immunity - mit opencourseware · immunity robbins and cotran chapter 6 pp. 193-240. tysabri recall...
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Immunity
Robbins and CotranChapter 6 pp. 193-240
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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%.
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Innate immunity
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.
• Present before infection
• Evolved to recognize microbes
• Epithelial barriers, phagocytes, natural killer (NK) cells, and plasma proteins (including complement)
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Adaptive immunity
Figure removed for copyright reasons.
Source: Figure 6-2 in [RC]
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T cells
• T cell receptor (TCR) rearrangement allows for antigen binding
• 95% αβ TCR– 60% CD4+– 30% CD8+
• 2 signals for activation– TCR + CD28
Figure removed for copyright reasons.
Source: Figure 6-4 B in [RC]
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Figure by MIT OCW.
"Variable"Segments
"Diversity"Segments
"Joining"Segments
"Constant"Region
V(D)J Recombination
V-J Recombination
Ig/T-cell Receptor mRNA
5'
3'
V-DJ Recombination
Transcription, Splicing
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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]
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Dendritic cells (DC)
Figure removed for copyright reasons.
Source: Figure 6-6 in [RC]
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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]
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Major histocompatabilitycomplex (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]
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Major histocompatabilitycomplex (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]
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Figure by MIT OCW.
Endocytosis of extracellular protein
Invariant chain (I)
CLASS I MHC PATHWAY
Pathways of Antigen Processing & Presentation
CLASS II MHC PATHWAY
ER
ER
Proteasome TAPCytosolicprotein
CD4+ T cell
CD8+
CTL
Antigen uptake
Antigen processing
MHC biosynthesis
Peptide-MHCassociation
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Figure removed for copyright reasons.
Source: Figure 6-23 in [RC]
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Figure removed for copyright reasons.
Source: Figure 6-27 in [RC]
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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).
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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
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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
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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
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Preventing immune homing
Figure removed for copyright reasons.
Source: Figure 2-6 in [RC]
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Natalizumab (TYSABRI)• Recombinant humanized MAb against α4
integrin• The α4 subunit of α4β1 and α4β7 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-β (AVONEX)• Indications include MS, Crohn’s disease and
rheumatoid arthritis
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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 multifocalleukoencephalopathy (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).