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1.
Integr Comp Biol ; 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39122659

RESUMO

Birds exhibit a variety of migration strategies. Because sustained flapping flight requires the production of elevated levels of energy compared to typical daily activities, migratory birds are well-documented to have several physiological adaptations to support the energy demands of migration. However, even though mitochondria are the source of ATP that powers flight, the respiratory performance of the mitochondria is almost unstudied in the context of migration. We hypothesized that migratory species would have higher mitochondrial respiratory performance during migration compared to species that do not migrate. To test this hypothesis, we compared variables related to mitochondrial respiratory function between two confamilial bird species-the migratory Gray Catbird (Dumetella carolinensis) and the non-migratory Northern Mockingbird (Mimus polyglottos). Birds were captured at the same location along the Alabama Gulf Coast, where we assumed that Gray Catbirds were migrants and where resident Northern Mockingbirds live year-round. We found a trend in citrate synthase activity, which suggests that Gray Catbirds have a greater mitochondrial volume in their pectoralis muscle, but we observed no other differences in mitochondrial respiration or complex enzymatic activities between individuals from the migrant versus the non-migrant species. However, when we assessed the catbirds included in our study using well-established indicators of migratory physiology, birds fell into two groups: a group with physiological parameters indicating a physiology of birds engaged in migration and a group with the physiology of birds not migrating. Thus, our comparison included catbirds that appeared to be outside of migratory condition. When we compared the mitochondrial performance of these three groups, we found that the mitochondrial respiratory capacity of migrating catbirds was very similar to that of Northern Mockingbirds, while the catbirds judged to be not migrating were lowest. One explanation for these observations is these species display very different daily flight behaviors. While the mockingbirds we sampled were not breeding nor migrating, they are highly active birds, living in the open and engaging in flapping flights throughout each day. In contrast, Gray Catbirds live in shrubs and fly infrequently when not migrating. Such differences in baseline energy needs likely confounded our attempt to study adaptations to migration.

2.
Blood Adv ; 8(17): 4568-4580, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-38924728

RESUMO

ABSTRACT: Cytomegalovirus (CMV) disease occurs occasionally before allogeneic hematopoietic cell transplantation (HCT) and is associated with poor post-HCT outcomes; however, the impact of pre-HCT CMV reactivation is unknown. Pre-HCT CMV reactivation was assessed in HCT candidates from the preemptive antiviral therapy (2007-2017) and letermovir prophylaxis (2018-2021) eras. CMV DNA polymerase chain reaction (PCR) surveillance was routinely performed during the pre-HCT workup period, and antiviral therapy was recommended according to risk of progression to CMV disease. Risk factors for pre-HCT CMV reactivation were characterized, and the associations of pre-HCT CMV reactivation with post-HCT outcomes were examined using logistic regression and Cox proportional hazard models, respectively. A total of 1694 patients were identified, and 11% had pre-HCT CMV reactivation 14 days (median; interquartile range [IQR], 6-23) before HCT. Lymphopenia (≤0.3 × 103/µL) was the strongest risk factor for pre-HCT CMV reactivation at multiple PCR levels. In the preemptive therapy era, patients with pre-HCT CMV reactivation had a significantly increased risk of CMV reactivation by day 100 as well as CMV disease and death by 1 year after HCT. Clearance of pre-HCT CMV reactivation was associated with a lower risk of post-HCT CMV reactivation. Similar associations with post-HCT CMV end points were observed in a cohort of patients receiving letermovir prophylaxis. Pre-HCT CMV reactivation can be routinely detected in high-risk HCT candidates and is a significant risk factor for post-HCT CMV reactivation and disease. Pre-HCT CMV DNA PCR surveillance is recommended in high-risk HCT candidates, and antiviral therapy may be indicated to prevent post-HCT CMV reactivation.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Ativação Viral , Humanos , Infecções por Citomegalovirus/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fatores de Risco , Masculino , Citomegalovirus/fisiologia , Pessoa de Meia-Idade , Feminino , Adulto , Antivirais/uso terapêutico , Idoso
3.
J Clin Invest ; 134(11)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38828727

RESUMO

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.


Assuntos
Inibidores de Calcineurina , Doença Enxerto-Hospedeiro , Isoantígenos , Células T de Memória , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/patologia , Animais , Camundongos , Isoantígenos/imunologia , Inibidores de Calcineurina/farmacologia , Doença Crônica , Células T de Memória/imunologia , Tacrolimo/farmacologia , Linfócitos T CD4-Positivos/imunologia , Ciclosporina/farmacologia , Feminino , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia
4.
Immunity ; 57(7): 1648-1664.e9, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38876098

RESUMO

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.


Assuntos
Doença Enxerto-Hospedeiro , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/microbiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T CD4-Positivos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Microbiota/imunologia , Seleção Clonal Mediada por Antígeno , Transplante Homólogo , Teorema de Bayes , Transplante de Células-Tronco/efeitos adversos , Camundongos Endogâmicos BALB C , Microbioma Gastrointestinal/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos
5.
Sci Immunol ; 9(94): eadg1094, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38640253

RESUMO

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ+ TPHEX. We also observed IFN-γ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. An IFN-γ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ+ TPHEX represent a potential target for immunotherapy of blood cancers.


Assuntos
Neoplasias Hematológicas , Mieloma Múltiplo , Humanos , Receptor Celular 2 do Vírus da Hepatite A , Mieloma Múltiplo/metabolismo , Linfócitos T CD8-Positivos , Fenótipo , Microambiente Tumoral
6.
J Clin Invest ; 134(7)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38557487

RESUMO

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.


Assuntos
Transplante de Medula Óssea , Infecções por Citomegalovirus , Imunidade Humoral , Interleucina-6 , Antivirais , Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Imunoglobulina G , Interleucina-6/metabolismo , Animais , Camundongos
7.
Sci Rep ; 14(1): 9456, 2024 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658588

RESUMO

Migration is one of the most energy-demanding behaviors observed in birds. Mitochondria are the primary source of energy used to support these long-distance movements, yet how mitochondria meet the energetic demands of migration is scarcely studied. We quantified changes in mitochondrial respiratory performance in the White-crowned Sparrow (Zonotrichia leucophrys), which has a migratory and non-migratory subspecies. We hypothesized that the long-distance migratory Gambel's subspecies (Z. l. gambelii) would show higher mitochondrial respiratory performance compared to the non-migratory Nuttall's subspecies (Z. l. nuttalli). We sampled Gambel's individuals during spring pre-migration, active fall migration, and a period with no migration or breeding (winter). We sampled Nuttall's individuals during periods coinciding with fall migration and the winter period of Gambel's annual cycle. Overall, Gambel's individuals had higher citrate synthase, a proxy for mitochondrial volume, than Nuttall's individuals. This was most pronounced prior to and during migration. We found that both OXPHOS capacity (state 3) and basal respiration (state 4) of mitochondria exhibit high seasonal flexibility within Gambel's individuals, with values highest during active migration. These values in Nuttall's individuals were most similar to Gambel's individuals in winter. Our observations indicate that seasonal changes in mitochondrial respiration play a vital role in migration energetics.


Assuntos
Migração Animal , Mitocôndrias , Pardais , Animais , Migração Animal/fisiologia , Pardais/fisiologia , Mitocôndrias/metabolismo , Estações do Ano , Fosforilação Oxidativa , Respiração Celular , Metabolismo Energético
8.
J Exp Biol ; 227(9)2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38634224

RESUMO

In many species of animals, red carotenoid-based coloration is produced by metabolizing yellow dietary pigments, and this red ornamentation can be an honest signal of individual quality. However, the physiological basis for associations between organism function and the metabolism of red ornamental carotenoids from yellow dietary carotenoids remains uncertain. A recent hypothesis posits that carotenoid metabolism depends on mitochondrial performance, with diminished red coloration resulting from altered mitochondrial aerobic respiration. To test for an association between mitochondrial respiration and red carotenoids, we held wild-caught, molting male house finches in either small bird cages or large flight cages to create environmental challenges during the period when red ornamental coloration is produced. We predicted that small cages would present a less favorable environment than large flight cages and that captivity itself would decrease both mitochondrial performance and the abundance of red carotenoids compared with free-living birds. We found that captive-held birds circulated fewer red carotenoids, showed increased mitochondrial respiratory rates, and had lower complex II respiratory control ratios - a metric associated with mitochondrial efficiency - compared with free-living birds, though we did not detect a difference in the effects of small cages versus large cages. Among captive individuals, the birds that circulated the highest concentrations of red carotenoids had the highest mitochondrial respiratory control ratio for complex II substrate. These data support the hypothesis that the metabolism of red carotenoid pigments is linked to mitochondrial aerobic respiration in the house finch, but the mechanisms for this association remain to be established.


Assuntos
Carotenoides , Tentilhões , Mitocôndrias , Animais , Carotenoides/metabolismo , Masculino , Tentilhões/fisiologia , Tentilhões/metabolismo , Mitocôndrias/metabolismo , Respiração Celular , Consumo de Oxigênio
9.
Cytotherapy ; 26(7): 719-728, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38530690

RESUMO

BACKGROUND AIMS: Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity. METHODS: We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs. RESULTS: We showed that Tregs could be enriched to 87- 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136-732×106 gene-marked cells, sufficient for a cell dose of at least 2 × 106 cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro, but a small percentage could secrete proinflammatory cytokines, including interferon-γ and interleukin-17A. CONCLUSIONS: This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response.


Assuntos
Citometria de Fluxo , Fatores de Transcrição Forkhead , Linfócitos T Reguladores , Linfócitos T Reguladores/imunologia , Humanos , Citometria de Fluxo/métodos , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Separação Celular/métodos , Vetores Genéticos/genética
12.
Nat Commun ; 15(1): 542, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38228644

RESUMO

Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of BALs, 49% of which also have HHV-6B mRNA detection. We establish HHV-6B DNA viral load thresholds in BALF that are highly predictive of HHV-6B mRNA detection and associated with increased risk for overall mortality and death from respiratory failure. Participants with HHV-6B DNA in BALF exhibit distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 6 , Pneumonia , Infecções por Roseolovirus , Humanos , Herpesvirus Humano 6/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estudos Prospectivos , Infecções por Roseolovirus/genética , Transcriptoma , DNA , Pneumonia/complicações , RNA Mensageiro
13.
Blood Adv ; 8(8): 2032-2043, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38295282

RESUMO

ABSTRACT: Autophagy is an intracellular survival process that has established roles in the long-term survival and function of hematopoietic stem cells (HSC). We investigated the contribution of autophagy to HSC fitness during allogeneic transplantation and graft-versus-host disease (GVHD). We demonstrate in vitro that both tumor necrosis factor and IL-1ß, major components of GVHD cytokine storm, synergistically promote autophagy in both HSC and their more mature hematopoietic progenitor cells (HPC). In vivo we demonstrate that autophagy is increased in donor HSC and HPC during GVHD. Competitive transplant experiments demonstrated that autophagy-deficient cells display reduced capacity to reconstitute the hematopoietic system compared to wild-type counterparts. In a major histocompatibility complex-mismatched model of GVHD and associated cytokine dysregulation, we demonstrate that autophagy-deficient HSC and progenitors fail to establish durable hematopoiesis, leading to primary graft failure and universal transplant related mortality. Using several different models, we confirm that autophagy activity is increased in early progenitor and HSC populations in the presence of T-cell-derived inflammatory cytokines and that these HSC populations require autophagy to survive. Thus, autophagy serves as a key survival mechanism in HSC and progenitor populations after allogeneic stem cell transplant and may represent a therapeutic target to prevent graft failure during GVHD.


Assuntos
Autofagia , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Camundongos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Modelos Animais de Doenças , Transplante Homólogo , Rejeição de Enxerto , Citocinas/metabolismo
14.
Blood ; 143(16): 1656-1669, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38295333

RESUMO

ABSTRACT: Autologous stem cell transplantation (ASCT) is the standard of care consolidation therapy for eligible patients with myeloma but most patients eventually progress, an event associated with features of immune escape. Novel approaches to enhance antimyeloma immunity after ASCT represent a major unmet need. Here, we demonstrate that patient-mobilized stem cell grafts contain high numbers of effector CD8 T cells and immunosuppressive regulatory T cells (Tregs). We showed that bone marrow (BM)-residing T cells are efficiently mobilized during stem cell mobilization (SCM) and hypothesized that mobilized and highly suppressive BM-derived Tregs might limit antimyeloma immunity during SCM. Thus, we performed ASCT in a preclinical myeloma model with or without stringent Treg depletion during SCM. Treg depletion generated SCM grafts containing polyfunctional CD8 T effector memory cells, which dramatically enhanced myeloma control after ASCT. Thus, we explored clinically tractable translational approaches to mimic this scenario. Antibody-based approaches resulted in only partial Treg depletion and were inadequate to recapitulate this effect. In contrast, a synthetic interleukin-2 (IL-2)/IL-15 mimetic that stimulates the IL-2 receptor on CD8 T cells without binding to the high-affinity IL-2Ra used by Tregs efficiently expanded polyfunctional CD8 T cells in mobilized grafts and protected recipients from myeloma progression after ASCT. We confirmed that Treg depletion during stem cell mobilization can mitigate constraints on tumor immunity and result in profound myeloma control after ASCT. Direct and selective cytokine signaling of CD8 T cells can recapitulate this effect and represent a clinically testable strategy to improve responses after ASCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/patologia , Linfócitos T Reguladores , Transplante de Células-Tronco Hematopoéticas/métodos , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante Autólogo , Transplante de Células-Tronco
15.
Blood ; 143(10): 912-929, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38048572

RESUMO

ABSTRACT: Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognized, in which brain-infiltrating donor major histocompatibility complex (MHC) class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early after transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients, in which CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signaling after transplant failed to reverse GVHD-induced behavioral changes. Moreover, we observed aberrant behavior in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Animais , Doenças Neuroinflamatórias , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos T CD4-Positivos , Macrófagos/patologia , Receptores Proteína Tirosina Quinases , Receptores de Fator Estimulador de Colônias
17.
Transplant Cell Ther ; 29(11): 696.e1-696.e7, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37634844

RESUMO

The use of granulocyte colony-stimulating factor (G-CSF) after autologous stem cell transplantation (ASCT) has been shown to reduce the time to neutrophil engraftment, as well as the duration of hospitalization post-transplantation. However, prior studies have focused on inpatient-based ASCT, where patients are routinely admitted for conditioning and frequently remain hospitalized until signs of neutrophil recovery. Given improvements in post-transplantation care, an increasing number of patients, particularly those receiving ASCT for multiple myeloma, are now undergoing transplantation in an outpatient setting. We hypothesized that the routine use of G-CSF for outpatient-based ASCT might not result in the same benefit with respect to a reduced duration of hospitalization and thus should be reconsidered in this setting. We performed a retrospective cohort study of 633 consecutive patients with multiple myeloma (MM; n = 484) or non-Hodgkin lymphoma (NHL; n = 149) who underwent ASCT between September 2018 and February 2023. Outpatient ASCT comprised 258 (53%) of combined MM and NHL cases. Starting in September 2021, post-transplantation G-CSF was incorporated into the supportive care regimen for all ASCTs. A total of 410 patients (309 with MM, 101 with NHL) underwent ASCT during the pre-G-CSF policy period and 223 (175 with MM, 48 with NHL) did so in the post-G-CSF policy period. The primary outcome focused on the duration of hospitalization within the first 30 days following graft infusion. As expected, after implementation of the G-CSF policy, the time to neutrophil engraftment was reduced in the patients with MM (mean, -2.8 days; P < .0001) and patients with NHL (mean, -2.9 days; P < .0001). However, among the patients with MM, roughly one-half of whom underwent outpatient-based ASCT, the inpatient duration during the first 30 days was not reduced after G-CSF implementation (P = .40). Comparatively, the inpatient duration (mean, -1.8 days; P = .030) was reduced among patients with NHL, all of whom were electively admitted for ASCT. For patients with MM at an outpatient-based transplant center, incorporation of G-CSF post-ASCT resulted in reduced time to neutrophil engraftment but did not significantly reduce the time spent in the inpatient setting through day +30.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin , Mieloma Múltiplo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Transplante Autólogo/métodos , Pacientes Ambulatoriais , Estudos Retrospectivos , Linfoma não Hodgkin/terapia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico
18.
Biol Rev Camb Philos Soc ; 98(6): 2320-2332, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37563787

RESUMO

Even as numerous studies have documented that the red and yellow coloration resulting from the deposition of carotenoids serves as an honest signal of condition, the evolution of condition dependency is contentious. The resource trade-off hypothesis proposes that condition-dependent honest signalling relies on a trade-off of resources between ornamental display and body maintenance. By this model, condition dependency can evolve through selection for a re-allocation of resources to promote ornament expression. By contrast, the index hypothesis proposes that selection focuses mate choice on carotenoid coloration that is inherently condition dependent because production of such coloration is inexorably tied to vital cellular processes. These hypotheses for the origins of condition dependency make strongly contrasting and testable predictions about ornamental traits. To assess these two models, we review the mechanisms of production of carotenoids, patterns of condition dependency involving different classes of carotenoids, and patterns of behavioural responses to carotenoid coloration. We review evidence that traits can be condition dependent without the influence of sexual selection and that novel traits can show condition-dependent expression as soon as they appear in a population, without the possibility of sexual selection. We conclude by highlighting new opportunities for studying condition-dependent signalling made possible by genetic manipulation and expression of ornamental traits in synthetic biological systems.


Assuntos
Carotenoides , Pigmentação , Carotenoides/metabolismo , Pigmentação/fisiologia
19.
Immunity ; 56(8): 1876-1893.e8, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37480848

RESUMO

Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic stem cell transplantation (SCT), and severe intestinal manifestation is the major cause of early mortality. Intestinal microbiota control MHC class II (MHC-II) expression by ileal intestinal epithelial cells (IECs) that promote GVHD. Here, we demonstrated that genetically identical mice of differing vendor origins had markedly different intestinal microbiota and ileal MHC-II expression, resulting in discordant GVHD severity. We utilized cohousing and antibiotic treatment to characterize the bacterial taxa positively and negatively associated with MHC-II expression. A large proportion of bacterial MHC-II inducers were vancomycin sensitive, and peri-transplant oral vancomycin administration attenuated CD4+ T cell-mediated GVHD. We identified a similar relationship between pre-transplant microbes, HLA class II expression, and both GVHD and mortality in a large clinical SCT cohort. These data highlight therapeutically tractable mechanisms by which pre-transplant microbial taxa contribute to GVHD independently of genetic disparity.


Assuntos
Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Camundongos , Animais , Vancomicina , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante Homólogo/efeitos adversos
20.
Mucosal Immunol ; 16(5): 606-623, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37321403

RESUMO

Type I regulatory (Tr1) cells are defined as FOXP3-IL-10-secreting clusters of differentiation (CD4+) T cells that contribute to immune suppression and typically express the markers LAG-3 and CD49b and other co-inhibitory receptors. These cells have not been studied in detail in the context of the resolution of acute infection in the lung. Here, we identify FOXP3- interleukin (IL)-10+ CD4+ T cells transiently accumulating in the lung parenchyma during resolution of the response to sublethal influenza A virus (IAV) infection in mice. These cells were dependent on IL-27Rα, which was required for timely recovery from IAV-induced weight loss. LAG-3 and CD49b were not generally co-expressed by FOXP3- IL-10+ CD4+ T cells in this model and four populations of these cells based on LAG-3 and CD49b co-expression were apparent [LAG-3-CD49b- (double negative), LAG-3+CD49b+ (double positive), LAG-3+CD49b- (LAG-3+), LAG-3-CD49b+ (CD49b+)]. However, each population exhibited suppressive potential consistent with the definition of Tr1 cells. Notably, differences between these populations of Tr1 cells were apparent including differential dependence on IL-10 to mediate suppression and expression of markers indicative of different activation states and terminal differentiation. Sort-transfer experiments indicated that LAG-3+ Tr1 cells exhibited the capacity to convert to double negative and double positive Tr1 cells, indicative of plasticity between these populations. Together, these data determine the features and suppressive potential of Tr1 cells in the resolution of IAV infection and identify four populations delineated by LAG-3 and CD49b, which likely correspond to different Tr1 cell activation states.

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