scholarly journals Interleukin (IL)-10 Is an Effective Therapeutic for Murine Transfusion Related Acute Lung Injury (TRALI)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 92-92
Author(s):  
Rick Kapur ◽  
Michael Kim ◽  
Shanjee Shanmugabhavananthan ◽  
Jonathan Liu ◽  
Noel Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Mhc Class I ◽  
Lung Tissue ◽  
Cd4 T Cells ◽  
Class I ◽  
Second Hit ◽  
Tissue Histology

Abstract Transfusion related acute lung injury (TRALI) is the leading cause of transfusion-induced fatalities and is characterized by acute respiratory distress following blood transfusion. Donor antibodies present in the transfused blood product such as anti-human leukocyte antigen (HLA) or anti-human neutrophil antigen (HNA) antibodies are frequently involved. Currently, there is no treatment available for TRALI apart from supportive measures such as oxygen. The pathogenesis the disorder is incompletely understood, however, several animal models have contributed to our understanding of TRALI disease pathology. Most TRALI reactions are considered to be due to a two-hit paradigm where the first hit is a predisposing patient factor such as inflammation while the second hit is the transfusion. It is widely believed that the second hit delivers antibodies that trigger TRALI in the recipient. The anti-MHC class I antibody, 34-1-2s, has been widely used as an agent that delivers the second TRALI hit in mice. We have previously shown that CD4+ T cells, more specifically, CD4+CD25+FoxP3+ T-regulatory cells (Tregs) convey protection against TRALI (Blood. 126 (23):2342, 2015; abstract #82075, manuscript submitted). In the current study, we utilized a C57BL/6 mouse model of severe TRALI by first depleting mice of CD4+ T cells and then injecting them with the anti-MHC class I monoclonal antibodies (34-1-2s+AF6-88.5.5.3) and we examined the effects of the anti-inflammatory cytokine IL-10 on the antibody-mediated TRALI reaction. IL-10 (45 µg/kg iv) or volume-matched PBS was injected 15 minutes after the administration of anti-MHC antibodies when the onset of TRALI symptoms (e.g. a 2 degree drop in rectal temperature indicative of systemic shock) began. Results show that 90 minutes after anti-MHC class I antibody injection, control mice injected with PBS exhibited a high degree of pulmonary edema as assessed by significantly elevated lung wet-to-dry weight ratios (W/D: 5.84 ± 1.02). Pulmonary neutrophil levels were also found to be increased and lung tissue histology confirmed severe signs of acute lung injury. In contrast, mice injected with IL-10 completely recovered from TRALI; after 90 minutes post-antibody injection they displayed no signs of pulmonary edema (W/D: 4.76 ± 0.04, ** p<0.004 compared to mice injected with PBS) and no signs of severe acute lung injury as assessed by lung tissue histology. Pulmonary neutrophil levels, however, were equally increased in both groups indicating that although IL-10 rescues the mice from acute lung injury, it does not interfere with pulmonary neutrophil recruitment. Preliminary data suggests that IL-10 administration interferes with the ability of neutrophils to generate reactive oxygen species (ROS) that mediate lung injury. Our results suggest that IL-10 therapy significantly rescues an ongoing severe TRALI reaction and this may prove to be an effective and feasible therapeutic strategy in combating human TRALI. Disclosures No relevant conflicts of interest to declare.

scholarly journals Gastrointestinal Flora Dictates the Biological Response in Murine Transfusion Related Acute Lung Injury (TRALI)

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 766-766
Author(s):  
Rick Kapur ◽  
Michael Kim ◽  
Johan Rebetz ◽  
Alisa Takabe-French ◽  
Noel Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Antibiotic Treatment ◽  
Cd4 T Cells ◽  
Biological Response ◽  
Gut Flora ◽  
Lung Histology

Abstract Transfusion related acute lung injury (TRALI) is a syndrome of respiratory distress which occurs within 6 hours of blood transfusion. It is the leading cause of transfusion-related fatalities and the pathogenesis is incompletely understood. In the majority of the cases, anti-leukocyte antibodies present in the transfused blood product, in combination with recipient predisposing risk-factors such as inflammation, are implicated to be responsible for the onset of TRALI. Unfortunately, no therapies are available for TRALI. Recently, using novel murine models of TRALI, CD4+T cells were found to be important protector cells against antibody-mediated TRALI and administration of interleukin (IL)-10 was demonstrated to be a successful treatment strategy for TRALI, rescuing mice therapeutically from pulmonary edema, the hallmark of acute lung injury (Kapur et al, Blood 2017, 129(18):2557-2569). Whether the gut microbiome plays any role in the development of TRALI is currently unknown. For that purpose, we compared the biological TRALI response in mice housed in a barrier-free (BF) setting versus mice housed in a specific pathogen-free (SPF) environment. We utilized our TRALI model in which C57BL/6 mice were first depleted of CD4+ T cells in vivo followed by injection of anti-major histocompatibility complex class I antibodies (clones 34-1-2s and AF6-88.5.5.3). The TRALI response was analyzed after 90 minutes for several parameters including pulmonary edema (lung wet-to-dry weight ratios, W/Ds), rectal temperatures (indicative of systemic shock), plasma levels of macrophage inflammatory protein (MIP)-2 (murine homologue of IL-8, a neutrophil chemoattractant), levels of pulmonary neutrophils (major effector cells in TRALI) and lung histology. We observed that after one week of housing, baseline rectal temperatures of BF mice significantly increased from 38.7o C to 39.5° C (p&lt;0.001) while SPF mice remained stable around 38.3 °C. When comparing BF versus SPF mice, the baseline temperature of BF mice was significantly higher than SPF mice after one week of housing (P&lt;0.0001). The gut flora was subsequently depleted in BF mice via administration of broad-spectrum antibiotics through the drinking water. When both aerobic and anaerobic gut microbes were efficiently depleted after a week of antibiotic treatment, rectal temperatures of the treated BF mice significantly dropped again to 38.7 °C (P&lt;0.05). When inducing TRALI by depleting CD4+ T cells and injecting TRALI-antibodies, the rectal temperatures of the untreated BF mice remained low while the rectal temperatures of SPF mice and gut flora depleted-BF mice normalized again from 60 minutes onwards (34.9 versus 36.8 versus 37.8 °C, respectively). Moreover, the untreated BF mice suffered from TRALI while the SPF mice and the gut flora depleted-BF mice were protected from TRALI development (lung W/Ds 5.77 versus 4.63 versus 4.49, respectively) which was also evident from lung histology-analyses. The prevention of TRALI in SPF mice and gut flora depleted BF mice was paralleled by decreased plasma MIP-2 levels compared to the untreated BF mice which suffered from TRALI (MIP-2: 0.09 versus 0.08 versus 82.94 pg/ml, respectively) which also corresponded to pulmonary neutrophil numbers. As previously shown, low IL-10 levels were associated with TRALI development and IL-10 KO mice were found to be susceptible to antibody-mediated murine TRALI (without prior in vivo cell-depletion). However, when IL-10 KO mice were housed under SPF conditions and injected with TRALI-inducing antibodies, they did not display increased lung W/Ds levels compared to naïve SPF mice indicating that the gut flora precedes and dictates the biological TRALI response. These data collectively link the gut flora to the development of antibody-mediated TRALI in mice and antibiotic treatment prevents TRALI and may perhaps prevent the onset of human TRALI which may help in TRALI risk-assessment prior to transfusion. Disclosures Semple: Rigel: Consultancy; Novartis: Consultancy; Amgen: Consultancy; UCB: Consultancy.

Alloreactive CD8 T Cells Process and Present Acquired MHC Class I Alloantigen To Indirect Pathway Helper CD4 T Cells.

2014 ◽  
Vol 98 ◽  
pp. 310
Author(s):  
E. Wlodek ◽  
A. Jason ◽  
K. Saeb-Parsy ◽  
M. Chhubra ◽  
G. Pettigrew
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Class I ◽  
Indirect Pathway

T Cell Receptor Gene Transfer to Produce MHC Class I-Restricted CD4 Helper T Cells: Implications for Immunotherapy of Leukaemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5262-5262
Author(s):  
Emma Morris ◽  
Aristotle Tsallios ◽  
Gavin Bendle ◽  
Shao-an Xue ◽  
Hans Stauss
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd4 T Cells ◽  
Tumour Cells ◽  
Class I ◽  
Helper T Cells ◽  
Specific Response ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Irrelevant Peptide

Abstract CD4 helper T cells play a critical role in the anti-tumour immune response. Cytokines secreted by CD4 T cells can have a direct effect on tumour cells and provide help for CTL priming and effector function. In this study we tested if it was possible to generate MHC class I-restricted helper T cells by retroviral TCR gene transfer into CD4 lymphocytes. Methods: We used a TCR (utilising V11) that recognises the influenza virus A nucleoprotein (NP366–379) peptide in the context of murine Db MHC class I. Murine splenocytes were isolated from C57BL/6 mice (H2b) and activated with conconavalin A and IL-7, and after 48 hours transduced with the pMX-TCR-IRES-TCR retroviral vector. The transduced splenocytes were then cultured in the presence of IL2 for a further 48 hours before staining with anti-murine CD4, CD8 and V11 antibodies and sorting into CD4+ V11+ and CD8+ V11+ populations. Sorted cells were expanded for a further 48–72 hours prior to functional assays. Functional Assays: Purified TCR-transduced (TCR-Td) CD8+ cells and purified TCR-Td CD4+ cells were tested for IFN secretion in response to dendritic cells (DCs) pulsed with NP peptide, an irrelevant peptide (pMDM100) or no peptide. Further experiments examined IFN secretion in response to peptide-loaded tumour cells (EL4 murine lymphoma cells) or transfected tumour cells expressing NP endogenously. Secretion of IFN was measured by ELISA. Results: (1) Antigen-specific IFN secretion was observed by both CD8+ (100% purity) and CD4+ cells (99.93% purity) expressing the class I-restricted TCR when incubated with peptide-loaded DCs. When tested with no peptide or irrelevant peptide, no IFN secretion was observed. The CD8+ cells were more sensitive, recognizing lower concentrations of peptide (10pM) than CD4+ cells (100pM). With peptide-coated EL4 tumour cells as stimulator cells, CD8+ cells showed a peptide-specific response. In contrast, the TCR-Td CD4+ cells were only able to elicit a weak peptide-specific response. Similarly, TCR-Td CD8+ cells were able to recognise NP transfected EL4 tumour cells (EL4NP68), whereas the CD4+ cells were unable to. However, the addition of syngeneic DCs restored the CD4+ cell response to NP transfected EL4 tumour cells to one equivalent to that seen with the TCR-Td CD8+ populations (Table 1). Summary: We have demonstrated that it is feasible to generate MHC class I-restricted CD4+ helper T cells, that are specific for peptide epitopes presented in the context of MHC class I. The CD4+ T cells can recognise antigen-expressing tumour cells in the presence of professional APC, such as DCs. The mechanism by which APC restore tumour recognition may involve trans-costimulation or cross presentation. The data suggest that class I-restricted CD4+ T cells may be able to contribute to enhanced anti-tumour immunity. αββββγγγγγβ γIFN Secretion (ng/ml) After Stimulation with DCs or Tumour Cells T Cell (Responder Cell) Stimulator Cell/s No Peptide NP (100nM) pMDM100 (100nM) Abbreviations: ND not done; DC, EL4 and EL4NP68 as indicated in text. TCR-Td CD8+ DCs 0.1 163.2 0.7 TCR-Td CD8+ EL4 0.1 19.9 0.2 TCR-Td CD8+ EL4NP68 16.6 ND ND TCR-Td CD8+ EL4NP68 + DCs 31.2 ND ND TCR-Td CD4+ DCs 0.1 163.9 0.2 TCR-Td CD4+ EL4 0.1 0.8 0.0 TCR-Td CD4+ EL4NP68 0.2 ND ND TCR-Td CD4+ EL4NP68 + DCs 25.3 ND ND

MHC Class I Molecules on CD4 T Cells Regulate Receptor-Mediated Activation Signals

1999 ◽  
Vol 193 (1) ◽  
pp. 108-114 ◽  
Author(s):  
Zhi-qin Wang ◽  
Abhijit S. Bapat ◽  
Valia Trejo ◽  
Thorsten Orlikowsky ◽  
Robert S. Mittler ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd4 T Cells ◽  
Class I ◽  
Mhc Class I Molecules

scholarly journals Human MHC Class I-restricted high avidity CD4+T cells generated by co-transfer of TCR and CD8 mediate efficient tumor rejection in vivo

2013 ◽  
Vol 2 (1) ◽  
pp. e22590 ◽  
Author(s):  
Shao-An Xue ◽  
Liquan Gao ◽  
Maryam Ahmadi ◽  
Sara Ghorashian ◽  
Rafael D Barros ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd4 T Cells ◽  
Tumor Rejection ◽  
Class I ◽  
High Avidity

scholarly journals The Activation State of CD4 T Cells Alters Cellular Peptidase Activities, HIV Antigen Processing, and MHC Class I Presentation in a Sequence-Dependent Manner

2019 ◽  
Vol 202 (10) ◽  
pp. 2856-2872 ◽  
Author(s):  
Julie Boucau ◽  
Julien Madouasse ◽  
Georgio Kourjian ◽  
Christopher S. Carlin ◽  
Daniel Wambua ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd4 T Cells ◽  
Antigen Processing ◽  
Class I ◽  
Dependent Manner ◽  
Sequence Dependent ◽  
Hiv Antigen

Chronic and low-level particulate matter exposure can sustainably mediate lung damage and alter CD4 T cells during acute lung injury

2019 ◽  
Vol 112 ◽  
pp. 51-58 ◽  
Author(s):  
Yusheng Li ◽  
Tiancao Dong ◽  
Xiaoping Jiang ◽  
Chunmei Wang ◽  
Ying Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lung Injury ◽  
Particulate Matter ◽  
Lung Injury ◽  
Cd4 T Cells ◽  
Lung Damage ◽  
Low Level ◽  
Particulate Matter Exposure

scholarly journals Curcumin regulates the differentiation of naïve CD4+T cells and activates IL-10 immune modulation against acute lung injury in mice

2020 ◽  
Vol 125 ◽  
pp. 109946 ◽  
Author(s):  
Yu-sen Chai ◽  
Yan-qing Chen ◽  
Shi-hui Lin ◽  
Ke Xie ◽  
Chuan-jiang Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Cd4 T Cells ◽  
Immune Modulation

A Two-Event In Vivo Model of Transfusion-Related Acute Lung Injury.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 19-19 ◽  
Author(s):  
Christopher C. Silliman ◽  
Marguerite Kelher ◽  
Tomohiko Masuno ◽  
Ernest E. Moore ◽  
Sagar Damle ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Normal Saline ◽  
Class Ii ◽  
Class I ◽  
In Vivo Model ◽  
Blue Dye

Abstract TRALI is the most common cause of transfusion-related death in the US, and the pathogenesis is related to the infusion of donor anti-leukocyte antibodies or biologic response modifiers (BRMs) including lipids that accumulate during storage of cellular components. We hypothesize that TRALI is the result of two distinct events: the first related to the clinical condition of the patient resulting in pulmonary endothelial activation and sequestration of PMNs and the second is the infusion of antibodies or BRMs along with the transfused product. Methods: PRBCs were obtained from 5 donors and 50% were pre-storage leukoreduced by filtration and the other 50% left as a control, and both stored per AABB criteria. Plasma samples were obtained serially from these units and was heat-treated (56°C for 30 min) to destroy fibrinogen and complement prior to administration. Antibodies to antigens present on leukocytes from Sprague Dawley rats including MHC class I: OX18 & OX27, MHC class II: OX3 & OX6 and anti-granulocyte (PMN) antibodies were obtained commercially. Male rats were given saline (NS) or 2 mg/kg IP of endotoxin (LPS S.enteritidies, non-lethal), incubated for 2 hrs, anesthetized with pentobarbital, the femoral vessels were cannulated, and 10% of the blood volume was withdrawn over 15 min. Plasma from day 1 (10% final) and day 42 (5–10%) PRBCs and 10% LR-PRBCs, and 50 or 100 μg of antibodies (500μl of sera, anti-PMN) were infused over 30 min, followed by IV Evan’s Blue dye (30 mg/kg; 1ml) that binds to albumin. At 6 hours, plasma and bronchoalveolar lavage (BAL) fluid were obtained to determine the % of Evan’s Blue leak into the BAL at 620 nm. Mortality was < 5%. Acute lung injury (ALI) was precipitated in LPS-treated animals by day 42 PRBC plasma (5% & 10%), 10% day 42 LR-PRBC plasma and antibodies to MHC class I antigens (Table). With NS as the first event, rats did not evidence ALI for all groups, including MHC class I antibodies. Moreover, in LPS pre-treated rats, second events consisting of NS, day 0 PRBC, day 0 LR-PRBC plasma, antibodies to MHC class II antigens (OX3 & OX6) and anti-PMN antibodies did not elicit ALI (Table). We conclude that 1) this in vivo model approximates the mortality of the clinical condition, 2) it demonstrates that the pathogenesis requires two events to elicit antibody-induced or BRM-mediated TRALI, and 3) ALI as the result of LPS/MHC class I antibodies evidences a dose-response. ALI as a a Function of Evans Blue Dye Leak 1st Event ⇒ Normal Saline NS LPS 2nd Event ⇓ †=p<.05 vs. 1st event or 2nd event Normal Saline 0.08±0.03 0.24±0.11 MHC Class I OX18 50μg 0.06±0.06 0.18±0.03 MHC Class I OX18 100μg 0.17 1.91±0.7] MHC Class I OX27 50μg 0.19±0.04 1.26±0.1† MHC Class II OX3 50μg 0.07 0.4 MHC Class II OX6 50μg 0.07±0.07 0.2±0.07 Anti-Granulocyte serum 500μl 0.25±0.14 0.22±0.17 Anti-Granulocyte 100μg 0.174 0.09±.02 PRBCs day 1 [10%] 0.10±0.08 0.25±0.09 PRBCs day 42 [5%] 0.13±0.07 2.48±0.46† PRBCs day 42 [10%] 0.16±0.10 1.16±0.34† LR-PRBCs day 1 [10%] 0.16±0.09 0.19±0.05 LR-PRBCs day 42 [10%] 0.20±0.12 2.69±0.58†

Identification of a Two-Step Mechanism Responsible for Antibody-Mediated Transfusion Related Acute Lung Injury (TRALI)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 846-846
Author(s):  
Christopher G.J. McKenzie ◽  
Michael Kim ◽  
Tarandeep Singh ◽  
John W. Semple
Keyword(s):  
Reactive Oxygen Species ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Mhc Class I ◽  
Reactive Oxygen ◽  
Lung Damage ◽  
Class I ◽  
Oxygen Species ◽  
Neutrophil Accumulation

Abstract Abstract 846 Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion fatalities, and most TRALI reactions are thought to be caused by donor antibodies. It is currently thought that the donor antibodies activate pulmonary neutrophils to produce reactive oxygen species that damage lung tissue. There have been several animal models of TRALI developed including, for example, ex vivo lung models demonstrating the importance of human anti-neutrophil antibodies in TRALI, and in vivo models showing how biological response modifiers can induce recipient lung damage. An in vivo murine model of antibody-mediated TRALI was developed in 2006, and has also shown several similarities with human TRALI induction (Looney MR et al., J Clin Invest 116: 1615, 2006). Specifically, a monoclonal anti-mouse MHC class I antibody (34-1-2s) causes significant increases in excess lung water, lung vascular permeability and mortality within 2 hours after administration. These adverse reactions were found to be due to the antibody's ability to activate pulmonary neutrophils to produce reactive oxygen species (ROS) in an Fc receptor (FcR)-dependent manner. In contrast, however, it was recently shown that 34-1-2s induces pulmonary damage by activating macrophages to generate ROS in a complement (C5a)-dependent process (Strait RT J et al., Exp Med 208: 2525, 2011). In order to better understand this apparent controversy, we attempted to determine the nature of how 34-1-2s mediates its lung damaging properties. 34-1-2s was digested with pepsin or papain to produce F(ab')2 or Fc fragments respectively, and the fragments were tested for their ability to mediate TRALI reactions. In control mice, when intact 34-1-2s antibody was intravenously injected into either CB.17 mice with severe combined immunodeficiency or C5 deficient DBA/2 mice, increased shock, serum MIP-2 (murine equivalent to human IL-8) levels, pulmonary neutrophil accumulation, pulmonary edema and mortality all occurred within 2 hours. In contrast, however, injection with 34-1-2s F(ab')2 fragments was only able to generate MIP-2 production and pulmonary neutrophil accumulation; no lung damage or mortality occurred. Injection of 34-1-2s Fc fragments either alone or together with equal molar concentrations of F(ab')2 fragments failed to induce any lung damage or mortality. These results suggest that 34-1-2s recognition of it's cognate MHC class I antigen may be a priming reaction that stimulates MIP-2 and chemotaxis of neutrophils to the lungs, whereas the Fc portion of the intact molecule is responsible for the second step of exacerbating TRALI symptoms in a complement independent manner. Disclosures: No relevant conflicts of interest to declare.

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