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1.
Sci Transl Med ; 12(528)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996462

RESUMO

One quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Although most infected individuals successfully control or clear the infection, some individuals will progress to TB disease. Immune correlates identified using animal models are not always effectively translated to human TB, thus resulting in a slow pace of translational discoveries from animal models to human TB for many platforms including vaccines, therapeutics, biomarkers, and diagnostic discovery. Therefore, it is critical to improve our poor understanding of immune correlates of disease and protection that are shared across animal TB models and human TB. In this study, we have provided an in-depth identification of the conserved and diversified gene/immune pathways in TB models of nonhuman primate and diversity outbred mouse and human TB. Our results show that prominent differentially expressed genes/pathways induced during TB disease progression are conserved in genetically diverse mice, macaques, and humans. In addition, using gene-deficient inbred mouse models, we have addressed the functional role of individual genes comprising the gene signature of disease progression seen in humans with Mtb infection. We show that genes representing specific immune pathways can be protective, detrimental, or redundant in controlling Mtb infection and translate into identifying immune pathways that mediate TB immunopathology in humans. Together, our cross-species findings provide insights into modeling TB disease and the immunological basis of TB disease progression.

2.
Transfusion ; 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31880330

RESUMO

BACKGROUND: Conventional platelet (PLT) storage at room temperature under continuous agitation results in a limited shelf life (5 days) and an increased risk of bacterial contamination. However, both of these aspects can be ameliorated by cold storage. Preliminary work has suggested that PLTs can be cold stored for up to 3 weeks, while preserving their metabolic activity longer than in PLTs stored at room temperature. As such, in the present study, we hypothesized that the metabolic phenotypes of PLTs stored at 4°C for 3 weeks could be comparable to that of room temperature-stored PLTs at 22°C for 5 days. STUDY DESIGN AND METHODS: Metabolomics analyses were performed on nine apheresis PLT concentrates stored either at room temperature (22°C) for 5 days or refrigerated conditions (4°C) for up to 3 weeks. RESULTS: Refrigeration did not impact the rate of decline in glutamine or the intracellular levels of Krebs cycle metabolites upstream to fumarate and malate. It did, however, decrease oxidant stress (to glutathione and purines) and slowed down the activation of the pentose phosphate pathway, glycolysis, and fatty acid metabolism (acyl-carnitines). CONCLUSION: The overall metabolic phenotypes of 4°C PLTs at Storage Day 10 are comparable to PLTs stored at 22°C at the end of their 5-day shelf life, while additional changes in glycolysis, purine, and fatty acid metabolism are noted by Day 21.

3.
Blood Transfus ; 17(4): 321-330, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31385802

RESUMO

Reports from both adult and paediatric populations indicate that approximately two-thirds of platelet transfusions are used prophylactically to prevent bleeding, while the remaining one-third are used therapeutically to manage active bleeding. These two indications, prophylactic and therapeutic, serve two very distinct purposes and therefore will have two different functional requirements. In addition, disease aetiology in a given patient may require platelets with different functional characteristics. These characteristics can be derived from the various manufacturing methods used in platelet product production, including collection methods, processing methods, and storage options. The iterative combinations of manufacturing methods can result in a number of unique platelet products with different efficacy and safety profiles, which could potentially be used to benefit patient populations by meeting diverse clinical needs. In particular, cold storage of platelet products causes many biochemical and functional changes, of which the most notable characterised to date include increased haemostatic activity and altered expression of molecules inherent to platelet:leucocyte interactions. The in vivo consequences, both short- and long-term, of these molecular and cellular cold-storage-induced changes have yet to be clearly defined. Elucidation of these mechanisms would potentially reveal unique biologies that could be harnessed to provide more targeted therapies. To this end, in this new era of personalised medicine, perhaps there is an opportunity to provide individual patients with platelet products that are tailored to their clinical condition and the specific indication for transfusion.


Assuntos
Plaquetas/citologia , Preservação de Sangue/métodos , Hemostasia , Animais , Plaquetas/imunologia , Plaquetas/metabolismo , Comunicação Celular , Temperatura Baixa , Células Endoteliais/citologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Humanos , Leucócitos/citologia , Leucócitos/imunologia , Leucócitos/metabolismo , Transfusão de Plaquetas/métodos , Medicina de Precisão/métodos
4.
Hematol Oncol Clin North Am ; 33(5): 873-885, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31466610

RESUMO

Bleeding related to thrombocytopenia is common in hematology-oncology patients. Platelets stored at room temperature (RTPs) are the current standard of care. Platelets stored in the cold (CSPs) have enhanced hemostatic function relative to RTPs. CSPs were reported to reduce bleeding in hematology-oncology patients. Recent studies have confirmed the enhanced hemostatic properties of CSPs. CSPs may be the better therapeutic option for this population. CSPs may also offer a preferable immune profile, reduced thrombotic risk, and reduced transfusion-transmitted infection risk. The logistical advantages of CSPs would improve outcomes for many patients who currently cannot access platelet transfusions.

5.
Transfusion ; 59(S2): 1568-1577, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30980740

RESUMO

BACKGROUND: We set out to define the impact of collection, processing, and storage on plasma product microparticle (MP) abundance, potential for nitric oxide (NO) scavenging, and vasoactivity. STUDY DESIGN AND METHODS: Three currently US licensed products were tested: liquid plasma (LP), fresh frozen plasma (FFP), and solvent detergent plasma (SDP), along with a product under development, spray-dried solvent detergent plasma (SD-SDP) with/without beads. Vasoactivity was assessed in vitro using rabbit aortic vascular rings; MP abundance was determined by flow cytometry; and NO scavenging capacity/rate was determined using a biochemical NO consumption assay. All samples were analyzed unprocessed and following centrifugation at two speeds (2,500× g to remove platelets, and 25,000× g to remove microparticles). RESULTS: Significant differences in vasoactivity were observed, with SD-SDP minus beads demonstrating the greatest constriction and FFP the lowest constriction response. All products exhibited the same total NO scavenging capacity; however, significant differences were observed in the maximal rate of scavenging, with SD-SDP minus beads and FFP reacting fastest and SDP the slowest. Across all products, platelet and microparticle depletion had no effect on vasoactivity or NO scavenging (total or rate). Microparticles (RBC derived) were found only in FFP and LP, with relative abundance (LP > FFP). Additionally, storage had no effect on total or RBC-derived MP abundance, NO scavenging, or vasoactivity. CONCLUSION: Although vasoactivity differed between plasma products, we did not find similar differences in either total or RBC-derived MP abundance or NO scavenging capacity/rate.


Assuntos
Aorta/metabolismo , Preservação de Sangue , Micropartículas Derivadas de Células/química , Eritrócitos/química , Depuradores de Radicais Livres , Plasma/química , Vasoconstritores , Animais , Aorta/fisiopatologia , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Humanos , Óxido Nítrico/metabolismo , Coelhos , Vasoconstritores/química , Vasoconstritores/farmacologia
6.
Transfusion ; 59(S2): 1539-1548, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30980757

RESUMO

BACKGROUND: There is renewed interest in the use of whole blood (WB) for resuscitation of patients in hemorrhagic shock. Leukoreduction with platelet-sparing filters and pathogen reduction may be used to improve the safety profile of WB, yet the effects of leukoreduction and pathogen reduction on WB hemostatic function are not well characterized. STUDY DESIGN AND METHODS: Blood from 32 healthy group O donors was divided into treatment groups (n = 8 for each group): untreated, pathogen reduced (PR+ ), leukoreduced using an in-line filter (LR+ ), or PR+ LR+ . Units were stored without agitation for 21 days between 1° and 6°C, with sampling on days 0 (pre- and post-treatments), 1, 3, 5, 10, 15, and 21 for hemostatic function as assessed by thromboelastometry, thrombin generation, platelet activation factors, and platelet impedance aggregometry. RESULTS: From day 3 (D3) to D15 of storage, platelet count was reduced in PR+ /LR+ units compared to PR- /LR- units. From D10 to D21 of storage, maximum clot firmness (MCF) was reduced in PR+ /LR+ units compared to PR- /LR- units. From D3 to D21 of storage, platelet aggregation was reduced in PR+ /LR+ units compared to PR- /LR- units. Total thrombin generation was similar in all groups from D0 to D21. CONCLUSIONS: The combination of LR with a platelet-sparing filter and PR significantly reduces hemostatic function compared to either treatment alone or untreated WB. The clinical consequences of LR and PR of WB in patients with severe bleeding should be examined in trials before both are used in combination in patients.


Assuntos
Plaquetas/metabolismo , Preservação de Sangue/métodos , Segurança do Sangue/métodos , Procedimentos de Redução de Leucócitos/métodos , Agregação Plaquetária , Plaquetas/patologia , Transfusão de Sangue , Feminino , Hemorragia/sangue , Hemorragia/patologia , Hemorragia/terapia , Humanos , Masculino , Ressuscitação , Choque Hemorrágico/sangue , Choque Hemorrágico/patologia , Choque Hemorrágico/terapia , Tromboelastografia
7.
J Pediatr Surg ; 54(8): 1613-1616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30270118

RESUMO

BACKGROUND: In trauma research, accurate estimates of mortality that can be rapidly calculated prior to enrollment are essential to ensure appropriate patient selection and adequate sample size. This study compares the accuracy of the BIG (Base Deficit, International normalized ratio and Glasgow Coma scale) score in predicting mortality in pediatric trauma patients to Pediatric Risk of Mortality III (PRISM III) score, Pediatric Index of Mortality 2 (PIM2) score and Pediatric Logistic Organ Dysfunction (PELOD) score. METHODS: Data were collected from Virtual Pediatric Systems (VPS, LLC) database for children between 2004 and 2015 from 149 PICUs. Logistic regression models were developed to evaluate mortality prediction. The Area under the Curve (AUC) of Receiver Operator Characteristic (ROC) curves were derived from these models and compared between scores. RESULTS: A total of 45,377 trauma patients were analyzed. The BIG score could only be calculated for 152 patients (0.33%). PRISM III, PIM2, and PELOD scores were calculated for 44,360, 45,377 and 14,768 patients respectively. The AUC of the BIG score was 0.94 compared to 0.96, 0.97 and 0.93 for the PRISM III, PIM2, and PELOD respectively. CONCLUSIONS: The BIG score is accurate in predicting mortality in pediatric trauma patients. LEVEL OF EVIDENCE: Level I prognosis.


Assuntos
Ferimentos e Lesões , Criança , Humanos , Modelos Logísticos , Curva ROC , Índices de Gravidade do Trauma , Ferimentos e Lesões/epidemiologia , Ferimentos e Lesões/mortalidade , Ferimentos e Lesões/fisiopatologia
8.
Transpl Int ; 31(7): 761-772, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29537702

RESUMO

Complement-mediated allograft injury, elicited by donor-specific HLA antibodies (DSA), is a defining pathophysiological characteristic of allograft damage. We aimed to study DSA-induced complement activation as a diagnostic marker of antibody-mediated rejection (AMR) and a risk stratification tool for graft loss in the context of lung transplantation (LT). We identified 38 DSA-positive patients whose serum samples were submitted for C3d deposition testing via the C3d assay. Among these 38 patients, 15 had AMR (DSAPos AMRPos ). Results were reported for each patient as the C3d ratio for each DSA, the immunodominant DSA, and the C3d ratio for all DSA present in a sample (C3d ratioSUM ). DSAPos AMRPos patients had higher C3d ratioSUM values (58.66 (-1.32 to 118.6) vs. 1.52 (0.30 to 2.74), P = 0.0016) and increased immunodominant C3d ratios (41.87 (1.72 to 82.02) vs. 0.69 (0.21 to 1.19), P = 0.001) when compared with DSAPos AMRNeg patients. Specificity and calculated positive predictive value of the immunodominant C3d ratio and BCMsum tests for AMR diagnosis were both 100% (CI = 17.4-100) in this cohort. Worst graft survival was associated with both immunodominant C3d ratio ≥4 or C3d ratioSUM ≥10 or BCMsum >7000, suggesting that the antibody composition and/or strength are the principal determinants of an HLA DSA's capacity to activate complement.


Assuntos
Complemento C3d/análise , Via Clássica do Complemento/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Transplante de Pulmão , Adulto , Estudos de Coortes , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Front Med (Lausanne) ; 4: 155, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29075627

RESUMO

Although donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) are frequently found in recipients after lung transplantation (LT), the characteristics of DSA which influence antibody-mediated rejection (AMR) in LT are not fully defined. We retrospectively analyzed 206 consecutive LT patients of our center (2010-2013). DSAs were detected by using luminex single antigen beads assay and mean fluorescence intensity was assessed. Within the study population, 105 patients had positive DSA. Patients with and without AMR (AMRPos, n = 22, and AMRNeg, n = 83, respectively) were compared. AMRPos patients had significantly greater frequencies of anti-HLA DQ DSA (DQ DSA) than AMRNeg patients (95 vs 58%, respectively, p < 0.0001). Compared to AMRNeg patients, AMRPos patients had higher DQ DSA sum MFI [7,332 (2,067-10,213) vs 681 (0-1,887), p < 0.0001]. DQ DSA when associated with AMR, had more frequent graft loss and chronic lung allograft dysfunction (CLAD). These data suggest (i) that DSA characteristics clearly differ between AMRPos and AMRNeg patients and (ii) the deleterious impact of DQ DSA on clinical outcome.

10.
Transplantation ; 101(7): 1559-1572, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28640789

RESUMO

BACKGROUND: Antibody-mediated rejection (AMR) of most solid organs is characterized by evidence of complement activation and/or intragraft macrophages (C4d + and CD68+ biopsies). We previously demonstrated that crosslinking of HLA I by antibodies triggered endothelial activation and monocyte adhesion. We hypothesized that activation of the classical complement pathway at the endothelial cell surface by HLA antibodies would enhance monocyte adhesion through soluble split product generation, in parallel with direct endothelial activation downstream of HLA signaling. METHODS: Primary human aortic endothelial cells (HAEC) were stimulated with HLA class I antibodies in the presence of intact human serum complement. C3a and C5a generation, endothelial P-selectin expression, and adhesion of human primary and immortalized monocytes (Mono Mac 6) were measured. Alternatively, HAEC or monocytes were directly stimulated with purified C3a or C5a. Classical complement activation was inhibited by pretreatment of complement with an anti-C1s antibody (TNT003). RESULTS: Treatment of HAEC with HLA antibody and human complement increased the formation of C3a and C5a. Monocyte recruitment by human HLA antibodies was enhanced in the presence of intact human serum complement or purified C3a or C5a. Specific inhibition of the classical complement pathway using TNT003 or C1q-depleted serum significantly reduced adhesion of monocytes in the presence of human complement. CONCLUSIONS: Despite persistent endothelial viability in the presence of HLA antibodies and complement, upstream complement anaphylatoxin production exacerbates endothelial exocytosis and leukocyte recruitment. Upstream inhibition of classical complement may be therapeutic to dampen mononuclear cell recruitment and endothelial activation characteristic of microvascular inflammation during AMR.


Assuntos
Anticorpos Monoclonais/farmacologia , Adesão Celular/efeitos dos fármacos , Inativadores do Complemento/farmacologia , Via Clássica do Complemento/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Antígenos HLA-A/imunologia , Imunossupressores/farmacologia , Monócitos/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Complemento C3a/farmacologia , Complemento C5a/farmacologia , Relação Dose-Resposta a Droga , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Exocitose/efeitos dos fármacos , Antígenos HLA-A/metabolismo , Humanos , Antígeno de Macrófago 1/imunologia , Antígeno de Macrófago 1/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Selectina-P/imunologia , Selectina-P/metabolismo
11.
J Immunol Res ; 2017: 7903471, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28373996

RESUMO

Consistent with Dr. Paul Terasaki's "humoral theory of rejection" numerous studies have shown that HLA antibodies can cause acute and chronic antibody mediated rejection (AMR) and decreased graft survival. New evidence also supports a role for antibodies to non-HLA antigens in AMR and allograft injury. Despite the remarkable efforts by leaders in the field who pioneered single antigen bead technology for detection of donor specific antibodies, a considerable amount of work is still needed to better define the antibody attributes that are associated with AMR pathology. This review highlights what is currently known about the clinical context of pre and posttransplant antibodies, antibody characteristics that influence AMR, and the paths after donor specific antibody production (no rejection, subclinical rejection, and clinical dysfunction with AMR).


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Fatores Imunológicos/imunologia , Isoanticorpos/imunologia , Humanos , Transplante de Rim , Doadores de Tecidos , Transplante Homólogo
12.
J Leukoc Biol ; 100(1): 177-84, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26753760

RESUMO

The triggering receptor expressed on myeloid cell locus encodes a family of receptors that is emerging as an important class of molecules involved in modulating the innate immune response and inflammation. Of the 4 conserved members, including triggering receptor expressed on myeloid cells 1 and 2 and triggering receptor expressed on myeloid cell-like transcripts 1 and 2, relatively little is known about triggering receptor expressed on myeloid cell-like transcript 2 expression and function, particularly in humans. In this study, experiments were performed to determine if triggering receptor expressed on myeloid cell-like transcript 2 expression is conserved between mouse and human, demonstrating that human triggering receptor expressed on myeloid cell-like transcript 2 is expressed on cells of the lymphoid, as well as myeloid/granuloid lineages, similar to murine triggering receptor expressed on myeloid cell-like transcript 2. Consistent with studies in the mouse, triggering receptor expressed on myeloid cell-like transcript 2 expression is up-regulated in response to inflammatory mediators on human neutrophils. Importantly, it was shown that triggering receptor expressed on myeloid cell-like transcript 2, in resting human neutrophils, is predominantly localized to intracellular vesicles, including secretory vesicles and primary granules; with the majority of triggering receptor expressed on myeloid cell-like transcript 2 stored in primary granules. In contrast to other primary granule proteins, triggering receptor expressed on myeloid cell-like transcript 2 is not expelled on neutrophil extracellular traps but is retained in the plasma membrane following primary granule exocytosis. In summary, these findings establish that triggering receptor expressed on myeloid cell-like transcript 2 expression is conserved between species and is likely to be important in regulating neutrophil antimicrobial function following primary granule exocytosis.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade Inata/imunologia , Mediadores da Inflamação/farmacologia , Inflamação/imunologia , Neutrófilos/imunologia , Receptores Imunológicos/metabolismo , Vesículas Secretórias/metabolismo , Células Cultivadas , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptores Imunológicos/imunologia , Vesículas Secretórias/efeitos dos fármacos , Vesículas Secretórias/imunologia
13.
Trends Mol Med ; 21(5): 319-29, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25801125

RESUMO

The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multifaceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLAs). Despite the clearly detrimental impact of HLA antibodies (HLA-Abs) on graft function and survival, the prevention, diagnosis, and treatment of AMR remain a challenge. The histological manifestations of AMR reflect the signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient leukocytic infiltrate, and complement deposition. We review the interconnected mechanisms of HLA-Ab-mediated injury that might synergize in a 'perfect storm' of inflammation. Characterization of antibody features that are critical for effector functions may help to identify HLA-Abs that are more likely to cause rejection. We also highlight recent advances that may pave the way for new, more effective therapies.


Assuntos
Anticorpos/imunologia , Proteínas do Sistema Complemento/imunologia , Endotélio/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Receptores de IgG/imunologia , Animais , Humanos
14.
J Immunol ; 187(5): 2346-55, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21804015

RESUMO

Receptors encoded within the Trem locus have been shown to play an important role in modulating the cellular response to pattern recognition receptor signaling. TREM-like transcript 2 (TLT2) is a member of the Trem locus that is conserved in mouse and human. TLT2 exhibits a unique expression pattern in that it is expressed on cells of the myeloid and lymphoid lineage, suggesting that it plays a role in both innate and adaptive immunity. In this work, studies reveal that TLT2 plays an important role in potentiating neutrophil antibacterial activity and chemotaxis. TLT2 ligation enhances the neutrophil response to the formylated peptide FMLF, leading to increased reactive oxygen species production, degranulation, and chemotaxis. Moreover, TLT2 has the ability to specifically potentiate neutrophil activation and chemotaxis in response to a range of agonists that bind to G protein-coupled receptors, as it does not potentiate the response of cells to growth factor receptor-, Fc receptor-, or TLR-mediated signaling. Finally, TLT2 ligation potentiates the recruitment of neutrophils to sites of inflammation in vivo. These findings reveal a novel functional role for TLT2 that involves potentiation of neutrophil responses to G protein-coupled receptor signaling. Thus, TLT2 appears to play an important role in enhancing the innate immune response via a novel molecular mechanism.


Assuntos
Quimiotaxia de Leucócito/imunologia , Neutrófilos/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Receptores Imunológicos/imunologia , Transdução de Sinais/imunologia , Animais , Separação Celular , Citometria de Fluxo , Imunidade Inata/imunologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ativação de Neutrófilo/imunologia , Neutrófilos/metabolismo
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