Immune response to reovirus (REO) in phase I study with chemotherapy in patients with KRAS mutant metastatic colorectal cancer (mCRC).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 217-217 ◽  
Author(s):  
Ruwan Parakrama ◽  
Imran Chaudhary ◽  
Matthew C. Coffey ◽  
Sanjay Goel ◽  
Radhashree Maitra
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Cells ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Interleukin 1 ◽  
Peripheral Circulation ◽  
Strong Immune Response ◽  
Peripheral Blood Mononuclear ◽  
Gm Csf

217 Background: Viruses are well known immune sensitizing agents. The therapeutic efficacy of oncolytic reovirus in combination with chemotherapy is underway in a phase 1 study of mCRC. This study evaluates the nature of immune response by determining the distribution of antigen presenting cells (APCs) and activated T lymphocytes along with the cytokine expression pattern in peripheral circulation. Methods: REO was administered as a 60-minute intravenous infusion for 5 consecutive days every 28 days, at a tissue culture infective dose (TCID50) of 3x106. Serum was collected pre- and post- REO on days 1, pre REO on days 2-5, and days 8, 15, 22, and 29. Peripheral blood mononuclear cells (PBMC) were isolated and stained with fluorophore labelled antibodies against CD4, CD8, CD56, CD70, and CD123. Stained cells were fixed and evaluated by flow cytometry. The expression profile of 25 cytokines in plasma was assessed (post PBMC isolation) on an EMD Millipore multiplex Luminex platform. Results: Patients mount a robust immune response with dendritic cell maturation at 48 hrs (p < 0.01) followed by activation of cytotoxic T (CD8+) cells at Day 8 (p < 0.01). Cytokine assay indicated upregulation of Interleukin 1 beta (IL-1β; p = 0.004), Granulocyte-macrophage colony-stimulating factor (GM-CSF; p = 0.05), the chemokine Macrophage Inflammatory Proteins (MIP-1β; p = 0.05) at day 15. Furthermore, consistent upregulation of inflammatory cytokine IL-6 was seen from days 3 through 8 (p < 0.05), and decrease in IL-8 at 72 hrs (p = 0.03) was observed. Conclusions: REO induces strong immune response in patients with mCRC. APCs are stimulated within 48 hrs and activated (CD8+ CD70+) T cells within 168 hrs. Cytokine profiling indicates stimulation for maturation of APCs, chemotactic induction for macrophages and activation of T cells as highlighted by release of IL-1β, GM-CSF and MIP-1β respectively. Sustained increased expression of IL-6 (triggering lymphocyte maturation) and downregulation of IL-8 (pro-angiogenic cytokine) is also observed. REO thus functions bimodally as an oncolytic agent causing lysis of tumor cells, and facilitator of immune-mediated recognition and destruction of tumor cells. Clinical trial information: NCT01274624.

scholarly journals Single-cell multi-omics analysis of the immune response in COVID-19

2021 ◽  
Author(s):  
Emily Stephenson ◽  
◽  
Gary Reynolds ◽  
Rachel A. Botting ◽  
Fernando J. Calero-Nieto ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Single Cell ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
Effector Memory ◽  
Peripheral Blood Mononuclear ◽  
Cross Sectional ◽  
Hematopoietic Stem ◽  
Symptomatic Disease

AbstractAnalysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

scholarly journals Human Autologous In Vitro Models of Glioma Immunogene Therapy Using B7-2, GM-CSF, and IL12

2002 ◽  
Vol 29 (3) ◽  
pp. 267-275 ◽  
Author(s):  
Ian F. Parney ◽  
Maxine A. Farr-Jones ◽  
Kevin Kane ◽  
Lung-Ji Chang ◽  
Kenneth C. Petruk
Keyword(s):  
Tumor Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Wild Type ◽  
Peripheral Blood Mononuclear ◽  
Gm Csf ◽  
Blood Mononuclear Cells ◽  
Immunogene Therapy ◽  
Tumor Cytotoxicity

Background:Cancer immunogene therapy is based on vaccination with radiated, autologous tumor cells transduced with immunostimulatory genes. To help determine an optimal glioma immunogene therapy strategy, we stimulated lymphocytes with autologous human glioma cells transduced with B7-2 (CD86), granulocyte-macrophage colony-stimulating factor (GM-CSF), and/or interleukin-12 (IL12).Methods:A human glioma-derived cell culture (Ed147.BT) was transduced with B7-2, GM-CSF, and/or IL12 using retroviral vectors. Autologous peripheral blood mononuclear cells (PBMC) were co-cultured with irradiated gene-transduced tumor alone or a combination of radiated wild type and gene-transduced cells. Peripheral blood mononuclear cells proliferation was determined by serial cell counts. Peripheral blood mononuclear cells phenotype was assessed by flow cytometry for CD4, CD8, and CD16. Anti-tumor cytotoxicity was determined by chromium-51 (51Cr) release assay.Results:Peripheral blood mononuclear cells cell numbers all decreased during primary stimulation but tumor cells expressing B7-2 or GM-CSF consistently caused secondary proliferation. Tumors expressing B7-2 and GM-CSF or B7-2, GM-CSF, and IL12 consistently increased PBMC CD8+ (cytotoxic T) and CD16+ (natural killer) percentages. Interestingly, anti-tumor cytotoxicity only exceeded that of PBMC stimulated with wild type tumor alone when peripheral blood mononuclear cells were stimulated with both wild type tumor and B7-2/GM-CSF- (but not IL12) transduced cells.Conclusion:PBMC proliferation and phenotype is altered as expected by exposure to immunostimulatory gene-transduced tumor. However, transduced tumor cells alone do not stimulate greater anti-tumor cytotoxicity than wild type tumor. Only B7-2/GM-CSF-transduced cells combined with wild type produced increased cytotoxicity. This may reflect selection of tumor subclones with limited antigenic spectra during retrovirus-mediated gene transfer.

scholarly journals IL-38: A New Player in Inflammatory Autoimmune Disorders

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 345 ◽  
Author(s):  
Lihui Xie ◽  
Zhaohao Huang ◽  
He Li ◽  
Xiuxing Liu ◽  
Songguo Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Autoimmune Disorders ◽  
Current Data ◽  
Peripheral Blood Mononuclear ◽  
Anti Inflammatory ◽  
Inflammatory Autoimmune Diseases

Interleukin (IL)-38, a newly discovered IL-1 family cytokine, is expressed in several tissues and secreted by various cells. IL-38 has recently been reported to exert an anti-inflammatory function by binding to several receptors, including interleukin-36 receptor (IL-36R), interleukin-1 receptor accessory protein-like 1 (IL-1RAPL1), and interleukin-1 receptor 1 (IL-1R1) to block binding with other pro-inflammatory cytokines and inhibit subsequent signaling pathways; thereby regulating the differentiation and function of T cells, peripheral blood mononuclear cells, macrophages, and dendritic cells. Inflammatory autoimmune diseases, which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T helper cells (Ths), especially Th1s and Th17s, and regulatory T cells (Tregs). Recent findings have shown that abnormal expression of IL-38 in inflammatory autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, primary Sjogren’s syndrome, psoriasis, inflammatory bowel disease, hidradenitis suppurativa, ankylosing spondylitis, and glaucoma, involves Th1s, Th17s, and Tregs. In this review, the expression, regulation, and biological function of IL-38 are discussed, as are the roles of IL-38 in various inflammatory autoimmune disorders. Current data support that the IL-38/IL-36R and/or IL-38/IL-1RAPL1 axis primarily play an anti-inflammatory role in the development and resolution of inflammatory autoimmune diseases and indicate a possible therapeutic benefit of IL-38 in these diseases.

scholarly journals Anti-lymphocyte globulin stimulates normal human T cells to proliferate and to release lymphokines in vitro. A study at the clonal level

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 956-963
Author(s):  
GC Barbano ◽  
A Schenone ◽  
S Roncella ◽  
R Ghio ◽  
A Corcione ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Gm Csf ◽  
Recombinant Interleukin 2 ◽  
Macrophage Colony

Abstract Human peripheral blood mononuclear cells (PBMC) were stimulated in vitro with anti-lymphocyte globulin (ALG), and the phenotypic and functional properties of the blasts obtained were investigated. When stained with monoclonal antibodies (MoAbs), all of the blasts were identified as T cells that expressed predominantly the CD4 phenotype (70% of the cells). The remaining blasts were CD8+. These findings demonstrate that ALG stimulates both helper-inducer and cytotoxic- suppressor cells at random since the CD4 to CD8 ratio in the stimulated blasts was the same as in resting PBMC. This ratio is different from that observed in short-term cultures of T cells stimulated with phytohemagglutinin (PHA) under the same conditions (CD4 to CD8 ratio less than 1). ALG-stimulated T cells were cloned by limiting dilution in the presence of recombinant Interleukin-2 (rIL-2). The clones obtained were expanded and maintained in long term cultures with rIL-2. Thirty-two clones were tested for their capacity of producing colony stimulating activity (CSA) or burst promoting activity (BPA). Twenty- eight of them produced CSA and 12 produced BPA. No correlation was found between the surface phenotype and the ability of the clones to produce CSA or BPA (ie, both the CD4+ and CD8+ clones released the cytokines). When 16 of the same clones were tested for II-2 and gamma interferon (gamma IFN) production, 12 were found to be gamma INF and IL- 2 producers. All of the gamma IFN producers also released IL-2, whereas in the single clones no correlation was found with the capacity of releasing BPA and CSA. Supernatants from selected T-cell clones were also tested for hematopoietic growth factor activities in the presence of neutralizing antisera to human granulocyte-macrophage colony stimulating factor (GM-CSF) or to Interleukin-3 (IL-3). It was found that most CSA was attributable to GM-CSF, whereas BPA was mainly related to the presence of IL-3.

scholarly journals Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer

2008 ◽  
Vol 105 (40) ◽  
pp. 15505-15510 ◽  
Author(s):  
Yoshihiro Miyahara ◽  
Kunle Odunsi ◽  
Wenhao Chen ◽  
Guangyong Peng ◽  
Junko Matsuzaki ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Cells ◽  
Ovarian Tumor ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Immune Response To Cancer ◽  
Ovarian Tumor Cells

Despite the important role of Th17 cells in the pathogenesis of many autoimmune diseases, their prevalence and the mechanisms by which they are generated and regulated in cancer remain unclear. Here, we report the presence of a high percentage of CD4+ Th17 cells at sites of ovarian cancer, compared with a low percentage of Th17 cells in peripheral blood mononuclear cells from healthy donors and cancer patients. Analysis of cytokine production profiles revealed that ovarian tumor cells, tumor-derived fibroblasts, and antigen-presenting cells (APCs) secreted several key cytokines including IL-1β, IL-6, TNF-α and TGF-β, which formed a cytokine milieu that regulated and expanded human IL-17-producing T-helper (Th17) cells. We further show that IL-1β was critically required for the differentiation and expansion of human Th17 cells, whereas IL-6 and IL-23 may also play a role in the expansion of memory Th17 cells, even though IL-23 levels are low or undetectable in ovarian cancer. Further experiments demonstrated that coculture of naïve or memory CD4+ T cells with tumor cells, APCs, or both could generate high percentages of Th17 cells. Treatment with anti-IL-1 alone or a combination of anti-IL-1 and anti-IL-6 reduced the ability of tumor cells to expand memory Th17 cells. Thus, we have identified a set of key cytokines secreted by ovarian tumor cells and tumor-associated APCs that favor the generation and expansion of human Th17 cells. These findings should accelerate efforts to define the function of this important subset of CD4+ T cells in the human immune response to cancer.

scholarly journals Role of Capsule and Interleukin-6 in Long-Term Immune Control of Cryptococcus neoformans Infection by Specifically Activated Human Peripheral Blood Mononuclear Cells

2006 ◽  
Vol 74 (9) ◽  
pp. 5302-5310 ◽  
Author(s):  
Asna A. Siddiqui ◽  
Robin J. Shattock ◽  
Thomas S. Harrison
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Interleukin 6 ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Immune Control ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

ABSTRACT Cryptococcus neoformans is a frequent cause of meningoencephalitis in immunosuppressed individuals. To better understand the mechanisms of a protective immune response to C. neoformans, a long-term in vitro model of human immune control of cryptococcal infection was developed. Peripheral blood mononuclear cells (PBMC) prestimulated with heat-killed C. neoformans significantly restricted the growth of C. neoformans after a subsequent live infection compared to that with unstimulated PBMC. Live infection with encapsulated C. neoformans was controlled for as long as 10 days, while infection with acapsular organisms could sometimes be eradicated. During immune control, fungal cells were both intracellular and extracellular within aggregates of mononuclear phagocytes and lymphocytes. Optimal immune control depended on the presence of both CD4+ and CD8+ T cells. Immune control of cryptococcal growth was more effective following prestimulation with acapsular compared with encapsulated organisms. Prestimulation with acapsular organisms was associated with a significant and prolonged increase in interleukin-6 (IL-6) production compared with prestimulation with encapsulated C. neoformans. Addition of IL-6 and depletion of CD25+ T cells prior to prestimulation and infection with encapsulated organisms resulted in reductions in cryptococcal growth that reached borderline statistical significance. Depletion of CD25+ T cells significantly reduced cryptococcal growth in wells with unstimulated PBMC. The results demonstrate an association between high levels of IL-6 and resistance to infection and, through suppression of IL-6 release, an additional mechanism whereby the cryptococcal capsule subverts a protective immune response. Further work is required to clarify the mechanism of action of IL-6 in this setting and any interaction with regulatory T cells.

scholarly journals Immune Response Profiling of Patients with Anogenital Warts

2017 ◽  
Vol 21 (1) ◽  
pp. 11-16
Author(s):  
Manjula Singh ◽  
Deepshi Thakral ◽  
Hemanta K Kar ◽  
Narayan Rishi ◽  
Dipendra K Mitra
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mononuclear Cells ◽  
Anogenital Warts ◽  
Th2 Response ◽  
Peripheral Blood Mononuclear ◽  
Intracellular Cytokines ◽  
Venereal Warts ◽  
Near Future

ABSTRACT The incidence of anogenital warts, commonly caused by human papillomavirus (HPV-6 and HPV-11), is increasing worldwide. These infections are frequently associated with relapse, possibly due to weak host immunity. However, the role of cell-mediated immune players in combating infection is not clearly understood till date. Here, we attempted to understand the immune profile among patients with anogenital warts. In this study, we compared the T-helper cell (Th1 and Th2) response in patients with venereal warts due to HPV-6 and HPV-11 infection relative to healthy controls (HCs) in vitro. In the in vitro model, the peripheral blood mononuclear cells were stimulated with HPV peptide 6 or 11, stained for T-cell surface marker and intracellular cytokines (interferon [IFN]-□ and interleukin [IL]-4), and were analyzed by flow cytometry. In the present study, significant decrease was observed in the frequency of IFN-□ T cells as compared with HCs. On the contrary, frequency of T cells expressing IL-4 was significantly increased in the patients. The observed functional skewing of HPV-specific T cells from Th1 to Th2 response in patients indicated suppressed immunity against the HPVs. Findings of our study have potential in the near future for strategizing adjunct immunomodulation approaches with the standard treatment for early remission and prevention of recurrence. How to cite this article Singh M, Thakral D, Kar HK, Rishi N, Mitra DK. Immune Response Profiling of Patients with Anogenital Warts. Indian J Med Biochem 2017;21(1):11-16.

Effect of vorinostat (VOR) and hydroxychloroquine (HCQ) on immunity and autophagy in metastatic colorectal cancer (mCRC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 670-670
Author(s):  
Sukeshi R. Patel ◽  
Vincent Hurez ◽  
Steffan T Nawrocki ◽  
Martin Goros ◽  
Joel Michalek ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Immunity ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Peripheral Blood Mononuclear ◽  
Lysosomal Protease ◽  
Grade 5 ◽  
Grade 3 ◽  
Expansion Cohort

670 Background:HCQ enhances the anti-cancer activity of the histone deacetylase inhibitor, VOR in pre-clinical CRC models. Our phase 1 dose escalation trial found that patients (pts) with mCRC obtained prolonged clinical benefit from VOR + HCQ. Thus, a single arm expansion cohort in refractory mCRC was done. Methods: Pts with refractory mCRC received VOR 600 mg by mouth (PO) + HCQ 400 mg PO daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS), adverse events (AE) (NCI-CTCAEv3.0), flow cytometry (FACS) of peripheral blood mononuclear cells (PBMCs), tumor biopsies. Results: 20 pts were enrolled (19 evaluable for survival): mean age 61 (44-74). Female 7/male 23, 9 Caucasian/10 Hispanic/1 Black, 11 KRAS mutated. ECOG 0-1 (18 pts). 3+ prior lines (13), previous regorafenib (4). Dose level reduction on study (7). mPFS 2.8 months (95% CI: 1.63-8.16). mOS 6.7 months (95% CI: 4.63-NR). Treatment-related grade 3 AEs: nausea/vomiting (3), anemia (3). Grade 4 thrombocytopenia (3). Grade 4 INR elevation (1 pt on Coumadin). No grade 5 AEs. Five pts (26%) had stable disease ≥12 weeks. Treatment significantly reduced regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and increased CD45RO+CD62L-CD4+ (effector) T cells, consistent with improved anti-tumor immunity. On-study biopsies (3) showed increased lysosomal protease CTSD and LC3-II consistent with autophagy inhibition. Conclusions: VOR/HCQ is active, safe and tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity (decreased exhausted and regulatory T cells and increased effector phenotype T cells) and reduced tumor autophagy. A randomized phase II trial of VOR/HCQ versus regorafenib is now open. Clinical trial information: NCT01023737.

Activated Dendritic Cells From Bone Marrow Cells of Mice Receiving Cytokine-Expressing Tumor Cells Are Associated With the Enhanced Survival of Mice Bearing Syngeneic Tumors

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4328-4335
Author(s):  
Shin-ichiro Fujii ◽  
Hirofumi Hamada ◽  
Koji Fujimoto ◽  
Taizo Shimomura ◽  
Makoto Kawakita
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Cells ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Interleukin 4 ◽  
Gm Csf ◽  
Tumor Bearing ◽  
Macrophage Colony

Dendritic cells (DCs), which phagocytose antigens and subsequently proliferate and migrate, may be the most powerful antigen-presenting cells that activate naive T cells. To determine their role in the immune response to tumors, we used WEHI-3B murine leukemia cells transduced with adenovirus vectors expressing cytokines. We found that mixtures of irradiated cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) plus those expressing interleukin-4 (IL-4) or tumor necrosis factor  (TNF) protected mice against WEHI-3B–induced leukemias. When bone marrow mononuclear cells (BMMNCs) obtained from mice that had been injected with irradiated, cytokine-expressing tumor cells were injected into tumor-bearing mice, the survival of the latter was significantly prolonged; the longest survival was observed in mice receiving BMMNCs containing an increased number of DCs from animals injected with a mixture of tumor cells expressing GM-CSF with those expressing IL-4. Assay for antileukemic effects in spleen of the latter animals showed specific antitumor cytotoxicity against WEHI-3B, suggesting that DCs from donor mice activate specific T cells in the tumor-bearing recipients. These results suggest that the infusion of syngeneic BMMNCs stimulated with cytokine-expressing tumor cells may be effective in treating certain types of tumors.

scholarly journals Spermine Inhibits Proinflammatory Cytokine Synthesis in Human Mononuclear Cells: A Counterregulatory Mechanism that Restrains the Immune Response

1997 ◽  
Vol 185 (10) ◽  
pp. 1759-1768 ◽  
Author(s):  
Minghuang Zhang ◽  
Theresa Caragine ◽  
Haichao Wang ◽  
Pamela S. Cohen ◽  
Galina Botchkina ◽  
...  
Keyword(s):  
Immune Response ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Mononuclear Cells ◽  
Molecular Mimicry ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
Peripheral Blood Mononuclear ◽  
Cytokine Synthesis

The local production of proinflammatory cytokines mediates the host response to inflammation, infection, and injury, whereas an overexpression of these mediators can injure or kill the host. Recently, we identified a class of multivalent guanylhydrazone compounds that are effective inhibitors of proinflammatory cytokine synthesis in monocytes/macrophages. The structure of one such cationic molecule suggested a molecular mimicry with spermine, a ubiquitous endogenous biogenic amine that increases significantly at sites of inflammation and infection. Here, we addressed the hypothesis that spermine might counterregulate the innate immune response by downregulating the synthesis of potentially injurious cytokines. When spermine was added to cultures of human peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), it effectively inhibited the synthesis of the proinflammatory cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, MIP-1α, and MIP-1β. The inhibition of cytokine synthesis was specific and reversible, with significant inhibition of TNF synthesis occurring even when spermine was added after LPS. The mechanism of spermine-mediated cytokine suppression was posttranscriptional and independent of polyamine oxidase activity. Local administration of spermine in vivo protected mice against the development of acute footpad inflammation induced by carrageenan. These results identify a distinct molecular counterregulatory role for spermine in downregulating the monocyte proinflammatory cytokine response.

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