Immunity Robbins and Cotran Chapter 6 pp 193 240 Tysabri Recall Batters Biotechs Peter Kang 03 04 05 The outlook for the biotech sector suddenly became very bleak this week as shares of Biogen Idec tanked after the company halted sales of its Tysabri multiple sclerosis drug which was deemed by a bevy of Street pundits as a blockbuster drug The American Stock Exchange Pharmaceutical Index DRG logged another modest gain of 1 2 this week while the Nasdaq Biotechnology Index NBI plunged 6 2 Innate immunity Present before infection Evolved to recognize microbes Epithelial barriers phagocytes natural killer NK cells and plasma proteins including complement Figure removed for copyright reasons Source Box 6 1 B in RC Kumar V A K Abbas and N Fausto Robbins and Cotran Pathologic Basis of Disease 7th ed Philadelphia PA Elsevier 2005 ISBN 0721601871 Adaptive immunity Figure removed for copyright reasons Source Figure 6 2 in RC T cells T cell receptor TCR rearrangement allows for antigen binding 95 TCR 60 CD4 30 CD8 2 signals for activation TCR CD28 Figure removed for copyright reasons Source Figure 6 4 B in RC 3 Constant Region Joining Segments V J Recombination Diversity Segments V DJ Recombination Transcription Splicing Ig T cell Receptor mRNA Variable Segments V D J Recombination 5 Figure by MIT OCW B cells B cell receptor is surface bound immunoglobulin M IgM and IgD Activated B cells differentiate into plasma cells and secrete soluble Ig Figure removed for copyright reasons Source Figure 6 5 A B in RC Dendritic cells DC Figure removed for copyright reasons Source Figure 6 6 in RC Natural killer NK cells No TCR or BCR CD16 CD56 Large granular lymphocytes Can kill tumor cells and viral infected cells without prior exposure Target cells with decreased MHC Class I expression Figure removed for copyright reasons Source Figure 6 8 in RC Major histocompatability complex MHC Present peptide fragments to TCR Human leukocyte antigen HLA Highly polymorphic HLA A B and C HLA DP PQ DR Figure removed for copyright reasons Source Figure 6 9 in RC Major histocompatability complex MHC Present peptide fragments to TCR Human leukocyte antigen HLA Highly polymorphic HLA A B and C HLA DP PQ DR Figure removed for copyright reasons Source Figure 6 10 in RC Antigen uptake Cytosolic protein Antigen processing MHC biosynthesis Proteasome Peptide MHC association Pathways of Antigen Processing Presentation TAP CD8 CTL ER CLASS I MHC PATHWAY CD4 T cell Endocytosis of extracellular protein ER Invariant chain I CLASS II MHC PATHWAY Figure by MIT OCW Figure removed for copyright reasons Source Figure 6 23 in RC Figure removed for copyright reasons Source Figure 6 27 in RC Biogen Idec and Elan announce update on TYSABRI Cambridge MA and Dublin Ireland March 3 2005 Biogen Idec NASDAQ BIIB and Elan Corporation plc NYSE ELN announced today an update on the voluntary suspension in the marketing of TYSABRI natalizumab a treatment for multiple sclerosis MS Multiple sclerosis Distinct episodes of neurologic deficits separated in time due to white matter lesions which are separated in space Gradual progressive disease of the brain and spinal cord Characterized by patches of demyelination of nerve fibers Most common neurological disease of young adults in temperate climates Prevalence is 1 in 1 000 in USA female male around 2 1 Whites Blacks Asians Clinical picture Onset of symptoms occurs around age 30 Often long periods of remission followed by relapses at intervals of months to years Early symptoms are mild frequently affecting vision but gradually involve the limbs speech emotion sensation and bladder control ultimately leading to paralysis Course of disease is highly variable with average duration 25 years Pathogenesis Loss of myelin oligodendrocytes from nerve fibers in the CNS Effect of demyelination is inability to transmit nerve impulses Demyelination occurs in foci or plaques Characterization by perivascular cuffing of mononuclear cells Acute lesions have CD4 T cells and reactive microglial cells Active plaques have myelin breakdown PAS macrophages Inactive plaques have few oligodendrocytes increased astrocytes with most axons intact Preventing immune homing Figure removed for copyright reasons Source Figure 2 6 in RC Natalizumab TYSABRI Recombinant humanized MAb against 4 integrin The 4 subunit of 4 1 and 4 7 are expressed on all leukocytes except PMNs Bind to VCAM 1 CNS and MadCAM 1 GI tract Clinically shown to reduce relapses with or without recombinant IFN AVONEX Indications include MS Crohn s disease and rheumatoid arthritis Suspension of TYSABRI On February 28 2005 the companies reported that they had suspended marketing of TYSABRI based on one confirmed case and one suspected case of progressive multifocal leukoencephalopathy PML a rare and frequently fatal demyelinating disease of the central nervous system The investigator has now changed the status of the second case from suspected to confirmed The companies are continuing to examine these two cases As indicated in the announcement on February 28 2005 both patients received more than two years of TYSABRI therapy in combination with AVONEX Interferon beta 1a