scholarly journals 615 Reactivating antitumor immunity in gliomas with osteopontin/integrin blocking peptide

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A645-A645
Author(s):  
Paulina Pilanc-Kudlek ◽  
Katarzyna Poleszak ◽  
Aleksandra Ellert-Miklaszewska ◽  
Adria-Jaume Roura Canalda ◽  
Salwador Cyranowski ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Rgd Peptide ◽  
Phase Iii ◽  
List Type ◽  
Malignant Cells ◽  
Cell Functions ◽  
Tumor Bearing ◽  
Immunosuppressive Microenvironment ◽  
Gl261 Glioma

BackgroundGlioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Despite improvements in imaging, surgical techniques, radiotherapy and chemotherapy, the prognosis of patients with GBM remains poor with a median overall survival of 15 months [1,2]. GBM is immunologically a ”cold” tumor with low infiltration of functional T and NK cells, which imposes poor responsiveness of GBM patients to immunotherapies. The immunosuppressive microenvironment in GBM is created by the malignant cells and tumor-associated macrophages (TAMs), such as resident brain microglia and recruited peripheral myeloid cells [3]. Osteopontin/Spp1 is one of glioma-derived factors that is responsible for the protumorigenic reprogramming of TAMs [4]. SPP1 expression is highly elevated in tumor tissues and sera from GBM patients, and inversely correlates with patient survival [5]. Cross-talk between malignant cells and TAMs relays on osteopontin binding to integrin receptors (mainly αvβ3 and αvβ5) via its RGD motif [6]. Thus, with the use of a RGD peptide (our in-house designed competitor of binding to integrins) we interfered with glioma-microglia interaction in vitro and evaluated the in vivo antitumor efficacy of integrin blockade as a monotherapy and in combination with an immune check-point inhibitor.MethodsThe efficacy of the RGD peptide to block microglia-dependent glioma invasion was determined in a Matrigel invasion assay. Antitumor activity of the peptide was assessed in a murine syngeneic orthotopic GL261 glioma model. RGD peptide was administrated intratumorally via osmotic pomps. For combination therapy, the animals received anti-PD-1 or isotype IgG antibody (4 inj. x 10 mg/kg i.p.). Tumor volume was measured using MRI. Heterogeneity of the immune cells compartment of glioma microenvironment was analysed by flow cytometry. The transcriptomes of CD11b+ cells immunosorted from tumor-bearing mouse brains were evaluated using RNAseq. Cytokine levels in the blood and the brain homogenates were measured using Luminex bead-based assays.ResultsThe microglia-stimulated invasion of GL261 glioma cells was reduced significantly in the presence of the RGD peptide in the in vitro co-culture system. The RGD peptide administrated to tumor-bearing mice induced proinflammatory reprogramming of TAMs. Combination of the RGD peptide with anti-PD-1 therapy increased the production of proinflammatory cytokines and the percentage of effector CD8+(CD44+CD62L-) cells in the tumors.ConclusionsThese results demonstrate that blockade of osteopontin/integrin signaling using the RGD peptide can mitigate the immunosuppressive microenvironment, reactivate the antitumor immunity and lay ground for improved response to immunotherapy in GBM.ReferencesJemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ: Cancer statistics, 2005. CA Cancer J Clin 2005, 55(1):10–30.Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC- NCIC trial. Lancet Oncol 2009, 10(5):459–466.Woroniecka KI, Rhodin KE, Chongsathidkiet P, Keith KA, Fecci PE: T-cell Dysfunction in Glioblastoma: Applying a New Framework. Clin Cancer Res 2018, 24(16):3792–3802Denhardt, D.T., M. Noda, A.W. O’Regan, D. Pavlin, and J.S. Berman. 2001. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 107:1055–1061.Grassinger, J., D.N. Haylock, M.J. Storan, G.O. Haines, B. Williams, G.A. Whitty, et al. 2009. Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with alpha9beta1 and alpha4beta1 integrins. Blood 114:49–59.Anborgh, P.H., J.C. Mutrie, A.B. Tuck, and A.F. Chambers. 2010. Role of the metastasis-promoting protein osteopontin in the tumour microenvironment. Journal of cellular and molecular medicine 14:2037–2044Ethics ApprovalAll research protocols conformed to the Guidelines for the Care and Use of Laboratory Animals (European and national regulations 2010/63/UE September 22, 2010 and Dz. Urz. UE L276/20.10.2010, respectively). Animals were decapitated by a qualified researcher. The First Warsaw Local Ethics Committee for Animal Experimentation approved the study (approval no. 812/2019).

scholarly journals Treatment of Brain Tumors Using DNA-Based Vaccines

2010 ◽  
Vol 3 (1) ◽  
pp. 23-29
Author(s):  
Terry Lichtor
Keyword(s):  
Breast Cancer ◽  
Brain Tumors ◽  
Cell Line ◽  
Tumor Immunity ◽  
Tumor Antigens ◽  
T Cell Subsets ◽  
In Vitro Assays ◽  
Malignant Cells ◽  
Tumor Bearing

Antigenic differences between normal and malignant cells of the cancer patient form the rationale for clinical immunotherapeutic strategies. Because the antigenic phenotype of neoplastic cells varies widely among different cells within the same malignant cell-population, immunization with a vaccine that stimulates immunity to the broad array of tumor antigens expressed by the cancer cells is likely to be more efficacious than immunization with a vaccine for a single antigen. A vaccine prepared by transfer of DNA from the tumor into a highly immunogenic cell line can encompass the array of tumor antigens that characterize the patient’s neoplasm. Poorly immunogenic tumor antigens, characteristic of malignant cells, can become strongly antigenic if they are expressed by highly immunogenic cells. A DNA-based vaccine was prepared by transfer of genomic DNA from a breast cancer that arose spontaneously in a C3H/He mouse into a highly immunogenic mouse fibroblast cell line, where genes specifying tumor-antigens were expressed. The fibroblasts were modified in advance of DNA-transfer to secrete an immune augmenting cytokine and to express allogeneic MHC class I-determinants. In an animal model of breast cancer metastatic to the brain, introduction of the vaccine directly into the tumor bed stimulated a systemic cellular anti-tumor immune response measured by two independent in vitro assays and prolonged the lives of the tumor-bearing mice. Furthermore, using antibodies against the various T-cell subsets, it was determined that the systemic cellular anti-tumor immunity was mediated by CD8+, CD4+ and NK/LAK cells. In addition an enrichment strategy has also been developed to increase the proportion of immunotherapeutic cells in the vaccine which has resulted in the development of enhanced anti-tumor immunity. Finally regulatory T cells (CD4+CD25+Fox p3+-positive) were found to be relatively deficient in the spleen cells from the tumor-bearing mice injected intracerebrally with the enriched vaccine. The application of DNA-based genomic vaccines for the treatment of a variety of brain tumors is being explored.

scholarly journals 850 Dual blockade of the EP2 and EP4 PGE2 receptors with TPST-1495 is an optimal approach for drugging the prostaglandin pathway

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A891-A891
Author(s):  
Brian Francica ◽  
Justine Lopez ◽  
Anja Holtz ◽  
Dave Freund ◽  
Dingzhi Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Whole Blood ◽  
List Type ◽  
Tumor Bearing ◽  
Dual Blockade ◽  
Cox 2 ◽  
Ct26 Tumor

BackgroundProstaglandin E2 (PGE2) is a bioactive lipid produced by tumor cells that drives disease progression through stimulating tumor proliferation, enhancing angiogenesis and suppressing immune function in the TME.1 PGE2 is also a mediator of adaptive resistance to immune checkpoint inhibitor therapy via the upregulation of cyclooxygenase-2 (COX-2). While the role of PGE2 signaling in cancer is clear, how best to inhibit PGE2 for cancer treatment remains under investigation. Inhibition of COX-1 and/or COX-2 has shown promising results in observational studies and meta-analyses, but inconsistent results in prospective studies. PGE2 signals through four receptors, EP1-4, that are variably expressed on tumor and immune cells and have distinct biological activities. The EP2/EP4 receptors signal through cAMP and drive pro-tumor activities, while EP1/EP3 receptors signal through calcium flux and IP3 and drive immune activation and inflammation. While COX-2 and single EP inhibitors continue to be developed, the nature of PGE2 signaling supports our rationale to inhibit PGE2 by dual antagonism of the pro-tumor EP2/EP4 receptors, while sparing the pro-immune EP1/EP3 receptors.MethodsWe utilized human and murine whole blood to perform in vitro characterization of PGE2/inhibitor activity. In vivo, CT26 tumors and APCmin/+ mice were used to model CRC and measure immune endpoints.ResultsIn mouse and human whole blood assays, dual blockade of EP2 and EP4 receptors with TPST-1495 reversed PGE2-mediated suppression of LPS induced TNF-α, while EP4 receptor antagonists were unable to block suppression at higher PGE2 concentrations. Similarly, in murine and human T cells in vitro, TPST-1495 inhibited PGE2-mediated suppression, resulting in a significant increase of IFN-γ production in response to stimulation with cognate peptide Ag. In vivo, TPST-1495 therapy alone also significantly reduced tumor outgrowth in CT26 tumor bearing mice, correlated with increased tumor infiltration by NK cells, CD8+ T cells, AH1-specific CD8+ T cells, and DCs. The induced NKp46+CD4-CD8- cell population appeared to have an important role in TPST-1495 efficacy, as significant anti-tumor activity was observed in murine models lacking T Cells, particularly CT26 tumor-bearing RAG2-/- mice. TPST-1495 monotherapy demonstrated a decrease of both the intestinal tumor size and number in Adenomatous Polyposis (APCmin/+) mice, as compared to a single EP4 antagonist.ConclusionsTPST-1495 is a potent inhibitor of PGE2 mediated immune suppression and is currently being evaluated in an ongoing Phase 1 first-in-human study (NCT04344795) to characterize PK, PD, safety, and to identify a recommended phase 2 dose for expansion cohorts in key indications and biomarker selected patients.ReferenceZelenay S, van der Veen AG, Böttcher JP, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 2015;162(6):1257–70. doi: 10.1016/j.cell.2015.08.015

Bortezomib Enhances the Antitumor Activity of Adoptively Infused Natural Killer Cells In Vivo: A Novel Approach To Override KIR-Mediated Inhibition of NK Cell Cytotoxicity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1786-1786 ◽  
Author(s):  
Andreas Lundqvist ◽  
Sheila Rao ◽  
Aleah Smith ◽  
Maria Berg ◽  
Su Su ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Single Injection ◽  
Combined Treatment ◽  
Malignant Cells ◽  
Tumor Bearing ◽  
Nk Cell Cytotoxicity

Abstract Natural killer (NK) cell killer immunoglobulin-like receptor (KIR) interactions with self MHC class I molecules can regulate NK cell function; such interactions typically inactivate NK cells potentially providing a dominant mechanism through which malignant cells evade host NK cell-mediated immunity. Recently we found that the proteasome inhibitor bortezomib up-regulated surface expression of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) on a variety of different human malignant cells rendering them susceptible to NK cell-mediated apoptosis in vitro; this effect appears to override KIR ligand-mediated NK cell inactivation, overcoming tumor resistance to both allogeneic KIR ligand-matched and autologous NK cell cytotoxicity. We also found that murine tumors were sensitized by bortezomib to the cytotoxic effects of syngeneic NK cells; the killing of RENCA and LLC1 tumors in vitro by syngeneic BALB/c and C57BL/6 NK cells respectively was enhanced when tumors were exposed to 10nM of bortezomib for 18h. Here, we show that the combined treatment of bortezomib followed by syngeneic NK cell infusions significantly delays tumor growth in tumor bearing animals. While treatment with bortezomib or interleukin-2 activated syngeneic NK cells alone had little effect on tumor growth, the combined treatment significantly delayed growth of RENCA tumors in BALB/c mice and LLC1 in C57BL/6 mice (p<0.01;figure). In contrast to human tumor cell lines where an increase in expression of TRAIL-R2 was observed following bortezomib exposure, no change in expression of death receptors was observed in either murine tumor line. Flow cytometry analysis showed caspase-8 activity was significantly enhanced in bortezomib-treated murine tumor cells upon co-culture with NK cells compared to untreated tumor cells. Concanamycin A treatment significantly reduced NK cell-mediated apoptosis (but not neutralizing antibodies to Fas ligand or TRAIL) demonstrating that the sensitizing effect was mediated through perforin. Moreover, bortezomib-treated tumor cells were resistant to killing by perforin-deficient NK cells in vitro and the reduction in tumor growth observed in tumor bearing animals treated with bortezomib and wild-type NK cells was not observed in animals treated with bortezomib and perforin-deficient NK cells. These findings demonstrate that bortezomib-induced tumor sensitization to NK cell perforin and/or TRAIL could be used as a novel strategy to potentiate anti-tumor effects of adoptively infused NK cells in patients with cancer. Figure. Left - BALB/c mice were injected with RENCA tumor cells (100.000 cells i.v) and treated with bortezomib (5ug/mouse i.v) on days 5, 12 and 19 followed by injection of sygeneric NK cells (2×106 i.v) on days 6,13 and 20. All animals received IL-2 (100.000 U i.p on days 6–9,13–16 and 20–23). Animals were euthanized on day 25 and evaluated for pulmonary metastasies. Right - C57BL/6 mice were injected with LLC1 tumor cells (500.000 s.c) and treated with bortezomib (15ug/mouse i.p) on day 14 followed by a single injection of syngeneic NK cells (1×106 i.v) on day 15. All mice were treated with IL-2 (100.000U i.p on days 15–18). Data depicts tumor sizes on day 28 post tumor injection. Figure. Left - BALB/c mice were injected with RENCA tumor cells (100.000 cells i.v) and treated with bortezomib (5ug/mouse i.v) on days 5, 12 and 19 followed by injection of sygeneric NK cells (2×106 i.v) on days 6,13 and 20. All animals received IL-2 (100.000 U i.p on days 6–9,13–16 and 20–23). Animals were euthanized on day 25 and evaluated for pulmonary metastasies. Right - C57BL/6 mice were injected with LLC1 tumor cells (500.000 s.c) and treated with bortezomib (15ug/mouse i.p) on day 14 followed by a single injection of syngeneic NK cells (1×106 i.v) on day 15. All mice were treated with IL-2 (100.000U i.p on days 15–18). Data depicts tumor sizes on day 28 post tumor injection.

scholarly journals Decrease in Intracellular Perforin Levels and IFN-γ Production in Human CD8+ T Cell Line following Long-Term Exposure to Asbestos Fibers

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Naoko Kumagai-Takei ◽  
Yasumitsu Nishimura ◽  
Hidenori Matsuzaki ◽  
Suni Lee ◽  
Kei Yoshitome ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Antitumor Immunity ◽  
Granzyme B ◽  
Cell Functions ◽  
Asbestos Fibers ◽  
Ifn Γ ◽  
Line Following

Although the tumorigenicity of asbestos, which is thought to cause mesothelioma, has been clarified, its effect on antitumor immunity requires further investigation. We previously reported a decrease in the percentage of perforin+ cells of stimulated CD8+ lymphocytes derived from patients with malignant mesothelioma. Therefore, we examined the effects of long-term exposure to asbestos on CD8+ T cell functions by comparing long-term cultures of the human CD8+ T cell line EBT-8 with and without exposure to chrysotile (CH) asbestos as an in vitro model. Exposure to CH asbestos at 5 μg/ml or 30 μg/ml did not result in a decrease in intracellular granzyme B in EBT-8 cells. In contrast, the percentage of perforin+ cells decreased at both doses of CH exposure. CH exposure at 30 μg/ml did not suppress degranulation following stimulation with antibodies to CD3. Secreted production of IFN-γ stimulated via CD3 decreased by CH exposure at 30 μg/ml, although the percentage of IFN-γ+ cells induced by PMA/ionomycin did not decrease. These results indicate that long-term exposure to asbestos can potentially suppress perforin levels and the production of IFN-γ in human CD8+ T cells.

scholarly journals Tumor-Derived Exosomes (TEX) and Their Role in Immuno-Oncology

2021 ◽  
Vol 22 (12) ◽  
pp. 6234
Author(s):  
Theresa Whiteside ◽  
Brenda Diergaarde ◽  
Chang-Sook Hong
Keyword(s):  
T Cells ◽  
Cancer Patients ◽  
Immune Cell ◽  
Parent Cell ◽  
Malignant Cells ◽  
Tumor Biopsy ◽  
Cellular Origin ◽  
Cell Functions

Extracellular vesicles (EVs) play a key role in health and disease, including cancer. Tumors produce a mix of EVs differing in size, cellular origin, biogenesis and molecular content. Small EVs (sEV) or exosomes are a subset of 30–150 nm (virus–size) vesicles originating from the multivesicular bodies (MVBs) and carrying a cargo that in its content and topography approximates that of a parent cell. Tumor-derived exosomes (TEX) present in all body fluids of cancer patients, are considered promising candidates for a liquid tumor biopsy. TEX also mediate immunoregulatory activities: they maintain a crosstalk between the tumor and various non-malignant cells, including immunocytes. Effects that EVs exert on immune cells may be immunosuppressive or immunostimulatory. Here, we review the available data for TEX interactions with immunocytes, focusing on strategies that allow isolation from plasma and separation of TEX from sEV produced by non-malignant cells. Immune effects mediated by either of the subsets can now be distinguished and measured. The approach has allowed for the comparison of molecular and functional profiles of the two sEV fractions in plasma of cancer patients. While TEX carried an excess of immunosuppressive proteins and inhibited immune cell functions in vitro and in vivo, the sEV derived from non-malignant cells, including CD3(+)T cells, were variably enriched in immunostimulatory proteins and could promote functions of immunocytes. Thus, sEV in plasma of cancer patients are heterogenous, representing a complex molecular network which is not evident in healthy donors’ plasma. Importantly, TEX appear to be able to reprogram functions of non-malignant CD3(+)T cells inducing them to produce CD3(+)sEV enriched in immunosuppressive proteins. Ratios of stimulatory/inhibitory proteins carried by TEX and by CD3(+)sEV derived from reprogrammed non-malignant cells vary broadly in patients and appear to negatively correlate with disease progression. Simultaneous capture from plasma and functional/molecular profiling of TEX and the CD3(+)sEV fractions allows for defining their role as cancer biomarkers and as monitors of cancer patients’ immune competence, respectively.

On the Role of Transferrin in 67Ga Uptake by Tumor Cells

1988 ◽  
Vol 27 (04) ◽  
pp. 151-153
Author(s):  
P. Thouvenot ◽  
F. Brunotte ◽  
J. Robert ◽  
L. J. Anghileri
Keyword(s):  
Specific Binding ◽  
Subcellular Fractionation ◽  
Animal Blood ◽  
Tumor Bearing ◽  
Cell Structures ◽  
The Difference ◽  
Sarcoma Cells ◽  
In Vitro Uptake

In vitro uptake of 67Ga-citrate and 59Fe-citrate by DS sarcoma cells in the presence of tumor-bearing animal blood plasma showed a dramatic inhibition of both 67Ga and 59Fe uptakes: about ii/io of 67Ga and 1/5o of the 59Fe are taken up by the cells. Subcellular fractionation appears to indicate no specific binding to cell structures, and the difference of binding seems to be related to the transferrin chelation and transmembrane transport differences

Defibrotide Inhibits Platelet Activation by Cathepsin G Released From Stimulated Polymorphonuclear Leukocytes

1992 ◽  
Vol 67 (06) ◽  
pp. 660-664 ◽  
Author(s):  
Virgilio Evangelista ◽  
Paola Piccardoni ◽  
Giovanni de Gaetano ◽  
Chiara Cerletti
Keyword(s):  
Platelet Activation ◽  
Polymorphonuclear Leukocytes ◽  
Direct Interaction ◽  
Cathepsin G ◽  
In Vivo Test ◽  
Cell Functions ◽  
Test Models ◽  
Antithrombotic Effects

SummaryDefibrotide is a polydeoxyribonucleotide with antithrombotic effects in experimental animal models. Most of the actions of this drug have been observed in in vivo test models but no effects have been reported in in vitro systems. In this paper we demonstrate that defibrotide interferes with polymorphonuclear leukocyte-induced human platelet activation in vitro. This effect was not related to any direct interaction with polymorphonuclear leukocytes or platelets, but was due to the inhibition of cathepsin G, the main biochemical mediator of this cell-cell cooperation. Since cathepsin G not only induces platelet activation but also affects some endothelial cell functions, the anticathepsin G activity of defibrotide could help to explain the antithrombotic effect of this drug.

DER EINFLUSS VON RESERPIN AUF DIE ANTITHYREOIDALE WIRKUNG VON KALIUMPERCHLORAT

1962 ◽  
Vol 39 (3) ◽  
pp. 423-430
Author(s):  
H. L. Krüskemper ◽  
F. J. Kessler ◽  
E. Steinkrüger
Keyword(s):  
Thyroid Gland ◽  
Male Rats ◽  
Normal Male ◽  
Tissue Respiration ◽  
List Type ◽  
Morphological Alterations ◽  
Hormone Synthesis ◽  
Stimulation Of

ABSTRACT 1. Reserpine does not inhibit the tissue respiration of liver in normal male rats (in vitro). 2. The decrease of tissue respiration of the liver with simultaneous morphological stimulation of the thyroid gland after long administration of reserpine is due to a minute inhibition of the hormone synthesis in the thyroid gland. 3. The morphological alterations of the thyroid in experimental hypothyroidism due to perchlorate can not be prevented with reserpine.

LACK OF EFFECT OF CORTICOSTEROIDS ON THE IN VIVO DISAPPEARANCE OF SULFHYDRYL-INHIBITED AND ANTIBODY-COATED ERYTHROCYTES

1964 ◽  
Vol 47 (3_Suppl) ◽  
pp. S28-S36
Author(s):  
Kailash N. Agarwal
Keyword(s):  
Red Cells ◽  
List Type ◽  
Red Cell

ABSTRACT Red cells were incubated in vitro with sulfhydryl inhibitors and Rhantibody with and without prior incubation with prednisolone-hemisuccinate. These erythrocytes were labelled with Cr51 and P32 and their disappearance in vivo after autotransfusion was measured. Prior incubation with prednisolone-hemisuccinate had no effect on the rate of red cell disappearance. The disappearance of the cells was shown to take place without appreciable intravascular destruction.

ÉTUDE IN VITRO DU MÉTABOLISME DES HYDRATES DE CARBONE DANS LE LEUCOCYTE CIRCULANT DU COBAYE TRAITÉ À LA CORTISONE

1966 ◽  
Vol 51 (2) ◽  
pp. 193-202
Author(s):  
J. A. Antonioli ◽  
A. Vannotti
Keyword(s):  
Glucose Concentration ◽  
Intramuscular Injection ◽  
Acute Inflammation ◽  
Glycogen Content ◽  
Glycogen Synthesis ◽  
Lactate Production ◽  
Glucose Consumption ◽  
List Type ◽  
Hydrates De Carbone

ABSTRACT 1. The metabolism of suspensions of circulating leucocytes has been studied after intramuscular injection of a dose of 50 mg/kg of a corticosteroid (cortisone acetate). The suspensions were incubated under aerobic conditions in the presence of a glucose concentration of 5.6 mm. Glucose consumption, lactate production, and variations in intracellular glycogen concentration were measured. After the administration of the corticosteroid, the anabolic processes of granulocyte metabolism were reversibly stimulated. Glucose consumption and lactate production increased 12 hours after the injection, but tended to normalize after 24 hours. The glycogen content of the granulocytes was enhanced, and glycogen synthesis during the course of the incubation was greatly stimulated. The action of the administered corticosteroid is more prolonged in females than in males. The injection of the corticosteroid caused metabolic modifications which resemble in their modulations and in their chronological development those found in circulating granulocytes of guinea-pigs suffering from sterile peritonitis. These results suggest, therefore, that, in the case of acute inflammation, the glucocorticosteroids may play an important role in the regulation of the metabolism of the blood leucocytes.

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