Inflammation & Allergy-Drug Targets (v.13, #2)

Rheumatoid Arthritis: An Autoimmune Disease with Female Preponderance and Cardiovascular Risk Equivalent to Diabetes Mellitus: Role of Cardiovascular Magnetic Resonance by Sophie Mavrogeni, Theodoros Dimitroulas, Chiara Bucciarelli-Ducci, Stacy Ardoin, Petros P. Sfikakis, Genovefa Kolovou, George D. Kitas (81-93).
Rheumatoid arthritis (RA) is a systemic, inflammatory disease with female preponderance, characterized bysevere articular and extraarticular manifestations. Cardiovascular (CV) disease in RA usually occurs a decade earlier thanage- and sex-matched controls and patients with RA are twice more likely to develop myocardial infarction irrespective ofage, history of prior CVD events and traditional CV risk factors. It has been shown that atherosclerotic CV disease in RAshares similarities with CV disease in diabetes mellitus (DM) in terms of clinical presentation and preclinicalatherosclerosis. In addition to atherosclerosis, RA also increases risk of non-ischemic heart failure, valvular disease andmyopericardial disease. Therefore, RA is considered at least a cardiovascular equivalent to diabetes mellitus.;Cardiovascular magnetic resonance (CMR), a non-invasive, nonradiating technique, and due to its capability to performtissue characterisation, can effectively identify CVdisease acuity and etiology during the course of RA. CMR, by using acombination of function evaluation, oedema-fibrosis detection and stress perfusion-fibrosis imaging can unveilmyocarditis, cardiomyopathy, diffuse subendocardial vasculitis, coronary and peripheral artery disease in RA patients,who usually are oligo-asymptomatic. Additionally, CMR is the ideal technique for operator independent, reproduciblediagnostic and follow up assessment. However, lack of availability, expertise and high cost still remain serious drawbacksof CMR.

Adaptation of the whole microbial normal flora residing in a host to its natural habitat over an evolutionaryperoid has resulted in peaceful coexistence with mutual benefits for both microbiota and host in steady state. Thissymbiotic relationship between host and microbiota has a significant impact on shaping the immune response in the hostto achieve an immune tolerance to microbiota but retaining the ability to respond to invading pathogens. Perturbation ofthis balance by manipulation of microbial communities in the host can lead to immune dysregulation and susceptibility todiseases. By studying the host in the absence of microbiota or with alteration of microbiota the complexity of microbialimpact on the immune system can be resolved. Conversely, the study of microbiota in the absence of immune systemfactors can show how the immune system contributes to preservation of the host-microbiota balance. The absence ofmolecules involved in innate or adaptive immunity in knockout models can perturb the balance between host andmicrobiota further adding to more immune dysregulation. A better understanding of Microbiome-immune systeminteraction provides a new opportunity to identify biomarkers and drug targets. This will allow the development of newtherapeutic agents for modulating the immune system to improve health with little or no toxicity. The study of interplaybetween host and microbiota has a promising role in the design of therapeutic interventions for immunopathologicaldiseases arising from imbalanced host and microbiota interactions.

Background: Cancer-related fatigue (CRF) affects a majority of patients (pts) with symptoms lasting up toseveral years after finishing therapy. These symptoms lead to decreased health related quality of life. Fatigue duringtreatment for colorectal cancer is common, but poorly understood and can affect compliance with post-surgical cancertherapy. We examined the fatigue levels during first-line chemo- or radio-chemotherapy protocols, which were supportedby a pharmaceutical mistletoe preparation (Iscador®Qu) (181patients). We compared the outcome to a parallel controlgroup (143 patients), which did not receive this supportive care treatment. Methods: The medical records of 324 patientswith non-metastasized colorectal cancer (UICC stage I - III), which were obtained from hospitals and resident physicians,were assessed. The documented treatment decision by chemo- or radio-chemotherapy supported by mistletoeinterventions was followed for a median treatment period of 8.6 months. During the post-surgical treatment period thepatients were diagnosed twice for the presence of fatigue symptoms by structural interviews carried out by physicians.Results: At the end of the median treatment period, 16/181 patients (8.8%) were diagnosed with CRF in the supportivecare group and 86/143 (60.1%) in the chemo - or radio-chemotherapy group without supportive mistletoe medication.Multivariable-adjusted ORs provided evidence for a chance to improve CRF by supportive mistletoe medicationcompared to chemo- or radio-chemotherapy alone over the time of treatment. The OR = 10.651 (95% CI 5.09-22.28; p <0.001) declined from the first visit to OR = 0.054 (95 CI 0.02-0.13; p < 0.001) at the end of therapy. Furthermore, 14confounding factors for risk assessment of CRF were compared by means of forest plots. It turned out that the hospitalversus office-based treatment and the co-morbidity/inflammation represent independent but important determinants forfatigue levels. Conclusion: The clinically used mistletoe medication (Iscador®Qu) is the first candidate to be included in asupportive care modus into chemo- or chemo-radiotherapy protocols for colorectal patients to improve CRF withoutdiscernable toxicities.

Substance P, a neuropeptide belonging to the tachykinin family is a pleiotropic peptide with specific neuralactivities and involved in immunomodulation and antimicrobial host defense. It has been found to modulate a variety ofinflammatory processes, including acute pancreatitis, sepsis, systemic inflammatory response syndrome and asthma. Alsonotably, substance P shares common bio-physical and -chemical properties such as low molecular mass, cathionicity andamphipathicity with antimicrobial peptides. It is therefore suggested to take part in host defense at specialized locations.;The review aims to highlight undated understanding on substance P in inflammation, allergy and its antimicrobialactivities with potential implications in infection and host defense.;Therapeutic implications of the peptide, modulators of peptide expression and receptor signalling will be highlighted ineach topic. Taken together, these topics will be of significant values for future pharmaceutical investigation andapplication of the field.

Biological agents such as monoclonal antibodies and soluble cytokine receptors have taken on an expandingrole in the treatment of chronic immune mediated diseases. Progressive multifocal leukoencephalopathy (PML) is a rarecentral neurological disease caused by JC virus infection that has been described in the setting of conditions with severeimpairment of immune surveillance, such as haematological malignancies, stem cell or solid organ transplantation andAIDS. This serious demyelinating disease has recently been described in patients receiving monoclonal antibodies forchronic inflammatory diseases such as multiple sclerosis, Crohn's disease, rheumatoid arthritis, systemic lupuserythematosus or psoriasis. We review here the disease of PML, the different biological agents used in chronicinflammatory diseases that are associated with an increased risk of PML (natalizumab, rituximab, efalizumab andalemtuzumab), and the potential mechanisms that may explain the development of PML. Based on current knowledge ofthe biology of the JC virus and on the mechanisms of action of these biological agents, we discuss currently availabletools that may be helpful in evaluating the risk of PML in this patient population.

Virus-Specific Peptide Dependent NK Cell Cytotoxicity by Lan Tong, Mario Assenmacher, Kurt S. Zanker, Peter Jahn (128-133).
NK cells do not express recombination-dependent antigen-specific receptors and are traditionally defined ascells of the innate immune response. The activation of NK cells was believed to be controlled by the net balance of signalsfrom a multitude of activating and inhibitory receptors irrespectively of antigen specificity. However, murine antigenspecificmemory NK cells in liver have been described to mediate hapten or viral specific recall response and are capableof infiltrating to the site of infection. The mechanisms by which NK cells recognize target cells in an antigen-specificmanner are largely unclear. Using a novel multiplex killing assay, we screened the NK cell (human) cytotoxic activity of35 different donors against different virus peptide pools loaded autologous B cells. We have found that human NK cellsfrom some CMV and EBV positive donors can recognize peptide loaded autologous B cells as targets and performantigen-specific cytotoxic killing. This may provide evidence that NK cells are able to scan the peptide repertoire on thetarget cell surface and virus-derived peptides may influence the NK cell activation-inhibition balance.

Monoclonal Antibodies: A Target Therapy for Multiple Sclerosis by Lorena Lorefice, Giuseppe Fenu, Jessica Frau, Giancarlo Coghe, Maria Giovanna Marrosu (134-143).
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system. It is characterized by aproinflammatory and neurodegenerative process that results in neuroaxonal damage. Over the last two decades, a widerange of immunomodulatory and immunosuppressive treatments have been used for the management of MS. Severaltreatments have been developed or are under evaluation for reducing relapses, disease progression and long-term MSrelateddisability. Recently, a growing interest has emerged for therapeutics with very selective actions, particularlymonoclonal antibodies, to target several biological pathways involved in MS. To date, only Natalizumab (Tysabri®) hasbeen approved for the treatment of active MS forms. Its therapeutic mechanism is the blockade of the a4-integrinmolecule of many leukocytes, which leads to a decrease of immune cells migration, in particular of lymphocytes, acrossthe blood-brain barrier. Furthermore, other promising molecules are under study in clinical trials. In this review, wesummarize and discuss the history, pharmacodynamics and safety of monoclonal antibodies that have been approved orare under evaluation for the selective treatment of MS.

R848, a Toll-Like Receptors 7 and 8 Agonist, a Potential Therapy for Allergic Rhinitis Patients by Ghada Boghdadi, Noha Hammad, Ahmed Amer, Somaya Sammour, Samir Sorour (144-149).
Background/Purpose(s): There is a growing interest in the targeting of Toll-like receptors (TLRs) for thetreatment of allergic diseases. TLRs7/8 ligands are future candidates of therapeutic value in allergic rhinitis (AR). Thisstudy focus on TLRs7/8 ligand; resiquimod (R848) as an adjuvant to immunotherapy (IT) in AR patient.;Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from atopic donors and non atopic donors. PBMCswere cultured in the absence and presence of date palm pollen allergen (Phoenix dactylifera; Pho d) and/or R848.Interleukin-4 (IL-4), IL-10, IL-13 and interferon gamma (IFN-?) were measured in the culture supernatants.;Results: R848 was able to significantly increase the anti-inflammatory response in atopic donors more than non atopicdonors. Nevertheless, the combination of both; R848 and Pho d provides inferior stimulus as compared to R848 alone inboth atopic and non atopic donors.;Conclusion: Invitro treatment of PBMCs with R484 hijacks the pro inflammatory immune process triggered by TLRs7/8 to mediate anti-inflammatory response. This may provide a conception about the activity and efficacy of TLRs7/8 ligandsin AR and open the gate for them to be applied in clinically in humans.