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He X.,Radboud University Nijmegen | Smeets R.L.,Immune Therapeutics | Koenen H.J.P.M.,Radboud University Nijmegen | Vink P.M.,Immune Therapeutics | And 4 more authors.
American Journal of Transplantation | Year: 2011

Mycophenolic acid is the active ingredient of the immunosuppressant mycophenolate mofetil that is widely used in transplantation medicine and autoimmunity. Mycophenolic acid inhibits inosinemonophosphate dehydrogenase, an enzyme involved in biosynthesis of guanine nucleotides required for lymphocyte clonal expansion. Here, we present novel insights into the mechanisms underlying mycophenolic acid-mediated suppression of human CD4+ T cells. Upon CD3/CD28 stimulation, mycophenolic acid inhibited T cell IL-17, IFN-γ and TNF-α production but not IL-2 production. Phenotypic analysis showed that drug treatment enhanced the expression of negative co-stimulators PD-1, CTLA-4 and the transcription factor FoxP3 and decreased the expression of positive costimulators CD27 and CD28, whereas CD25 was unaffected. Mycophenolic acid-treated cells were anergic, but not suppressive, and at the same time proved hyperblastoid with high metabolic activity. Moreover, a reduced Akt/mTOR and STAT5 signalingwas observed. Interestingly, the co-stimulatory molecule CD70 was uniquely and dose-dependently upregulated on mycophenolic acid-treated T cells and found to be directly linked to target enzyme inhibition. CD70 on mycophenolic acid-treated cells proved functional: an anti-CD70 agonistwas found to restore both STAT5 and Akt/mTOR signaling and may thereby prevent apoptosis and promote survival. These novel insights may contribute to optimization of protocols for MPA-based immunosuppressive regimens. © 2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.


Nicodemus C.F.,Immune Therapeutics | Wang L.,Immune Therapeutics | Lucas J.,Immune Therapeutics | Varghese B.,Stanford University | Berek J.S.,Stanford University
American Journal of Obstetrics and Gynecology | Year: 2010

Objective: The purpose of this study was to explore the potential of toll-like receptor-3 stimulation, with polyI:C12U (poly[l].poly[C12,U]; rintatolimod [Ampligen; Hemispherx Biopharma, Philadelphia, PA]) to enhance bioactivity of cancer immunotherapies. Study Design: Several models of immune activation were assessed with polyI:C12U at concentrations that were achieved clinically. Dendritic cell maturation and antigen-specific immune responses were evaluated in vitro and in a murine model. The potential for polyI:C12U to enhance antibody-dependent cellular cytotoxicity against tumor was also evaluated. Results: Dendritic cells are matured and T-cell stimulation is enhanced in the presence of polyI:C12U. In addition, polyI:C12U induced the release of proinflammatory chemokines and cytokines. Prostate-specific antigen-specific T-cell and antibody responses were enhanced significantly in a BALB/c prostate-specific antigen transgenic mouse model. Finally, rituximab-mediated antibody-dependent cellular cytotoxicity against tumor targets was improved significantly by the addition of polyI:C12U. Conclusion: PolyI:C12U shows promise as a potential agent for selective enhancement of effect with currently available and future cancer immunotherapies. © 2010 Mosby, Inc. All rights reserved.


Linssen M.M.L.,Leiden University | van Raalte D.H.,VU University Amsterdam | Toonen E.J.M.,Immune Therapeutics | Alkema W.,Merck And Co. | And 6 more authors.
Cellular Signalling | Year: 2011

Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2α. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death. © 2011 Elsevier Inc.


Frijters R.,Radboud University Nijmegen | van Vugt M.,Immune Therapeutics | Smeets R.,Immune Therapeutics | van Schaik R.,Schering | And 3 more authors.
PLoS Computational Biology | Year: 2010

The scientific literature represents a rich source for retrieval of knowledge on associations between biomedical concepts such as genes, diseases and cellular processes. A commonly used method to establish relationships between biomedical concepts from literature is co-occurrence. Apart from its use in knowledge retrieval, the co-occurrence method is also wellsuited to discover new, hidden relationships between biomedical concepts following a simple ABC-principle, in which A and C have no direct relationship, but are connected via shared B-intermediates. In this paper we describe CoPub Discovery, a tool that mines the literature for new relationships between biomedical concepts. Statistical analysis using ROC curves showed that CoPub Discovery performed well over a wide range of settings and keyword thesauri. We subsequently used CoPub Discovery to search for new relationships between genes, drugs, pathways and diseases. Several of the newly found relationships were validated using independent literature sources. In addition, new predicted relationships between compounds and cell proliferation were validated and confirmed experimentally in an in vitro cell proliferation assay. The results show that CoPub Discovery is able to identify novel associations between genes, drugs, pathways and diseases that have a high probability of being biologically valid. This makes CoPub Discovery a useful tool to unravel the mechanisms behind disease, to find novel drug targets, or to find novel applications for existing drugs. © 2010 Frijters et al.


PubMed | Nanjing Medical University, Immune Therapeutics and Shenyang University
Type: | Journal: International immunopharmacology | Year: 2016

Previously it was confirmed that naltrexone, a non-peptide -opioid receptor selective antagonist is mainly used for alcoholic dependence and opioid addiction treatment. However, there is increasing data on immune regulation of low dose naltrexone (LDN). The aim of this work was to explore the effect of LDN on the phenotype and function of macrophage. The changes of macrophage after treatment with LDN were examined using flow cytometry (FCM); FITC-dextran phagocytosis and enzyme-linked immunosorbent assay (ELISA). We have found that LDN enhances function of macrophage as confirmed by up-regulating MHC II molecule and CD64 on macrophage while down-regulating CD206 expression. Furthermore the productions of TNF-, IL-6, IL-1, increased significantly. Macrophages in LDN treated group performed the enhanced phagocytosis. Therefore it is concluded that LDN could promote function of macrophage and this work has provided concrete data of impact on immune system by LDN. Especially the data would support interaction between CD4+T cell and macrophage in AIDS treatment with LDN in Africa (LDN has already been approved in Nigeria for the use in AIDS treatment).


PubMed | China Medical University at Heping, Liaoning Medical University and Immune Therapeutics
Type: | Journal: International immunopharmacology | Year: 2016

Methionine enkephalin (MENK), an endogenous neuropeptide has a crucial role in both neuroendocrine and immune systems. MENK is believed to have an immunoregulatory activity to have cancer biotherapy activity by binding to the opioid receptors on immune and cancer cells. Clinical trial studies in cancer patients have shown that MENK activates immune cells directly and by inhibiting regulatory T-cells (Tregs). MENK may also change the tumor microenvironment by binding to opioid receptor on or in cancer cells. All of these mechanisms of action have biologic significance and potential for use in cancer immunotherapy. Furthermore, they reveal a relationship between the endocrine and immune systems. Due to the apparent role of MENK in cancer therapy we reviewed herein, the research undertaken with MENK in recent years; which has advanced our understanding of the role MENK has in cancer progression and its relationship to immunity, supporting MENK as a new strategy for cancer immunotherapy.


PubMed | Immune Therapeutics
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

5507 Background: Translating cancer specific immune stimulation into clinical benefit is a challenge. This ph III study tested the hypothesis that oregovomab (o) mono-immunotherapy IT following front-line therapy in a selected patient population pt would prolong time-to-relapse TTR and ultimately survival. The population was identified in an exploratory analysis of an earlier ph IIb study. O binds circulating CA125 stimulating a cellular immune response targeting CA125 and tumor.Stage III/IV OV CA pts with <2 cm residual disease, CA125 <65 U/nl prior to cycle 3 and NED with CA125 5-35 at end of primary therapy were randomized to o or placebo (pbo) in a double blind protocol. 2 mg of o or pbo was infused at wks 0, 4, and 8 and then q12 wks until recurrence or year 5. Pts received serial imaging and/or clinical evaluation for recurrence q12 wks. TTR was primary endpoint. The protocol was divided into two identical studies 17A &17B each with 80% power at =0.05 to detect a 6 m difference in TTR with N=177 randomized 2:1 to permit internal independent confirmation of results.371 pts were accrued at >60 centers, 251 to o and 120 to pbo. The arms were well balanced except for distant metastasis at staging which were observed in 17% of o but only 8% of pbo pt at staging CT. There were no differences in the clinical outcomes between treatment groups. TTR measured from randomization 4-12 weeks post completion of carboplatin- paclitaxel based chemotherapy was 10.3 m [9.7,13.0] for o and 12.9 m [10.1, 17.4] for pbo p=0.29 log rank test. Results were consistent in 17A&B. The treatment was well tolerated. The incidence of serious adverse events was 19% for pbo and 14% for o, mostly related to disease progression. Grade 3/4 toxicity was reported in 25% of pbo and 20% of o pts respectively. There were no differences in quality of life scores.Although o has demonstrated bioactivity, the strategy of monoIT is not effective as maintenance therapy following front-line treatment of advanced OV CA. The treatment was not associated with additive toxicity. Recent data demonstrating that schedule-sensitive concomitant chemoIT results in more vigorous immune stimulation than monoIT suggests that future studies of this or other tumor antigen specific immunization strategies focus on primary concurrent chemoIT. [Table: see text].


ORLANDO, FL--(Marketwired - Dec 12, 2016) - Immune Therapeutics, Inc. ( : IMUN) ("Immune Therapeutics"), a clinical-stage biotech company providing immunotherapy solutions for the treatment of autoimmune disease and cancer, today announced with immense sadness the passing of Christopher Pearce, one of the founders of Immune Therapeutics and its chief operating officer. Mr. Pearce passed away after a 10-year battle with cancer. "This is a very sad time for all of us at Immune Therapeutics," said Noreen Griffin, chief executive officer. "Chris was a great friend, respected colleague and a valuable member of our executive management team. We will miss him deeply. We extend our sympathies to his family and friends at this difficult time." Immune Therapeutics is a biotechnology company working to combat chronic, life-threatening diseases through the activation and modulation of the body's immune system using its patented immunotherapies with a focus of providing such therapies in emerging nations. Its products and immunotherapy technologies are designed to harness the power of the immune system to improve the treatment of cancer, infections such as HIV/AIDS, chronic inflammatory and autoimmune diseases. Immune Therapeutics' proprietary technology, therapies and patents include the treatment of a wide range of cancers. Its most advanced clinical programs involve immunotherapy with met-enkephalin (MENK) (sometimes referred to as opioid growth factor) and its Low Dose Naltrexone product (LDN) or Lodonal™, which have been shown to stimulate the immune system even in patients with advanced cancer.


ORLANDO, Fla., Nov. 15, 2016 (GLOBE NEWSWIRE) -- Immune Therapeutics, Inc. (OTCQB:IMUN) a clinical-stage biotech company providing immunotherapy solutions for the treatment of autoimmune disease and cancer, today announced it has redeemed its $656,250 convertible note issued to JMJ Financial. With stronger market confidence in the Company’s fundamentals based on its recent progress in licensing, producing and obtaining regulatory approvals for LodonalTM and other drugs in its portfolio in Africa, Immune Therapeutics reports its cost of capital is decreasing and is actively working to restructure and strengthen its balance sheet by year end. This effort includes a recent capital raise of $750,000 in a straight, non-convertible debt instrument, from a long-term investor, at a simple interest rate of 2% for one year. Those funds were allocated, in part, to pay off the JMJ convertible debenture.  The Company is also in active discussions to restructure approximately $1.7 million in liabilities by year end so it may enter 2017 with a stronger financial foundation. “In 2016, Immune Therapeutics achieved several important company milestones in collaboration with our joint venture and strategic industry partners here in the U.S., Latin America and Africa,” said Noreen Griffin, Chief Executive Officer of Immune Therapeutics. “With several important portfolio drugs in various stages of application, clinical trial, registration and commercialization, I am confident we are turning the corner both financially and operationally and believe that 2017 could be a breakout year for Immune Therapeutics and its shareholders,” concluded Ms. Griffin. Immune Therapeutics, Inc. (OTCQB:IMUN) is a biotechnology company working to combat chronic, life-threatening diseases through the activation and modulation of the body's immune system using its patented immunotherapies with a focus of providing such therapies in emerging nations. Its products and immunotherapy technologies are designed to harness the power of the immune system to improve the treatment of cancer, infections such as HIV/AIDS, chronic inflammatory and autoimmune diseases. The Company's proprietary technology, therapies and patents include the treatment of a wide range of cancers.  Its most advanced clinical programs involve immunotherapy with met-enkephalin (MENK) (sometimes referred to as opioid growth factor) and its Low Dose Naltrexone product (LDN) or LodonalTM, which have been shown to stimulate the immune system even in patients with advanced cancer. Forward Looking Statements This release may contain forward-looking statements. Actual results may differ from those projected due to a number of risks and uncertainties, including, but not limited to, the possibility that some or all of the matters and transactions considered by the Company may not proceed as contemplated, and by all other matters specified in the Company's filings with the Securities and Exchange Commission. These statements are made based upon current expectations that are subject to risk and uncertainty. The Company does not undertake to update forward-looking statements in this news release to reflect actual results, changes in assumptions or changes in other factors affecting such forward-looking information. Assumptions and other information that could cause results to differ from those set forth in the forward-looking information can be found in the Company's filings with the Securities and Exchange Commission (www.sec.gov), including its recent periodic reports.

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