Differential response induced by LPS and MPLA in immunocompetent and septic individuals

Vega, Chloé Albert; Karakike, Eleni; Bartolo, Francois; Mouton, William; Cerrato, Elisabeth; Brengel‐Pesce, Karen; Giamarellos‐Bourboulis, Evangelos J.; Mallet, François; Trouillet‐Assant, Sophie

doi:10.1016/j.clim.2021.108714

Cited by 9 publications

(7 citation statements)

References 28 publications

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“…For many diseases and therapies, the most relevant perturbome is the response induced in peripheral blood mononuclear cells by stimulation with inflammatory drivers. For example, acquisition of a so-called “endotoxin tolerant” phenotype in monocytes derived from patients with sepsis or acute respiratory distress syndrome is marked by reduced TNFα production in response to ex vivo stimulation with LPS 22 – 24 . This monocyte anergy phenotype can be used to stratify patients and predict mortality 25 and therapeutic restoration of function 26 .…”

Section: Discussionmentioning

confidence: 99%

Peripheral blood mononuclear cell phenotype and function are maintained after overnight shipping of whole blood

Johnson

Overlee

Sagen

et al. 2022

Sci Rep

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Same day processing of biospecimens such as blood is not always feasible, which presents a challenge for research programs seeking to study a broad population or to characterize patients with rare diseases. Recruiting sites may not be equipped to process blood samples and variability in timing and technique employed to isolate peripheral blood mononuclear cells (PBMCs) at local sites may compromise reproducibility across patients. One solution is to send whole blood collected by routine phlebotomy via overnight courier to the testing site under ambient conditions. Determining the impact of shipping on subsequent leukocyte responses is a necessary prerequisite to any experimental analysis derived from transported samples. To this end, whole blood was collected from healthy control subjects and processed fresh or at 6, 24 and 48 h after collection and handling under modeled shipping conditions. At endpoint, whole blood was assessed via a complete blood count with differential and immunophenotyped using a standardized panel of antibodies [HLADR, CD66b, CD3, CD14, CD16]. PBMCs and neutrophils were isolated from whole blood and subjected to ex vivo stimulation with lipopolysaccharide and heat-killed Staphylococcus aureus. Stimulated release of cytokines and chemokines was assessed by cytometric bead array. RNA was also isolated from PBMCs to analyze transcriptional changes induced by shipping. The complete blood count with differential revealed that most parameters were maintained in shipped blood held for 24 h at ambient temperature. Immunophenotyping indicated preservation of cellular profiles at 24 h, although with broadening of some populations and a decrease in CD16 intensity on classical monocytes. At the transcriptional level, RNAseq analysis identified upregulation of a transcription factor module associated with inflammation in unstimulated PBMCs derived from whole blood shipped overnight. However, these changes were limited in both scale and number of impacted genes. Ex vivo stimulation of PBMCs further revealed preservation of functional responses in cells isolated from shipped blood held for 24 h at ambient temperature. However, neutrophil responses were largely abrogated by this time. By 48 h neither cell population responded within normal parameters. These findings indicate that robust immunophenotyping and PBMC stimulated response profiles are maintained in whole blood shipped overnight and processed within 24 h of collection, yielding results that are representative of those obtained from the sample immediately following venipuncture. This methodology is feasible for many patient recruitment sites to implement and allows for sophisticated immunological analysis of patient populations derived from large geographic areas. With regard to rare disease research, this meets a universal need to enroll patients in sufficient numbers for immunoprofiling and discovery of underlying pathogenic mechanisms.

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Section: Discussionmentioning

confidence: 99%

Peripheral blood mononuclear cell phenotype and function are maintained after overnight shipping of whole blood

Johnson

Overlee

Sagen

et al. 2022

Sci Rep

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“…In humans, bacterial-derived LPS results in toxicities that limit its use. MPLA is a TLR4 agonist derived from LPS that retains the immunostimulatory characteristics of LPS but results in less toxicity ( 70 ). MPLA is an FDA approved cancer vaccine adjuvant.…”

Section: Combination Strategies To Improve Cancer Vaccinesmentioning

confidence: 99%

Fueling Cancer Vaccines to Improve T Cell-Mediated Antitumor Immunity

Hernandez

Malek

2022

Front. Oncol.

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Cancer vaccines offer the potential to enhance T cell-mediated antitumor immunity by expanding and increasing the function of tumor-specific T cells and shaping the recall response against recurring tumors. While the use of cancer vaccines is not a new immunotherapeutic approach, the cancer vaccine field continues to evolve as new antigen types emerge and vaccine formulations and delivery strategies are developed. As monotherapies, cancer vaccines have not been very efficacious in part due to pre-existing peripheral- and tumor-mediated tolerance mechanisms that limit T cell function. Over the years, various agents including Toll-like receptor agonists, cytokines, and checkpoint inhibitors have been employed as vaccine adjuvants and immune modulators to increase antigen-mediated activation, expansion, memory formation, and T effector cell function. A renewed interest in this approach has emerged as better neoepitope discovery tools are being developed and our understanding of what constitutes an effective cancer vaccine is improved. In the coming years, cancer vaccines will likely be vital to enhance the response to current immunotherapies. In this review, we discuss the various types of therapeutic cancer vaccines, including types of antigens and approaches used to enhance cancer vaccine responses such as TLR agonists, recombinant interleukin-2 and interleukin-2 derivatives, and checkpoint inhibitors.

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“…As early as 1986, MPLA was found to be a highly effective and low-toxic alternative to the TLR4 agonist, LPS ( 35 ). However, until now, most research has been limited to the fact that MPLA is a very good immunomodulator that can activate the immune system ( 36 ). Our department has found that MPLA could protect the intestine from radiation damage through activating the TLR4-MyD88 signal pathway and regulating inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

TLR4 Agonist MPLA Ameliorates Heavy-Ion Radiation Damage via Regulating DNA Damage Repair and Apoptosis

Liu¹,

Wang²,

et al. 2023

Radiation Research

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Heavy-ion radiation received during radiotherapy as well as the heavy-ion radiation received during space flight are equally considered harmful. Our previous study showed that TLR4 low toxic agonist, monophosphoryl lipid A (MPLA), alleviated radiation injury resulting from exposure to low-LET radiation. However, the role and mechanism of MPLA in heavy-ion-radiation injury are unclear. This study aimed to investigate the role of MPLA on radiation damage. Our data showed that MPLA treatment alleviated the heavy-ion-induced damage to microstructure and the spleen and testis indexes. The number of karyocytes in the bone marrow from the MPLA-treated group was higher than that in the irradiated group. Meanwhile, western blotting analysis of intestine proteins showed that pro-apoptotic proteins (cleaved-caspase3 and Bax) were downregulated while anti-apoptotic proteins (Bcl-2) were upregulated in the MPLA-treated group. Our in vitro study demonstrated that MPLA significantly improved cell proliferation and inhibited cell apoptosis after irradiation. Moreover, immunofluorescence staining and quantification of nucleic γ-H2AX and 53BP1 foci also suggested that MPLA significantly attenuated cellular DNA damage repair. Collectively, the above evidence supports the potential ability of MPLA to protect against heavy-ion-radiation injury by inhibiting apoptosis and alleviating DNA damage in vivo and vitro, which could be a promising medical countermeasure for the prevention of heavy-ion-radiation injury.

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Differential response induced by LPS and MPLA in immunocompetent and septic individuals

Cited by 9 publications

References 28 publications

Peripheral blood mononuclear cell phenotype and function are maintained after overnight shipping of whole blood

Peripheral blood mononuclear cell phenotype and function are maintained after overnight shipping of whole blood

Fueling Cancer Vaccines to Improve T Cell-Mediated Antitumor Immunity

TLR4 Agonist MPLA Ameliorates Heavy-Ion Radiation Damage via Regulating DNA Damage Repair and Apoptosis

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