Day 1 :
Keynote Forum
Giulio Tarro
Foundation de Beaumont Bonelli for Cancer Research, Italy
Keynote: Tumor associated antigen (TAA) as immune approach for early diagnosis and preventive therapy
Time : 10:00-10:30
Biography:
Giulio Tarro has done his graduation from Naples University (1962). He was a Research Associate, Division of Virology and Cancer Research, Children’s Hospital (1965-1968) and was an Assistant Professor of Research Pediatrics, College of Medicine (1968-1969), Cincinnati University, Ohio. He was a Professor of Oncology and Molecular Virology, Naples University (1972-1985). Since 2007, he is the Chairman of Committee of Biotechnologies, World Academy Biomedical Technologies, UNESCO, Adjunct Professor in the Department of Biology, Temple University, College of Science and Technology, Philadelphia. He is the President of Foundation de Beaumont Bonelli for Cancer Research. His researches have been concerned with the characterization of specific virus-induced tumor antigens, which were the "finger-prints" left behind in human cancer.
Abstract:
Tumor liberated protein (TLP) has been previously described as a TAA (complex) present in the sera of lung cancer patients with early stage disease. Since early detection improves overall survival in lung cancer, identification of screening biomarkers for patients at risk for the development of this disease represents an important target. Starting from the peptide epitope RTNKEASI previously isolated from TLP complexes, we generated a rabbit anti-RTNKEASI serum. This antiserum detected and immuno-precipitated a 55 kDa protein band in the lysate of the lung cancer cell line A549. This protein band was identified as aldehyde dehydrogenase isoform 1A1 through mass spectrometry, revealing the molecular nature of at least one component of the previously described TLP complex. Next, we screened a cohort of 29 lung cancer patients (all histologies), 17 patients with non-neoplastic lung pathologies and 9 healthy donors for the presence of serum ALDH1A1 and global serum ALDH by enzyme-linked immunosorbent assay. This analysis indicated that the presence of ALDH was highly restricted to patients with lung cancer. Interestingly, the global ALDH test could accurately detect more lung cancer patients compared to the ALDH1A1-specific test, suggesting that other ALDH isoforms might add to the sensitivity of the assay. Our data suggest that ALDH levels may therefore be evaluated as part of a marker panel for lung cancer screening. Finally, the ability of the immune system to recognize a TAA enables the development of a vaccine approach for preventive and therapeutic application and represents a main target in this field of research.
References:
1. E Trapanese, U Scognamiglio, P Amato and G Tarro (2016) Preliminary data on the role of contrast enhanced ultrasound (CEUS) in early diagnosis and staging of rheumatoid arthritis. International Education and Research Journal, 2(8):41-42.
2. G Tarro (2015) Migratory Phenomenons, Biothics and Vaccinations Advances in Microbiology. Scientific Research Publishing 5:720-723.
3. G Tarro (2016) Lights and shadows of vaccinations. J. of Vaccine Research and Development 1 (1):1-4.
4. G Tarro (2014) Viral latency, molecular pathogenesis and malignancy. Global Journal of Science Frontier Research 14(3):55-60.
5. P Altucci, G Tarro (2014) Ruolo dell’ Etio-patogenesi in Medicina Interna. Policlinico Sez. Med. 121:61-81.
Keynote Forum
Michael G Hanna
Vaccinogen Inc., USA
Keynote: A backdoor into the castle: The clinical ramifications of immuno-editing driven by antigenic compe
Time : 10:30-11:00
Biography:
Michael G Hanna has received his PhD in Experimental Pathology and Immunology from the University of Tennessee (TN, USA). He was a Consultant in NASA for the lunar receiving laboratory during Apollo 11 and 12, for which his expertise in Immunology was used in the testing of the lunar core powder for immunogenic or pathogenic materials. He has worked as the Director of the National Cancer Institute, Frederick Cancer Research Center (MD, USA) during 1974-83.
Abstract:
At the cellular level, it is clear that cancer is a genetic disease arising as a clone that expands and grows in an unregulated manner. While it has always been presumed that neoplasia is a consequence of somatic cell mutations, only in the last few years the magnitude and diversity of these mutations have been elucidated by modern DNA sequencing technology. Immunotherapy is the premier biological approach to targeted therapies. In this case, the targets are tumor specific or associated antigens and the proteins expressed from these somatic cell mutations. While the immunotherapeutic approach for eliminating cancer was launched with the assumption that cancer cells were homogeneous, the recent genomic understanding of tumor cells indicates that there is both inter- and intra-tumoral heterogeneity. This presentation will discuss the paradoxes and consequences of this new knowledge of tumor cell biology for the immunotherapeutic approach to treating cancer. Also, it will explain on the key host-tumor interactions such as antigenic-competition and immune editing and how the former drives the immunogenic characterization of the tumor, which helps it, survive in an immunocompetent host. In addition the use of immuno-edited tumors as a source of a patient specific, autologous vaccine may provide a pathway for the development of a peptide based vaccine for prophylaxes of adenocarcinomas.
- Cellular Immunology | Microbial Immunology | Molecular Immunology | Auto Immune Diseases | Tumor Immunology | Immunodermatology
Location: Rome, Italy
Chair
Giulio Tarro
Foundation de Beaumont Bonelli for Cancer Research, Italy
Co-Chair
Jessy S Deshane
University of Alabama at Birmingham, USA
Session Introduction
Saadia Kerdine-Römer
University Paris-Sud, France
Title: Protein kinase CK2 controls T cell polarization through dendritic cells activation in response to contact sensitizers
Biography:
Saadia Kerdine-Römer has experience in Immunotoxicology in the field of Skin Allergy. She has been working for many years in the activation of dendritic cells by allergenic molecules. She demonstrated that haptens can be real danger signals. She has worked on the identification of new signaling pathways in immunity cells in response to haptens. Currently, she is working on the transcription factor Nrf2 and its link in the inflammatory response of skin allergic origin.
Abstract:
Statement of the Problem: Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T cell-mediated inflammatory skin disease caused by chemicals present in daily or professional environment. Nickel sulfate (NiSO4) and 2, 4-dinitrochlorobenzene (DNCB) are two chemicals involved in ACD. These contact sensitizers are known to induce an up-regulation of phenotypic markers and cytokine secretion in dendritic cells (DCs), professional antigen-presenting cells, leading to the generation of CD8+ Tc1/Tc17 and CD4+ Th1/Th17 effector T cells.
Findings: In the present study, using a peptide array approach, we identify protein kinase CK2 as a new kinase involved in the activation of human monocytes-derived DCs (MoDCs) in response to NiSO4 and DNCB. Inhibition of CK2 activity in MoDCs leads to an altered mature phenotype with lower expression of CD54, PDL-1, CD86 and CD40 in response to NiSO4 or DNCB. We also show that CK2 activity regulates pro-inflammatory cytokine production such as TNF-a, IL-1b and IL-23 in MoDCs. Moreover, using a DC/T cell co-culture model in an allogeneic set-up, our work demonstrate that CK2 activity in MoDCs plays a major role in the Th1 polarization in response to NiSO4 and DNCB. Interestingly, we also demonstrate that CK2 inhibition in MoDCs leads to an enhanced Th2 polarization in the absence of contact sensitizer stimulation.
Conclusion & Significance: CK2 plays: (1) a role in phenotypic maturation and cytokine production in response to NiSO4 and DNCB; and (2) a major role in CD4+ T lymphocytes activation and in the control of Th1 polarization without affecting Th17 polarization.
Yaffa Mizrachi Nebenzahl
Ben Gurion University of the Negev, Israel
Title: Identification of novel S. pneumoniae candidate vaccine antigens and the nature of the immune response elicited by them
Biography:
Yaffa Mizrachi Nebenzahl has her expertise in Microbiology and Immunology and has studied Microbial Pathogenesis (innate and adaptive immune to microbial infections). She has completed her PhD from the Weizmann Institute, Rehovot, Israel. She is Head of the Molecular Microbiology Laboratory, Department of Microbiology, Immunology and Genetics at the Faculty of Health Sciences in Ben Gurion University of the Negev, Israel.
Abstract:
Mortality due to pneumococcal infections remains high worldwide, augmented by widespread antibiotic resistance in many pneumococcal strains. To identify protein antigens that could be involved in the development of protective immunity to S. pneumoniae, a pneumococcal cell wall protein-enriched extract was screened using 2-D gel electrophoresis and immunoblotting with either sera obtained longitudinally from children attending day-care centers or sera obtained from mice immunized with the pneumococcal cell wall protein extract. The identified proteins that share no- or low- homology to human proteins and which are conserved among different S. pneumoniae strains were tested for their ability to elicit protection against S. pneumoniae challenge in animal models. Moreover the nature of the elicited immune response was studied in mice. S. pneumoniae proteins PtsA, GtS, Nox, PsipB, FBA, TF and FtsZ were amplified from TIGR4 strain, cloned, expressed in E. coli and purified. Mice were immunized three times intra-nasally or subcutaneously with these proteins in presence of adjuvant and challenged two weeks later. Nasopharyngeal and lung colonization levels were quantified for 48 hours following bacterial challenge and survival was monitored daily for seven days. The cytokine profile elicited by rFBA was determined by multiplex ELISA. All seven proteins elicited protective immune responses in mice as determined by reduced nasopharyngeal and lung colonization, prolonged survival, and the ability of antibodies obtained from immunized mice to ex-vivo neutralize bacterial virulence for the intra-peritoneal challenge model. Moreover, rFBA elicits Th1, Th2 and Th17-type cytokines in mice. Taken together several antigenic and immunogenic protein with no or low homology to human proteins were identified and found to elicit protective immune response in the mouse model accompanied by Th1, Th2 and Th17 type of immune responses.
References:
1. Muchnik L, Adawi A, Ohayon A, Dotan S, Malka I, Azriel S, Shagan M, Portnoi M, Kafka D, Nahmani H, Porgador A, Gershon J M, Morrison D A, Mitchell A, Tal M, Ellis R, Dagan R, Mizrachi Nebenzahl Y (2013) NADH oxidase functions as an adhesin in Streptococcus pneumoniae and elicits a protective immune response in mice. PLoS ONE 8:e61128.
2. Elhaik Goldman S, Dotan D, Talias A, Lilo A, Azriel S, Malka I, Portnoi M, Ohayon A, Kafka D, Ellis R, Elkabets M, Porgador A, Levin D, Azhar A, Swiatlo E, Ling E, Feldman G, Tal M, Dagan R, Mizrachi Nebenzahl Y (2016) Streptococcus pneumoniae fructose 1, 6-bisphosphate aldolase, a protein vaccine candidate, elicits Th1/Th2/Th17-type cytokines in mice. Int J Mol Med 37:1127-1138.
3. Mizrachi Nebenzahl Y, Blau K, Kushnir T, Shagan M, Portnoi M, Cohen A, Azriel S, Malka I, Adawi A, Kafka K, Dotan D, Guterman G, Troib S, Fishilevich T, Gershoni, J M, Braiman A, Mitchell A M, Mitchell T J, Porat N, Goliand I, Chalifa Caspi V, Swiatlo E, Tal M, Ellis R, Elia N, Dagan R (2016). Streptococcus pneumoniae cell-wall-localized phosphoenolpyruvate protein phosphotransferase can function as an adhesin: Identification of its host target molecules and evaluation of its potential as a vaccine. PLoS ONE. 11:e0150320.
4. Elhaik Goldman S, Moshkovits I, Shemesh A, Filiba A, Tsirulsky Y, Voronov E, Shagan M, Benharroch D, Karo-Atar D, Dagan R, Munitz A, Mizrachi Nebenzahl Y (2016) Natural killer receptor 1 dampens the development of allergic eosinophilic airway inflammation. PLoS ONE. 11:e0160779.
Azar Tahghighi
Pasteur Institute of Iran, Iran
Title: Design and synthesis of new heteroaromatic derivatives with anti-parasitic activity
Biography:
Azar Tahghighi is an Assistant Professor at Pasteur Institute of Iran (PII). She received her PhD in Medicinal Chemistry and is experienced in synthesis of leishmanicidal compounds and evaluation of their biological activity against promastigote and amastigote forms of L. major. She is also experienced in QSAR studies and molecular docking of synthetic compounds with leishmanicidal effect. With emerging resistance to the first-line anti-malarial drugs, there is an urgent need for the development of new anti-malarial drugs to curb the disease. Currently, she is working in the Drug Discovery Lab of MVRG and her areas of interest are: design and synthesis of novel compounds with antimalarial activity, antimalarial drug design with molecular docking, synthesis of insecticides, isolation and identification of natural compounds and medicinal plants with antimalarial activity, and identification of plants with insecticide, larvicidal and repellent activity.
Abstract:
Parasitic diseases are a major problem in tropical and subtropical regions of the world such as malaria and leishmaniasis. These diseases cause considerable mortality and morbidity annually. No vaccines are available to prevent infections. On the other hand, parasitic drug resistances have restricted the use of available drugs for the treatment of malaria and leishmaniasis. Actually, identification and development of new, cheap, efficient, and safe compounds as drug candidates for the prophylaxis and treatment of these diseases are imperative from pharmaceutical point of view. Therefore, a range of creative strategies are required to achieve new lead compounds. The first aim of our studies were to synthesize and assess antileishmanial activity of 5-(5-nitrohetero aryl-2-yl)-1,3,4-thiadiazoles with different substituents at the 2-position of thiadiazole ring. It was notable that the bioresponses and physicochemical properties of the molecules depended on the type of these substituents. In these studies, MLR and ANN models were used and predicted the antileishmanial activity of some thiadiazole derivatives. Also, molecular modeling and docking studies were conducted based on DNA topoisomerase as a target enzyme. The results suggested that hydrogen bonding and hydrophobic interactions of ligands with the active site of Leishmania major topoisomerase IB were responsible for their potent antileishmanial activity. The other aim of our study was to synthesize a series of 1,10-phenanthroline derivatives containing amino-alcohol and amino-ether substituents, and quinoline derivatives containing benzyl dialkyl amine and N-alkyl benzamidine substituents. Their anti-plasmodial activity was then evaluated intraperitoneally using the Peter's 4-day suppressive test against Plasmodium berghei-infected mice. Based on results, the synthetic compounds had about 90% suppression and also prolonged the mean survival time of treated mice in comparison with negative control groups.
References:
1. Parhizgar A R, Tahghighi A (2016) Introducing of new antimalarial analogues of chloroquine and amodiaquine: Narrative review. Iranaian Journal of Medical Science.
2. Tahghighi A, Dastmalchi S, Hamzeh-Mivehroud M, Asadpour-Zeynali K, Foroumadi A (2016) QSAR and docking studies on the (5-nitroheteroaryl-1,3,4-thiadiazole-2-yl) piperazinyl analogs with antileishmanial activity. Journal of Chemometrics 30: 284-293.
3. Tahghighi A (2014) Importance of metal complexes for development of potential leishmanicidal agents. Journal of Organometallic Chemistry 770: 51-60.
4. Tahghighi A, Emami , Razmi S, Marznaki M R, Ardestani S K, Dastmalchi S, Kobarfard F, Shafiee A, Foroumadi A (2013) New 5-(nitroheteroaryl)-1,3,4-thiadiazols containing acyclic amines at C-2: Synthesis and SAR study for their antileishmanial activity. Journal of Enzyme Inhibition and Medicinal Chemistry 28(4): 843-852.
5. Tahghighi A, Razmi S, Mahdavi M, Foroumadi P, Ardestani S K, Emami S, Kobarfard F, Dastmalchi S, Shafiee A, Foroumadi A (2012) Synthesis and anti-leishmanial activity of 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol- 2-amines containing N-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl] moieties. European Journal of Medicinal Chemistry 50: 124-128.
Kimihiko Okazaki
Okazaki Medical Clinic, Japan
Title: Basis of the novel concept that antibodies mutually exchange on the receptors
Biography:
Kimihiko Okazaki has graduated from the Faculty of Medicine, Kyoto University in 1959. He has worked on various medicinal and chemical researches from 1960-1981 in both hospitals and educational institutions. He has been practicing Internal Medicine since 1981. Currently, He works at the Okazaki Medical Clinic, Japan (private clinic) since 1989.
Abstract:
Although it is well established that an equilibrium state exists among antibody molecules in the vicinity of their receptors on the surface of immune cells, namely, cytolytic T lymphocytes and mast cells, it has long been taken for granted that molecular substitutions of antibodies on their receptors never occur. Obviously, these two concepts disagree with each other because existence of equilibrium state itself indicates that every molecule of antibody keeps changing its status being attached to or detached from its receptor. In addition, a certain molecule of antibody does not necessarily attach to one certain receptor. In other words, every receptor of antibody keeps changing antibodies. The alternative concept, namely, molecular substitutions of antibodies on their receptors do occur all the time, is extremely useful. Reason is that the concept can be applied to complete cure of immune diseases; allergies and autoimmune diseases, and there is another reason that the pathogen specific antibodies can be replaced by harmless non-specific antibodies if the latter are accumulated in patients’ bodies. The necessary and sufficient condition for the accumulation is to repeat injecting the patient with non-specific antigens.
Reyhaneh Abgoon
Islamic Azad University, Iran
Title: Gene expression of PTPN-22 in Iranian patients with alopecia areata
Biography:
Reyhaneh Abgoon has received her Master’s degree in Cellular and Molecular Biology from Azad University. Her research interests include immunology, molecular immunology, especially autoimmune diseases. She is working as a supervisor in Banej Elixir molecular research institute in Tehran. She has presented several research abstracts about alopecia areata which is an autoimmune disease at various international conferences.
Abstract:
Objective: In present study, effect of PTPN22 gene expression was investigated in Iranian AA patients and their respective controls.
Background: Alopecia areata (AA) is an autoimmune multifactorial disease characterized by hair loss especially from the scalp affecting approximately 5.3 million people. The gene encoding the protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which is exclusively expressed in immune cells, has been considered as a risk factor associated with the pathogenesis of AA.
Methods: The study group consisted of 30 patients with AA (13 female and 17 male, mean age 26.3±12.5) and 15 (5 female and 10 male, mean age 30±5.88) healthy controls. RNA was extracted from blood sample. Thereafter, cDNA was synthesized after RNA isolation. PTPN22 expression levels were measured by real-time PCR. Furthermore, association of this PTPN22 with some baseline clinical and demographical features was assessed.
Results: PTPN22 expression levels of patients with AA were significantly higher (4.6±3.8) than those in controls (1.14±0.56) (p value=0.01). PTPN22 expression was only associated with the sex of the AA patients (Fig.1).
Conclusion: In the present study, a significant association was found between PTPN22 gene expression and susceptibility to alopecia areata.
Figure1: PTPN22 gene expression in patients with Alopecia Areata and controls.
Sawsan Said
Istanbul Technical University, Turkey
Title: Expression profiling of Helicobacter-activated regulatory B cells
Biography:
Sawsan Said is a PhD candidate in the Department of Molecular Biology and Genetics at the Istanbul Technical University, Istanbul, Turkey. She has been working on a subset of B cells, namely regulatory B cells in the Lab of Dr. Ayca Sayi Yazgan.
Abstract:
The regulatory B and T cells have a pivotal role in balancing between immune pathogenicity and protection. Recently, it has been shown that the regulatory T cells could reduce H. pylori-induced gastritis in mice, at the same time allows the bacterium to colonize the mucosa at higher densities. Moreover, it was reported that IL-10+B cells were activated upon Helicobacter infection through TLR2-MyD88 activation, which leads to differentiation of T regulatory-1 (Tr-1) cells from naïve T cells. The interaction between Tr-1 and IL10+B cells may prevent the gastric precancerous lesions and serve as a good immune modulator against Helicobacter. Recently, RNA profile of B10 cells was investigated by RNA-seq, and differentially expressed genes in B10+ and B10-B cells were identified. CD9 was identified as a key surface marker for most mouse IL-10+ B cells, and PD-1was differentially expressed in IL10+/IL10-B cells. In our study, we focus on understanding the expression profile of Helicobacter activated regulatory B cells by microarray analysis, Agilent SurePrint G3 Gene Expression Microarrays of mouse (v2) 8x60K models. Furthermore, gene expression profiling of IL-10 producing regulatory B cells would provide detailed information of B cell genes, including immune function of specific genes. Next, we aim to investigate the expression levels of the recently described genes that are expressed in B 10 cells; CD9, and PDCD1(PD1) in our samples, unstimulated B cells, H. felis stimulated B cells, stimulated IL-10+ B cells and IL-10- B cells. Based on our microarray and real-time PCR data, we wanted to investigate the immune functions of PD1+ regulatory B cells on T cell differentiation to regulatory Tr-1 cells. The PD1 functional study directed the PD1/PD-L 1 interaction blockade as tool to understand the role of PD-1 upregulated B cells in induction (Tr1) upon PD1-PD-L 1 interaction.
Biography:
Yuanyuan Cheng has worked on the molecular mechanism of macrophage polarization and function in myocardial infarction regulated by active lipid mediators and natural compounds.
Abstract:
Macrophages play important roles in resolution of inflammation and cardiac remodeling in acute myocardial infarction due to its phenotypic and functional plasticity. Arachidonic acid metabolites are known to regulate the dynamic changes between inflammatory and resolving macrophages. The aim of the present study was to explore the interactions between arachidonic acid metabolites and cellular proteins. We employed ω-alkynyl arachidonic acid as probe to profile the cellular proteins with the capability to form covalent adducts with arachidonic acid metabolites. Following the treatment of RAW264.7 cells with ω-alkynyl arachidonic acid, the cellular proteins were biotinylated via “click chemistry” alkyne-azido cycloaddition, isolated by streptavidin beads and identified by proteomic approach. As a result, glycolytic enzyme pyruvate kinase M2 (PKM2) was identified as a predominant ω-alkynyl arachidonic acid modified protein. We also identified 15-keto-PGF2α as the specific metabolite for covalent binding to PKM2 by HPLC/MS/MS. We further investigated the effects of 15-keto-PGF2α on macrophage polarization and functions. By monitoring the expression of M1 biomarkers (IL-1β, TNF-α, CXCL10, iNOS, CCL2 and IL-6) and M2 biomarkers (IL-10 and arginase 1), we discovered that 15-keto-PGF2α suppressed macrophage M1 polarization and promoted macrophage M1 polarization in RAW264.7 macrophages and bone marrow-derived macrophages. We also found that 15-keto-PGF2α markedly enhanced the phagocytosis of fluorescently-labeled beads or apoptotic H9c2 cardiac cells. By examining the cardioprotective activities of 15-keto-PGF2α in a mouse model of acute myocardial infarction, we found: 1) 15-keto-PGF2α indeed reduced infarct size on day 3 and day 7; 2) promoted the shift of macrophage M1 polarization to M2 polarization based on the immunostaining of M1 biomarker CD86 and M2 biomarker CD206 in hearts after myocardial infarction; and 3) enhanced macrophage phagocytosis of apoptotic cardiomyocytes as a result from myocardial infarction. By elucidating the underlying mechanisms, we found that 15-keto-PGF2α inhibited PKM2 expression and the formation of PKM2 dimer and suppressed nuclear translocation of PKM2. Collectively, 15-keto-PGF2α may exhibit potential cardioprotective effects by promoting macrophage M2 polarization against acute myocardial infarction in a PKM2-dependent manner.
References:
1. Cheng Y Y, Tse H F, Li X C, Han Y F, Rong J H (2016 ) Gallic acid-l-leucine (GAL) conjugate enhances macrophage phagocytosis via inducing leukotriene B4 12-hydroxydehydrogenase (LTB4DH) expression. Molecular Immunology 74: 39-46.
2. Cheng Y Y, Xia Z Y, Han Y F, Rong J H (2016) Plant natural product formononetin protects rat cardiomyocyte H9c2 cells against oxygen glucose deprivation and re-oxygenation via inhibiting ROS formation and promoting GSK-3ß phosphorylation. Oxidative Medicine and Cellular Longevity.
3. Cheng Y Y, Yang C B, Zhao J, Tse H F, Rong J H (2015) Proteomic identification of calcium-binding chaperone calreticulin as a potential mediator for the neuroprotective and neuritogenic activities of botanical drug amygdalin, Journal of Nutritional Biochemistry 26: 146-154.
4. Cheng Y Y, Li S F, Zhang Y, Tang G H, Di Y T, Hao X J, Li S L, He H P (2012) Cleidbrevoids A–C, new clerodane diterpenoids from Cleidion brevipetiolatum. Fitoterapia 83: 1100-1104.5. Zhao J, Cheng Y Y, Yang C B, Lau S, Lao L X, Shuai B, Cai J, Rong J H (2015) Botanical drug puerarin attenuates 6-hydroxydopamine (6-OHDA)-induced neurotoxicity via upregulating mitochondrial enzyme arginase-2. Molecular Neurobiology 5: 1-12.
Jessy S. Deshane
University of Alabama at Birmingham, USA
Title: Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells
Biography:
Jessy S Deshane is currently an Associate Professor of Medicine at University of Alabama at Birmingham. Her work is focused on immune regulation by myeloid-derived regulatory cells (MDRCs) in chronic inflammatory lung diseases. Her team has recently identified and characterized free radical producing myeloid-lineage cells as master regulators of allergic airway inflammation. She is currently investigating the novel hypothesis that MDRCs can produce neo-antigens that trigger dysregulated immune responses in asthma.
Abstract:
Introduction & Aim: Myeloid derived suppressor cells (MDSCs) are major contributors of immunosuppression by inducing oxidative stress and by modulating amino acid metabolism. Indoleamine 2,3-dioxygenase (IDO) is a key regulator of tryptophan (Trp) metabolism. Poor prognosis in lung cancer patients is associated with elevated IDO expression and activity. We have previously shown that a combination strategy of gemcitabine and a superoxide dismutase mimetic promoted anti-tumor immunity by enhancing metabolism of CD8+ memory T cells and prolonging survival in mice with lung cancer. In this study, we aim to elucidate how modulation of IDO pathway alters metabolic signaling in the tumor microenvironment (TME) and influence mitochondrial dynamics to promote long term immunity against lung cancer.
Methods: Lewis lung carcinoma cells were injected by intracardiac route into wild type (WT) and IDO-/- mice. We assessed tumor burden, infiltration of MDSCs and CD8+ T cells by flow cytometry. Protein analyses of metabolic signaling pathways were performed on whole tissue and sorted cell lysates. Peripheral blood samples from Stage III–IV lung cancer patients and healthy normal relatives were used to measure serum IDO activity and percent circulating MDSCs.
Results: Circulating human MDSCs and serum IDO activity correlated with lung cancer. In a preclinical lung cancer mouse model, MDSCs were the significant contributors of IDO in the TME. Combination therapy targeted IDO signaling, specifically in MDSCs, tumor cells, and CD8+ T cells infiltrating the TME. Deficiency of IDO caused significant reduction in tumor burden, tumor-infiltrating MDSCs, GM-CSF, MDSC survival and infiltration of programmed death receptor-1 (PD-1)-expressing CD8+ T cells compared to controls. IDO-/- MDSCs downregulated nutrient-sensing AMP-activated protein kinase (AMPK) activity, but IDO-/- CD8+ T cells showed AMPK activation associated with enhanced effector function. Additionally, our studies showed that IDO pathway directly modulated mitochondrial dynamics to enhance memory T cell response.
Conclusions: Our study revealed a novel role of IDO in regulation of AMPK activation, distinct from Trp sufficiency and deficiency signaling. These data also provide mechanistic evidence that a combination treatment of gemcitabine and a SOD mimetic can metabolically reprogram the cellular components of the TME including suppressor cells, effector T cells, and tumor cells.
Bogdan Ion Gavrila
Carol Davila University of Medicine and Pharmacy, Romania
Title: Predictive role of rheumatoid factor and anti-cyclic citrullinated peptide regarding the response to anti-tumor necrosis factor therapy in rheumatoid arthritis
Biography:
Gavrilă B I did his PhD in Internal Medicine, and now he is an Assistant Professor at Dr. I Cantacuzino Clincal Hospital, Department of Internal Medicine and Rheumatology in Bucharest.
Abstract:
Background: The introduction of biologic therapy has revolutionized the treatment of rheumatoid arthritis (RA). Despite these advances, 20-40% of the patients are declared non-responders to at least one of the therapies.
Objectives: Evaluating the predictive role for the response to anti-tumor necrosis factor therapy of rheumatoid factor (RF) isotypes IgM, IgA, anti-cyclic citrullinated peptide (anti-CCP) and the evolution of serum levels of these biomarkers under biologic treatment. We have also assessed the status of this biomarkers and the response to treatment.
Methods: Prospective and observational study including 64 patients was followed for 12 months with active RA, uncontrolled by conventional synthetic DMARDs or declared non-responders to one of the biologic DMARDs.
Results: Lower baseline titres of RF type IgM (51.36±95.359 U/ml, p=0.01629), IgA (22.45±61.256 U/ml, p=0.03336) and anti-CCP (60.82±26.331 ng/ml, p=0.00011) had predictive value for achieving a good EULAR response at 6 months. Grouping patients in 2 categories (responders/non-responders), we identified significant differences between groups only for anti-CCP and response at 6 months (responders 96.04±50.355 ng/ml, non-responders 146.16±41.68 ng/ml, p=0.02834). For the EULAR response at 12 months, lower baseline titres for RF type IgM (92.93±120.22 U/ml, p=0.01032) and IgA (49.96±98.08 U/ml, p=0.00247) had predictive value for achieving a good response at 12 months. We didn’t obtain other information grouping patients in 2 categories. Monitoring the evolution of serum levels, we noticed reduction in all three biomarkers tested, statistically significant at 6 and/or 12 months from baseline. Regarding the status (positive/negative) pretreatment and the response to anti-TNF agents, we noticed significant differences regarding status for RF IgA isotype and response to treatment at 12 months (p=0.004).
Conclusion: It can be concluded that, beside their diagnostic role, these biomarkers can be used for other purposes in RA.
Biography:
Patricia Araujo has expertise in Phototherapy, area in which she has been working since 17 years. The major focuses of her study are: vitiligo, psoriasis and mycosis fungoides. She has developed theories on various responses to surgical treatments of vitiligo, which could improve NB-UVB response.
Abstract:
For stable forms of vitiligo, many are the surgical techniques proposed, in order to improve patients’ response to NB UVB. The surgical techniques for the treatment of vitiligo can be classified according to the nature of the graft. Some surgical techniques are: Minigrafts; suction blister, in which the top of the blister induced by suction is used as grafts; split thickness grafts in which a sheet of 0.2-0.3 mm thick skin, consisting almost exclusively of epidermis is used as a graft; Needling, in which, with the use of a needle it is possible to transplant pigment cells from the edge to the center in the leucoderma area. After, the patients are submitted to phototherapy NB UVB, however, patients submitted to needling have different degrees of repigmentation. We wondered why and supposed that when transplanting cells from the edge compared with when transplanting cells at least 3 cm further, better results could be achieved in the second case. Considering vitiligo as an auto immune disease, we supposed that cells far from the edge could be in better immunologic conditions, compared to those near the edge, where the number of auto antibodies could be higher. In order to put this hypothesis to test, we have done needling in both sides of the same patient. On the right side of the body, we have done needling near the edge of the lesion and, on the left side, we have done needling, at least, 3 cm far from the edge.
Orly Avni
Bar-Ilan University, Israel
Title: Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome
Biography:
Orly Avni is expert in gene regulation in the immune system. She has published many articles in reputed journals.
Abstract:
Dilated cardiomyopathy (DCM) is a life threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab-Christian-infants, ages 4-30 months from four families were diagnosed with DCM associated with mild skin, teeth and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at PPP1R13L encoding the iASPP protein, was identified in three infants, and in the mother of the other two. Patients’ fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to Lipopolysaccharide, as well as ppp1r13l-knocked down murine cardiomyocytes and hearts of ppp1r13l-deficient mice. The hypersensitivity to Lipopolysaccharide was NF-kB-dependent, and its inducible binding activity to promoters of pro-inflammatory cytokine genes was elevated in patients’ fibroblasts. RNA-sequencing of ppp1r13l-knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in ppp1r13l-deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined PPP1R13L as the gene underlying a novel autosomal recessive cardio cutaneous syndrome in humans, and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors.
References:
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2. R. Hod-Dvorai, E. Jacob, Y. Boyko, O. Avni, The binding activity of Mel-18 at the Il17a promoter is regulated by the integrated signals of the TCR and polarizing cytokines. Eur J Immunol 41, 2424-2435 (2011).
3. E. Jacob, R. Hod-Dvorai, O. L. Ben-Mordechai, Y. Boyko, O. Avni, Dual function of polycomb group proteins in differentiated murine T helper (CD4+) cells. Journal of molecular signaling 6, 5 (2011).
4. E. Jacob, R. Hod-Dvorai, S. Schif-Zuck, O. Avni, Unconventional association of the polycomb group proteins with cytokine genes in differentiated T helper cells. J Biol Chem 283, 13471-13481 (2008).
5. O. Shamriz, H. Mizrahi, M. Werbner, Y. Shoenfeld, O. Avni, O. Koren, Microbiota at the crossroads of autoimmunity. Autoimmun Rev 15, 859-869 (2016); (10.1016/j.autrev.2016.07.012).