Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/02—Algae
  • A61K36/05—Chlorophycota or chlorophyta (green algae), e.g. Chlorella
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
  • A61K2236/10—Preparation or pretreatment of starting material
  • A61K2236/13—Preparation or pretreatment of starting material involving cleaning, e.g. washing or peeling
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
  • A61K2236/10—Preparation or pretreatment of starting material
  • A61K2236/15—Preparation or pretreatment of starting material involving mechanical treatment, e.g. chopping up, cutting or grinding
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
  • A61K2236/50—Methods involving additional extraction steps
  • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
  • A61K2236/50—Methods involving additional extraction steps
  • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization

Definitions

• the present invention relates to an algae extract of the order of ulvals comprising sulfated and non-sulfated polyanionic polysaccharides whose molecular weight is less than or equal to 50 kDa, for its use for the prevention and / or treatment of complications induced by post-traumatic immunosuppression.
• MPS monophosphoryl lipid A
• TLR4 agonist activity The administration of monophosphoryl lipid A (MPLA), a non-toxic derivative of LPS known to have TLR4 agonist activity, has been shown to prevent mortality in an immunocompromised mouse model after hemorrhagic shock (Roquilly et al . 2010, PLoS One 7; 5 (10): e13228; international patent application WO201 1080126).
• MPLA monophosphoryl lipid A
• said sulfated and non-sulfated polyanionic polysaccharides of molecular weight less than or equal to 50 kDa have a molecular weight less than 15 kDa, and preferably greater than 500 Da.
• the algae extract does not include sulfated or non-sulfated polyanionic polysaccharides whose molecular weight is greater than 15 kDa.
• the extract of algae of the order of ulvals comprising sulfated and non-sulfated polyanionic polysaccharides whose molecular weight is less than or equal to 50 kDa is in particular an extract of green algae of the Ulva type.
• the masses mentioned in kDa are determined by any method usually used by those skilled in the art, in particular the masses of sulfated and non-sulfated polyanionic polysaccharides of algae extracts can be discriminated by ultrafiltration on membranes allowing only molecules of predetermined sizes to filter.
• the polysaccharides include mannose and / or arabinose, preferably mannose. More particularly still, the algae extract comprises at least 0.005% mannose and / or at least 0.005% arabinose, by weight relative to the weight of the total dry matter of the algae extract, in particular at least 0.01% mannose and / or at least 0.01% arabinose. Preferably, the algae extract comprises at least 0.005% of mannose.
• the algae extract comprises mannose in an amount ranging from 0.01 to 0.50%, for example from 0.01 to 0.20% or from 0.20 to 0.5%, in particular mannose in an amount ranging from 0.03 to 0.45%, for example from 0.03 to 0.15% or from 0.15 to 0.45 %%, by weight relative to the weight of the total dry matter of l algae extract.
• algae extract comprising:
• the algae extract comprises:
• This 1 H NMR spectrum was recorded at 298 K on a Bruker Avance 500 spectrometer equipped with a 5 mm 1 H / 13 C / 15 N TCI reverse cryogenic probe. Before analysis, the samples were dissolved in 99.97% of D 2 0. The chemical shifts are expressed in ppm relative to an external standard (trimethylsilylpropionic acid). No HOD signal suppression was performed.
• the liquid phase obtained is then clarified, for example with a plate clarifier, or by centrifugation, decantation or filtration (for example with a bag or a plate).
• the juice obtained is then ultrafiltered.
• the ultrafiltration is carried out on a membrane of 50 kDa or less, in particular on a membrane of 40, 30, 20 or 15 kDa. More particularly, the membrane is a membrane of 15 kDa or less.
• the concentration can be preceded by a demineralization step, in particular on a membrane having a size between 150 and 1000 Da.
• the process takes place in part at ambient temperature.
• ambient temperature is meant a temperature between 5 and 25 ° C.
• a pharmaceutical or medicinal composition for the implementation of the invention typically comprises the algae extract of the order of ulvals comprising sulfated and non-sulfated polyanionic polysaccharides whose molecular weight is less than or equal to 50 kDa, and a pharmaceutically acceptable excipient.
• Appropriate administration forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal administration forms, by inhalation, topical, parenteral administration forms such as transdermal, intraperitoneal, intratracheal, subcutaneous, intramuscular or intravenous, forms of rectal administration and implants.
• the drugs or pharmaceutical compositions comprising an algae extract for its use according to the invention can also be presented in liquid form, for example, in the form of solutions, emulsions, suspensions or syrups, and in particular in a form suitable for oral or intranasal administration, for example.
• suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
• the daily dose of the algae extract will be the lowest effective dose of the algae extract capable of producing a prophylactic and / or therapeutic effect on post-immunosuppression. traumatic.
• a subject for the prophylactic or therapeutic treatment according to the invention is an animal, preferably a mammal, for example a rodent, a canine, a feline, a bovid, an equine, or a primate.
• a subject is in particular a human, man, woman or child.
• the subject presents post-traumatic immunosuppression.
• a post-traumatic immunosuppression follows one or more traumas severe in the subject, such as a head trauma, in particular a head trauma with or without polytrauma, major surgery or a severe infection.
• the severely traumatized subject has an injury severity score (“Injury Severity Score” or ISS) of at least 16.
• the ISS is at least 25.
• the calculation of the ISS score takes into account the involvement of several regions of the patient's body (head and neck; face; thorax; abdomen and pelvis; pelvis and limbs; skin and subcutaneous tissue). The extent of each region is rated from 1 to 6 depending on its severity (1: minor impairment, 6: critical impairment).
• the severely traumatized subject presents a severe head trauma defined by a Glasgow score (CGS) of less than 8.
• CGS Glasgow score
• the determination of the CGS is a method which makes it possible to assess the depth of a coma by studying the variability of 3 very precise clinical criteria which are: 1) the opening of the eyes (rated from 1: absent to 4: spontaneous opening of the eyes), 2) the motility capacities (faculty to move), or if the '' we prefer the best motor response (rated from 1: absent to 6: adapted movements), and 3) the response to the questions asked (verbal responses, rated from 1: absent to 5: oriented response).
• the CGS is the sum of the results obtained with the three clinical criteria mentioned above. It is therefore a minimum of 3 and a maximum of 15 (Teasdale et al. 1974, Lancet 2: 81 -84).
• cytokines are typically measured in whole blood cultures stimulated by LPS (from Escherichia coli in general).
• the expression of HLA-DR is expressed versus healthy volunteers, either in number of HLA-DR molecules expressed on the surface of the cells (MFI for “mean fluorescence intensity”), or in percentage, the value 100% representing the level of expression of HLA-DR in healthy volunteers.
• MFI mean fluorescence intensity
• the drop in a) and / or b) above is at least about 20%. It is preferably at least approximately 25%, more preferably at least 30, 35, 40, 45% approximately, and more preferably at least 50, 55, 60% approximately, or even more.
• the prevention and / or treatment of post-traumatic immunosuppression leads to the prevention and / or treatment of a septic complication of post-traumatic immunosuppression.
• Gram-positive shells eg, S. aureus, coagulase-negative staphylococci
• yeasts such as Candida sp. for infections on central catheters
• Gram-negative bacilli eg, E. coli, P. mirabilis, P. aeruginosa
• Gram-positive shells eg, S. aureus, staphylococci coagulase negative, Streptococcus pneumoniae
• the place of infection (or focal point of infection) is the lung.
• the algae extract, or the composition or the drug containing it is administered one or more times during the patient's intubation period.
• the term "and / or” is a grammatical conjunction which must be interpreted as encompassing the fact that one or more of the cases which it connects may occur.
• the expression "mannose and / or arabinose” in the expression "said polysaccharides include mannose and / or arabinose” indicates that the polysaccharides can comprise mannose, or arabinose, or mannose and arabinose.
• the term “comprising” should be interpreted to include all the characteristics specifically mentioned, as well as optional, additional, unspecified characteristics. As used herein, the use of the term “comprising” also describes the embodiment in which no characteristic other than the characteristics specifically mentioned is present (i.e. "consisting of").
• FIG. 2 The algae extract has no effect on the weight loss of traumatized and secondarily infected mice.
• the mice in the Sham (S) and Pneumonia alone (PN) groups received the 1 cm incision on the skull without TC.
• the traumatized and infected mice, for which the pneumonia was carried out 24 hours after the TC, were divided into the untreated group (TC + PN) and treated with 6 injections of the compound (every 12 hours from the TC until euthanasia) ( TC + PN + TX).
• the pneumonia was performed 24 hours after the CT and the euthanized mice 48 hours after the pneumonia.
• The% weight loss results are given as means ⁇ standard deviation. * p ⁇ 0.05 traumatized groups and PN (after PN) versus S, * p ⁇ 0.05 for traumatized groups versus PN.
• FIG. 4 The algae extract does not have anti-SAMS activity in vitro.
• the kinetics of bactericidal activity were carried out in a liquid medium for concentration ranges of 50, 200 and 500 pg / ml of the compound.
• the bacterial loads were then counted on TS agars and the results expressed in Logio of CFU / mL. The results are from 2 independent and consistent experiments.
• FIG. 6 The intratracheal administration of the algae extract does not induce an increase in the secretion of pro-inflammatory cytokines at 2 hours and at 12 hours in the naive mouse.
• the intratracheal injection of the algae extract was carried out at a concentration of 50 pg 12 hours (T overnight) and 2 hours (T (H-2)) before euthanasia. It was compared to healthy mice (Na ⁇ ves) and to the instillation of 50pg of LPS two hours before euthanasia (LPS (H-2)).
• FIG. 10 The algae extract does not induce an increase in the secretion of INF Y nor an increase in expression of the activation factor KLRG 1 by pulmonary NK cells in vitro:
• the lungs of 6 mice naive and 6 traumatized mice were mechanically ground two by two 24 hours after the TC in order to obtain 3 pulmonary homogenates per group.
• the NK cells were cultured for 5 hours with IL-2 (control group: Ctrl), IL-2 + Algae at 500 pg / mL (Algae) and IL-2 + PMA (50ng / mL) and lonomycin (1 pg / mL) (PMA + lono).
• the rats were removed 12 hours after the induction of pneumonia, ground and then the level of chemokines CCL2 (A) and CCL3 (B) CCL4 (C) and CCL8 (D) were measured by the Luminex technique.
• the algae extract is prepared as described in Example 1 of the international patent application WO2015071497.
• the filtration juice (permeate) is then dried by lyophilization after concentration by evaporation.
• the powder obtained is then ground with a Philips brand MiniMill planetary mill.
• the product was introduced into grinding bowls (10 g of product in each grinding bowl with 4 zirconia balls). The assembly was rotated for 15 minutes at speed 10. This gives 14 kg of algae extract powder.
• Head trauma model Head trauma was carried out using the “weight drop device” technique (Flierl et al., 2009, Nat. Protoc.; 4 (9): 1328-37). A subcutaneous injection of 0.1 mg / kg of buprenorphine was carried out thirty minutes before the procedure and then the mice were anesthetized by continuous inhalation of isoflurane (flow rate of fresh gas 0.8L / min, inhaled fraction 3.5%) . A 1 cm incision at the top of the skull was used to identify the coronal and sagittal sutures and to optimize the procedure. The trauma was then achieved by the fall of a standardized weight of 2.5 cm in height, then the incision was closed with a stitch on wire 4.0. There should be no break-in of the skull. Adintegrum recovery was monitored immediately and then every 12 hours, and mice were given subcutaneous buprenorphine analgesia if necessary. In the event of pathological awakening, the mice were euthanized. The endpoints were evaluated according to Table I below:
• Pneumonia model A subcutaneous injection of 0.1 mg / kg of buprenorphine was carried out thirty minutes before the procedure, then the mice were anesthetized by continuous inhalation of isoflurane (flow rate of fresh gas 0.8 L / min, fraction inhaled 3.5%). The pneumonia was then induced by the intratracheal insertion of a 24-gavage cannula and then by the injection of 75 ⁇ L of inoculum.
• mice were divided into 4 groups: Sham (S) uninfected non-traumatized mice, infected non-traumatized (PN) mice, traumatized and infected, untreated (PN + TC) mice and traumatized infected and treated mice with 200 gp marine compound intraperitoneally every 12 hours (PN + TC + TX).
• the algae extract was administered intraperitoneally 2 hours and 12 hours before euthanasia at doses of 50, 200 and 500 pL in a total volume of 200pL of PBS.
• the algae extract was also administered at a dose of 50 pg in 75 pL intratracheally according to the same procedure as for bacterial inoculation during pneumonia.
• the rats and lungs were then removed and then the cell populations analyzed by flow cytometry after intra-cellular labeling of the pro-inflammatory cytokines (IL-12, TNF ⁇ , INF y).
• FACS analysis of cell populations The pulmonary and spleen cell suspensions were obtained by manual mechanical grinding then digestion with collagenase for 30 minutes (spleens) or 45 minutes (lungs) then passed through a sieve (pores of 70 ⁇ m). After treatment with a red cell lysis solution, the cell suspensions obtained were incubated for 30 minutes at 4 ° C. with the antibodies coupled to the specific fluorochromes.
• Luminex method Determination of the level of expression of pulmonary and splenic chemokines by Luminex method. After sampling the lungs and rats, the latter were mechanically homogenized at 4 ° C in the presence of lysis buffer (1 xPBS, pH 7.4 / 0.1% triton X-100) containing 1 mM protease inhibitor cocktail ( Sigma, Isle D'Abeau Chesnes, France). The homogenates were then centrifuged at 12,000 g for 20 minutes at 4 ° then the supernatant was removed and then stored at -80 ° C until analysis.
• lysis buffer (1 xPBS, pH 7.4 / 0.1% triton X-100
• 1 mM protease inhibitor cocktail Sigma, Isle D'Abeau Chesnes, France
• NK cells The pulmonary cell suspensions were obtained according to the protocol used for the FACS analysis. The cells were counted (approximately 2.10 7 per lung) and then centrifuged at 300 g for 10 minutes. The cells were suspended in 40 ⁇ L of FACS Buffer for 10 7 cells and then labeled with 10 ⁇ L of NK Cell Biotin- Antibody Cocktail (Miltenyi Biotec®, Germany) and incubated for 5 minutes at 4 ° C. After a further centrifugation at 300 g for 10 minutes, the cells were incubated for 10 minutes at 4 ° C. with 20 ⁇ L of Anti-Biotin MicroBeads (Miltenyi Biotec®, Germany) for 10 7 cells.
• NK cells were shredded in pairs to reach at least 10,000 NK cells per well (for a total of about 20 million cells per mouse lung) The purity of NK cells was greater than 90%.
• mice were divided into 4 groups: Sham (S), Pneumonia only (PN), Head trauma + Pneumonia (TC + PN), and traumatized and infected mice, treated every 12 h by intraperitoneal injection (IP) of 200pg of the compound (TC + PN + TX) starting 2 hours after trauma and until euthanasia.
• the mice of groups S and PN received an incision of 1 cm from the top of the skull without the trauma.
• Pneumonia was induced 24 hours after the head injury. Euthanasia occurred 24 to 48 hours after the induction of pneumonia according to the criteria studied ( Figure 1).
• SASM pneumonia induces transient weight loss of around 12% of body weight after 24 hours. Traumatic brain injury increases weight loss at the initial stage of infection but does not affect recovery from D + 3 compared to non-traumatized mice. The treatment had no effect on the weight loss of the traumatized and secondarily infected mice (Figure 2).
• the algae extract limits bacterial spread in traumatized mice 48 hours after the induction of SAMS pneumonia
• the pulmonary bacterial loads are similar in all the groups infected at 24 h (PN, TC + PN, TC + PN + TX) ( Figure 3A) as well as 48 h ( Figure 3B) of the induction of pneumonia.
• mice From the 24th hour following lung infection, all mice were bacteremic pneumonia suffered at SAMS (splenic bacterial load> 2 log).
• the treatment had no effect on the bacteremia at 24 h of the infection ( Figure 3C) but at the 48 th hour of the infection, Staphyloccocus aureus was detected in 22% of the mice in the treated group (TC + PN + TX) versus 100% in the group undergoing untreated post-traumatic pneumonia (CT + PN).
• the mice of the group treated with the algae extract therefore have spleen bacterial loads less than 48 hours from the induction of pneumonia (FIG. 3D). This effect seems to be related to the frequency of administration because the single injection of the algae extract induces a reduction in the bacteremia less than that observed in the event of multiple injections (results not shown).
• Intra-peritoneal administration of the algae extract 2 hours and 12 hours before euthanasia does not induce an increase in the production of pro-inflammatory cytokines (IL-12, TNFa, INF y) in mice naive
• Intra-tracheal administration of the algae extract 2 hours and 12 hours before euthanasia does not induce an increase in the production of pro-inflammatory cytokines (IL-12, TNFa, INF y) in mice naive
• the algae extract has no effect in vitro on secretion of interferon y or the expression of the activation factor KLRG1 by the lung NK cells.
• NK cells producing interferon g in the mice treated with the extract were magnetically sorted and then stimulated in vitro for 5 hours under 3 conditions: Control (Ctrl), algae extract, and PMA + lonomycin (PMA + lono).
• Seaweed extract does not limit splenic bacterial spread in traumatized mice depleted in NK cells. In order to assess whether the effects of the algae extract on the splenic bacterial spread were due to the increase in the number of pulmonary NK cells, it was evaluated whether this effect on the bacteremia was found in the event of depletion of the cells. NK in vivo.
• the administration of the sulfated polysaccharide induces an increase in the number of pulmonary NK cells in traumatized and infected mice.
• the splenic and pulmonary secretions of the chemokines CXCL1 (KC), CCL2 (MCP-1), CCL19 (MIP- 3b), CXCL2 (MIP-2), CXCL10 (IP-10), CCL8 (MCP-2), CCL3 (MIP-1 a), CCL20 (MIP-3a), CCL4 (MIP-1 b), and CCL21 ( 6Ckine) were evaluated in Luminex.
• These chemokines are involved in the chemoattraction of NK cells after acute inflammation.
• mice were divided into 7 groups: Naive mice (SHAM), traumatized mice alone (TC), mice traumatized and treated with the compound (TC + TX), infected mice alone (PN) (only for studies pulmonary chemokines), mice infected and treated with algae extract (PN + TX) (only for the study of pulmonary chemokines), traumatized and infected mice (TC + PN) and traumatized, infected and treated with seaweed extract (TC + PN + TX).
• Pneumonia was induced 24 hours after the head injury. Euthanasia occurred 12 hours after the induction of pneumonia.
• the splenic and pulmonary levels of the above-mentioned chemokines were analyzed by the Luminex technique ( Figure 13).
• the algae extract causes an increase in the spleen levels of the chemokines CCL2, CCL3, CCL4 and CCL8 ( Figure 14).
• the algae extract has no effect on the splenic secretion of the chemokines CXCL1, CCL19, CXCL2, CXCL10, CCL20, CCL4, CCL21 (data not shown).
• the intraperitoneal injection of the algae extract also does not increase the levels of chemokines analyzed in the lungs (data not shown).
• the algae extract also did not induce an increase in membrane expression of MHC II by dendritic cells (data not shown). In the absence of immunosuppression, administration of the algae extract does not induce stimulation of innate immunity cells. This corroborates the bacteriological results in which the administration of the extract of algae, in the absence of trauma (and therefore immunosuppression), does not limit the bacterial spread, contrary to what is observed in traumatized and infected mice .
• NK cells are essential for the antibacterial response, especially in acute lung infection.
• the action of NK cells is not limited to the secretion of pro-inflammatory substances but leads to a co-stimulation of the other cells of innate immunity, in particular by decreasing the apoptosis of neutrophils. and preserving their functional capacities.
• NK cells also play an immunomodulating role by destroying unactivated CDs and overactivated macrophages that can cause tissue damage.
• the effect of the extract was evaluated on the splenic bacterial spread in a post traumatic immunosuppression model in mice depleted in NK cells.
• the effects of the extract on the spleen bacterial load were not found in the event of depletion of NK cells (more than 95% depletion of pulmonary NK cells), confirming the role of these cells in the action of the extract marine in vivo.
• the secretion of chemokines in response to the injection of the algae extract, in particular by the epithelial cells via the TLR4-NF-kB pathway, is one of the hypotheses which may explain the increase in the number of NK cells at the sites of l 'infection.

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