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Immunopharmacology Institute of Pharmacology http://www.pki.unibe.ch/ PKI Immunopharmacology Prof. Dr. Stephan von Gunten MD PhD MME Lectures: Clinical Immunology Immunomodulation Endogenous or exogenous molecules that influence immune responses positively (immunostimulation) or negatively (immunoregulation) DC Based Vaccination Freund complete adjuvans (FCA) Freund incomplete adjuvans (FIA) (mycobacteria + mineral oils) (mineral oils, without mycobacteria) differential maturation alum (hydrated alumina) dendritic cell (DC) mycobacteria Toll-like Receptors alum, mineral NLR-Inflammasome oils in FCA/FIA Toll-Like Receptors PAMPs 2 major adapters: MyD88 and TRIF protein kinases transcription factor (NFkB, IRF-3/-7) [IRF: Interferon regulatory factor] gene transcription: inflammatory cytokines, IFNa/b, others BMSc Pharma Immuno Manicassamy S & Pulendran B, Seminars in Immunology 2009 (modified) TLR Agonists and Cancer Immunotherapy: BCG-CWS BCG: Bacillus Calmette-Guérin, attenuated form of Mycobacterium bovis CWS (cell-wall skeleton ): major adjuvant–active part of mycobacterial cells; contains muramyldipeptide (MDP) -> activation of TLR-2 and -4 and NOD2 BCG-CWS TLR-2 MyD88-pathway mDC cytokines CTL tumour cell killing Carbohydrate-based vaccines in development Infectious disease Infectious Cancer Astronomo RD & Burton DR Nat Rev Drug Discov 2016 (modified) Antibody repertoire: glycan immunogenicity linked to structure Schneider et al. Sci Transl Med 2015 Cancer Immunotherapy Galluzi L et al. Oncotarget 2014 Siglec expression on immune cells Jandus C et al. Biochem Pharmacol 2011 Illustration by Aldona von Gunten The sialoglycan shield Jandus C & Boligan KF et al. J Clin Invest. 2014 Siglecs on CD8 T cells? May 2019 Cover Story American Association of Cancer Research (AACR) Immunomodulation Endogenous or exogenous molecules that influence immune responses positively (immunostimulation) or negatively (immunoregulation) Antiinflammatory vs. immunosuppressive therapy Components of Inflammation cellular or humoral immunity E.g. inflammatory disease E.g. transplantation medicine, preventive Production of inflammatory mediators by arachidonic acid metabolites and cyclo-oxygenase Gastric epithelial cytoprotection by prostaglandins: role of COX-1 COX-1 COX-1 Misoprostol Prostaglandin analogues Substance Misoprostol: stable PGE1- Analogue Pharmacodynamics Cytoprotective effects: inhibition of H+ - Secretion, stimulation of mucus and HCO3- production, increase of gastrical blood perfusion Pharmakokinetics In contrast to endogenous PG oral uptake possible, short half-life (20 min) Indication Ulcus prophylaxis for chronic treatment with NSAID (ASS, Diclofenac) Side-effects • Frequent diarrhoea due to increased intestinal secretion of H2O and electrolytes • Increases tone of uterus-> CAVE: pregnancy Cox-1 and -2 selectivity of widely used NSAID Ev. higher risk of gastrointestinal events Ev. higher risk of cardiovascular events Modified from Park K & Bavry AA Vasc Health Risk Manag. 2014 Classes of immunoregulatory drugs 1. Drugs acting on immunophilins (cyclosporine, tacrolimus, sirolimus) 2. Cytostatics (alkylating agents, antimetabolites) 3. Glucocorticoids 4. Antibodies: • Polyclonal • Monoclonal (lecture PD Dr. S. Adler: Biologics) 5. Other drugs (lecture PD Dr. S. Adler: Biologics) Inhibitors of Calcineurin and mTOR (‘mammalian target of rapamycin’) phosphatases p-NFAT Cyclosporin A (CyA), Tacrolimus (T) Calcineurin Binding partners (immunophilins): - Cyclophilin (CyA) - FK-binding proteins (T) Lymphocyte Nucleus NFAT (TF) TF = transcription factor IL-2, other cytokines IL-2 receptor Sirolimus (Rapamycin) mTOR Binding partners (immunophilins): - FK-binding proteins Lymphocyte Proliferation Chemotherapeutics as immunosuppressive drugs Chemotherapeutics kill or inhibit proliferation of cancer cells with unwanted side effects on healthy cells, in particular hematopoietic immune cells => certain cytotoxic drugs can be used as immuno-suppressive drugs. Mode of action: induction of apoptosis/necrosis, inhibition of proliferation. i Image source: undisclosed master thesis Glukocorticoids: molecular mechanisms Ribonucleases Induction of IkB Transcortin/ Annexin I gene expression Interleukin-10 Albumin IL-1 rec. antagonist Cortisol Cortisol Cortisol glucocorticoid responsive Cortisol Cortisol element receptor receptor Hsp-90 NF-AT Cytokinee Adhesion molecules AP-1 Chemokines NF-kB Cyclooxygeneses Inhibition of gene expression N. Engl. J. Med. 353 (2005), 1711-1723 CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULINS (IVIG) Schneider C et al., in preparation IVIG PLURIPOTENCY – BROAD RANGE OF INDICATIONS von Gunten S et al. Nat Rev Immunol 2014 Schneider C et al. in preparation Fab- and Fc-mediated immunoregulatory effects of IVIG Specific antigen binding sites Fab-linked characteristics Specific binding (repertoire of donor population) • pathogens, superantigens • immunoregulatory molecules: cytokines, complement, immune receptors (e.g. Fas, MHC class I, CD4, Siglec-8, Siglec-9) • anti-idiotypic antibodies Fab Fab • DC-SIGN (sialylated Fab)? Effects • cytokines: neutralization • complement: inhibition • neutralization of pathogenic autoantibodies • immune cells: inhibition of cellular activity, anti-proliferative, cell death • tissue: survival and protection Fc Fc-linked characteristics Binding • Fc-receptors • DC-SIGN (sialylated Fc) Effects Modified from www.sci.sdsu.edu • increased turn-over of pathogenic antibodies (ITP; neonatal Fc-receptor blocking?) • sialylation-dependant anti-inflammatory effects in certain animal models von Gunten S et al. Nat Rev Immunol, 2014 FUNCTIONAL ANTI-FAS ANTIBODIES IN IVIG Blocking anti-Fas antibodies in IVIG Agonistic anti-Fas antibodies in IVIG - Toxic epidermal necrolysis [TEN] Prasad NK et al. J Immunol. 1998 Viard I et al. Science. 1998 Sooryanarayana et al. Biochem Biophys Res Commun. 1999 F(ab’)2-mediated and cytokine-dependent regulation of granulocyte survival by IVIG von Gunten S et al. Casulli S et al. PLoS One. 2011 J Allergy Clin Immunol. 2007 von Gunten S et al. Blood. 2006 Schneider C et al. Sci Rep 2016 Neutrophil-predominant vasculitis in Kawasaki disease Scardina GA et al. Med. oral patol. oral cir.bucal 2007 Neutrophil counts drop within 24 hrs following IVIG treatment due to induction of apoptosis Tsujimoto H et al. Clin Immunol 2002 IVIG-MEDIATED REGULATION OF GRANULOCYTE SURVIVAL von Gunten S, Simon HU. J Clin Immunol. 2010 IVIG/SCIG AND ALTERNATIVE IMMUNOGLOBULIN PREPARATIONS Späth P et al. Arch Immunol Ther Exp 2016.
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