: six units use lumbar drains and 15 do not. Three units showed partial usage, with mixed "yes/no" responses between consultants. Concerns of tonsillar herniation and familiarity with EVD were commonly given reasons against the usage of lumbar drains. Fifty-six per cent (56%) reported use in neurovascular patients. Conclusion This contemporary practice survey demonstrates mixed practice across the UK and within some centres. Responses and survey feedback demonstrate that the use of lumbar drains in TBI is a polarising topic. The variety of practice between and within neurosurgical units supports consideration of the prospective study of CSF diversion methods for control of refractory ICP in patients with TBI.
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Apoptotic cell death within the brain represents a significant contributing factor to impaired post-traumatic tissue function and poor clinical outcome after traumatic brain injury. After irradiation with light in the wavelength range of 600-1200 nm (photobiomodulation), previous investigations have reported a reduction in apoptosis in various tissues. This study investigates the effect of 660 nm photobiomodulation on organotypic slice cultured hippocampal tissue of rats, examining the effect on apoptotic cell loss. Tissue optical Raman spectroscopic changes were evaluated. A significantly higher proportion of apoptotic cells 62.8±12.2% vs 48.6±13.7% (P<0.0001) per region were observed in the control group compared with the photobiomodulation group. After photobiomodulation, Raman spectroscopic observations demonstrated 1440/1660 cm-1 spectral shift. Photobiomodulation has the potential for therapeutic utility, reducing cell loss to apoptosis in injured neurological tissue, as demonstrated in this in vitro model. A clear Raman spectroscopic signal was observed after apparent optimal irradiation, potentially integrable into therapeutic light delivery apparatus for real-time dose metering.
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Lesiones Traumáticas del Encéfalo , Terapia por Luz de Baja Intensidad , Animales , Apoptosis , Encéfalo , Lesiones Traumáticas del Encéfalo/metabolismo , Hipocampo/metabolismo , Terapia por Luz de Baja Intensidad/métodos , Ratas , Espectrometría RamanRESUMEN
Although neurons in the adult mammalian CNS are inherently incapable of regeneration after injury, we previously showed that exogenous delivery of pigment epithelium-derived factor (PEDF), a 50-kDa neurotrophic factor (NTF), promoted adult retinal ganglion cell neuroprotection and axon regeneration. Here, we show that PEDF and other elements of the PEDF pathway are highly upregulated in dorsal root ganglion neurons (DRGN) from regenerating dorsal column (DC) injury paradigms when compared with non-regenerating DC injury models. Exogenous PEDF was neuroprotective to adult DRGN and disinhibited neurite outgrowth, whilst overexpression of PEDF after DC injury in vivo promoted significant DC axon regeneration with enhanced electrophysiological, sensory, and locomotor function. Our findings reveal that PEDF is a novel NTF for adult DRGN and may represent a therapeutically useful factor to promote functional recovery after spinal cord injury.
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Axones/fisiología , Proteínas del Ojo/farmacología , Factores de Crecimiento Nervioso/farmacología , Regeneración Nerviosa/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Serpinas/farmacología , Traumatismos de la Médula Espinal/fisiopatología , Animales , Axones/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Neuroprotección/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores de Factor de Crecimiento Nervioso/metabolismo , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiopatología , Transducción de Señal/efectos de los fármacos , Traumatismos de la Médula Espinal/patología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Pilocytic astrocytoma is a benign glial tumor typically presenting in children. It is rare for adults to present with pilocytic astrocytoma and even less likely to manifest with multiple foci of lesions especially in nonoptic or hypothalamic locations. CASE DESCRIPTION: Our patient was a 37-year old man presenting with varied cranial neuropathies, cerebellar dysfunction, and long tract signs, with imaging demonstrating 3 discrete ill-defined contrast-enhancing lesions affecting the cerebellar peduncles, brainstem, and cervicomedullary junction. Neuronavigation-guided biopsy confirmed World Health Organization grade 1 pilocytic astrocytoma; the patient was treated with radiotherapy. CONCLUSIONS: To our knowledge, we believe this is the first reported case with multifocal infratentorial pilocytic astrocytoma on presentation in an adult patient in the absence of a prior history of associated risk factors such as neurofibromatosis 1 or chemoradiotherapeutic intervention.
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Astrocitoma/diagnóstico por imagen , Neoplasias Infratentoriales/diagnóstico por imagen , Neoplasias Primarias Múltiples/diagnóstico por imagen , Adulto , Astrocitoma/patología , Astrocitoma/radioterapia , Neoplasias del Tronco Encefálico/diagnóstico por imagen , Neoplasias del Tronco Encefálico/patología , Neoplasias del Tronco Encefálico/radioterapia , Neoplasias Cerebelosas/diagnóstico por imagen , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/radioterapia , Humanos , Biopsia Guiada por Imagen , Neoplasias Infratentoriales/patología , Neoplasias Infratentoriales/radioterapia , Imagen por Resonancia Magnética , Masculino , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/radioterapia , Neuronavegación , RadioterapiaRESUMEN
Cortical spreading depolarization (CSD) is an emerging mode of secondary neuronal damage in acute brain injury (ABI). Subsequent repolarisation is a metabolic process requiring glucose. Instances of CSD and glucose derangement are both linked to poor neurological outcome, but their causal inter-relationship is not fully defined. This systematic review seeks to evaluate the available human evidence studying CSD and glucose to further understand their dynamic relationship. We conducted a systematic review of studies examining CSD through electrocorticography and cerebral/systemic glucose concentrations in ABI, excluding animal studies. The search yielded 478 articles, of which 13 were eligible. Across 10 manuscripts, 125 patients received simultaneous monitoring, with 1987 CSD episodes observed. Eight of 10 studies observed correlation between CSD and glucose change. Seven of eight studies observed possible cumulative effect of recurrent CSD on glucose derangement and two identified correlation between glycopenia and incidence of CSD. These findings confirm a relationship between CSD and glucose, and suggest it may be cyclical, where CSD causes local glycopenia, which may potentiate further CSD. Positive observations were not common to all studies, likely due to differing methodology or heterogeneity in CSD propensity. Further study is required to delineate the utility of the clinical modulation of serum and cerebral glucose to alter the propensity for CSD following brain injury.
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Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/fisiopatología , Depresión de Propagación Cortical/fisiología , Glucosa/metabolismo , HumanosRESUMEN
Cerebral autoregulatory dysfunction after traumatic brain injury (TBI) is strongly linked to poor global outcome in patients at 6 months after injury. However, our understanding of the drivers of this dysfunction is limited. Genetic variation among individuals within a population gives rise to single-nucleotide polymorphisms (SNPs) that have the potential to influence a given patient's cerebrovascular response to an injury. Associations have been reported between a variety of genetic polymorphisms and global outcome in patients with TBI, but few studies have explored the association between genetic variants and cerebrovascular function after injury. In this Review, we explore polymorphisms that might play an important part in cerebral autoregulatory capacity after TBI. We outline a variety of SNPs, their biological substrates and their potential role in mediating cerebrovascular reactivity. A number of candidate polymorphisms exist in genes that are involved in myogenic, endothelial, metabolic and neurogenic vascular responses to injury. Furthermore, polymorphisms in genes involved in inflammation, the central autonomic response and cortical spreading depression might drive cerebrovascular reactivity. Identification of candidate genes involved in cerebral autoregulation after TBI provides a platform and rationale for further prospective investigation of the link between genetic polymorphisms and autoregulatory function.