Autoimmunity III

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Autoimmunity III

• Therapeutics of Autoimmune Diseases

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Autoimmune Therapeutics

• General
• Ag-specific
• Gene therapy
• IVIg
• Plasmapheresis
• BMT

• Specific
• SLE
• RA
• MS

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Antigen-specific Therapy

• Induce tolerance
• Determined by
• Form and purity of Ag
• Dose
• Route of administration
• Co-stimulation
• Systemic or mucosal

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Ag-induced Tolerance
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Gene Therapy/Anti-cytokine

• Local delivery of regulatory proteins by
  insertion and expression of foreign DNA in a host
  cell
• Viral vectors replication defective,
  infection-competent
• Anti-cytokine
• ?-TNF Abs, sTNFR, IL-6 Abs, NF?B
  inhibitors IL-4, IL-10, IL-13

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Intravenous Immunoglobulin (IVIg)

• High doses of IgG pooled from healthy donors
• Mechanism of action
• Regulatory properties of anti-idiotypic Abs
• Effects on cytokine synthesis, Rs, C Rs
• Block FcR on phagocytes, other cells
• Simultaneous ligation of FcR and B cell R
• Acceleration of rate of IgG catabolism

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Yu, Z. 1999. NEJM.
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Plasmapheresis

• Plasma components can be selectively removed
  remaining components combined with replacement
  plasma or inert substitute and returned to
  patient
• Without replacement immunoadsorption
• Density gradients affinity, hollow fiber, or
  filtration membranes columns
• Without immunosuppressants Ab rebound

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Cearlock, D.M. 2000. MLO.
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Plasmapheresis

• Plasma components one normal means for
  plasmapheresis is to
• Remove the plasma
• Replace with fresh frozen plasma
• This method removes Ig but does not remove immune
  cells.
• This method does afford the opportunity to
  administer B-cell immunosuppression.

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Bone Marrow Transplant

• Hematopoietic stem cells (HSCs)
• Transfer and prevent disease
• Intense immunosuppression (immunoablation)
  followed by autologous or allogeneic HSC
  transplant
• Total body irradiation, immunosuppressants
• T cell and B cell depletion
• Coincidental hematological malignancies

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SLE

• Goals treat active phase w/out causing long-term
  damage
• Limiting corticosteroid, immunosuppressive
  exposure
• Combinations of drugs
• Treat organ/system manifestations

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Summary of both established therapies and novel
therapies for SLE
Established pharmacological therapies New uses for established therapies Novel agents Cytokines and inflammatory mediators
Nonsteroidal antiinflammatory drugs Plasmapheresis LJP 394 Anti-IL10 antibody
Hydroxychloroquine Intravenous immunoglobulin IDEC-131 TNF alpha inhibitors
Prednisone Mycophenolate mofetil BG9588 BlyS blockers
Cyclophosphamide Tacrolimus CTLA4Ig Anti-C5a antibody
Azathioprine Methotrexate
Leflunomide
Rituximab
Cyclosporine
Stem cell transplantation
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SLE

• Clinical Trials
• Regulation of CD154 (CD40L)
• SELENA (Safety of Estrogens in SLE National
  Assessment) Phase III
• OCP Ortho-Novum 777 (oral contraceptive)
• HRT Premarin and Provera (replacement)
• II Dehydroepiandrosterone (GL701)
• UV A-1 light therapy

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IL1 and TNFa are central mediators in RA
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TNF-a central to the pathogenesis of RA
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Goals of Therapy for RA

• Relieve pain and Inflammation
• Prevent joint destruction
• Maintain function

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RA

• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Glucocorticoids

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RA

• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Reduce inflammation, relieve pain
• COX-1 and/or 2
• COX-2 celecoxib (Celebrex), rofecoxib (Vioxx)
  may be not now!
• meloxicam, flusolide, nimesulide

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RA

• Corticosteroid therapy
• Can be used to bridge gap between initiation of
  DMARD therapy and onset of action
• Anti-inflammatory and immunosuppressive effects
• Intra-articluar injections can be used for
  individual joint flares
• Does not conclusively affect disease progression
• Tapering and discontinuation of use often
  unsuccessful

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Newer drugs in the treatment of RA

• DMARDs
• Etanercept (Enbrel)
• Infliximab (Remicade)
• Leflunomide (Arava)

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Etanercept

• Etanercept binds specifically to tumor necrosis
  factor (TNF) and blocks its interaction with cell
  surface TNF receptors.
• It plays an important role in the inflammatory
  processes of rheumatoid arthritis (RA), juvenile
  polyarticular rheumatoid arthritis (JRA), and
  ankylosing spondylitis and the resulting joint
  pathology.

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Etanercept

• Two distinct receptors for TNF (TNFRs), a 55
  kilodalton protein (p55) and a 75 kilodalton
  protein (p75), exist naturally as monomeric
  molecules on cell surfaces and in soluble forms.
• Biological activity of TNF is dependent upon
  binding to either cell surface TNFR.

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Etanercept

• Etanercept is a fusion protein made up of two
  recombinant p75 soluble TNF receptors fused with
  the Fc portion of human IgG1. The dimeric
  structure of etanercept makes it approximately
  1000 times as efficient as the monomeric soluble
  p75 TNF receptor at neutralizing TNFa.
• Etanercept inhibits binding of both TNFa and TNFb
  (lymphotoxin alpha) to cell surface TNFRs,
  rendering TNF biologically inactive.

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Etanercept

• Etanercept can also modulate biological responses
  that are induced or regulated by TNF, including
  expression of adhesion molecules responsible for
  leukocyte migration (i.e., E-selectin and to a
  lesser extent ICAM-1, serum levels of cytokines
  (e.g., IL-6), and serum levels of MMP-3 or
  stromelysin.

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Etanercept - STUDY

• A study evaluated 234 patients with active RA who
  were 18 years old, had failed therapy with at
  least one but no more than four disease-modifying
  antirheumatic drugs (DMARDs e.g.,
  hydroxychloroquine, oral or injectable gold,
  methotrexate MTX, azathioprine,
  D-penicillamine, sulfasalazine), and had 12
  tender joints, 10 swollen joints, and either
  ESR 28 mm/hr, CRP gt 2.0 mg/dL, or morning
  stiffness for 45 minutes.

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Etanercept - STUDY

• Doses of 10 mg or 25 mg ENBREL or placebo were
  administered SC twice a week for 6 consecutive
  months.

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Etanercept - STUDY

• Among patients receiving ENBREL, the clinical
  responses generally appeared within 1 to 2 weeks
  after initiation of therapy and nearly always
  occurred by 3 months.
• A dose response of 25 mg ENBREL was more
  effective than 10 mg.
• ENBREL was significantly better than placebo in
  all components of the measures of RA disease
  activity, such as morning stiffness and disease
  progression.

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Heart Failure

• Decreased tissue TNF-a levels, it did not improve
  cardiac function, and at high doses it was
  associated with higher mortality.
• These results in a rodent model confirm the
  results of clinical trials with etanercept and
  infliximab (ie, that decreasing TNF levels in
  plasma or tissues does not improve cardiac
  function and may actually increase mortality).

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Infliximab Pharmacology

• A chimeric IgG1 antibody against TNF-a, composed
  of human constant and murine variable regions
• Binds specifically to human TNF-a
• Binds both to soluble and transmembrane forms,
  thus inhibiting binding of TNFa with its natural
  receptors

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Leflunomide

• Reduce pain and inflammation
• Retards structural damage erosion and joint space
  narrowing
• Inhibit pyrimidine nucleotides formation
• Hepatotoxicity and gastrointestinal toxicities

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• MS

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MS RR

• Recombinant IFN-?
• Reduce proliferation of T cells and TNF
  production
• Inhibits TH1 cytokines, cellular migration, Ag
  presentation, adhesion molecule and protease
  expression
• Induces TH2 cytokines
• RR s.c. or i.m.
• Side effects flu-like symptoms, headache,
  anemia, injection site reactions

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IFN-?

• IFN-?1b (Betaseron)
• Missing carbohydrate side chain, cys17?ser
• IFN-?1a (Avonex)
• Prevents brain atrophy
• Delay in time to physical disability
• 30 reduction in number of exacerbations
• 10,000/year

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MS RR

• Glatiramer acetate (Copaxone)
• Acetate salt of mixture of synthetic peptides
• Copolymer 1
• L-ala, L-glu, L-lys, L-tyr
• Daily s.c. injection site reactions
• Mimics MBP
• 33 reduction in relapse rate
• ? of relapses and and volume of T2
• Higher proportion free of relapse, fewer with
  worsening EDSS
• Possible benefit over IFN-? over time

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MS Other

• RR
• Relapses Glucocorticoids
• Symptom specific therapy
• Chronic-Progressive
• IFN-?1a, -?1b, cyclophosphamide, mitoxantrone,
  plasma exchange

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Mitoxantrone

• Cell-cycle non-specific anthracycline
  chemotherapeutic that intercalates with DMA
  leading to breaks in DNA.
• Inhibits both DNA and RNA synthesis
• Reacts with P450 reductase causing formation of
  free radicals and cell destruction.

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MS Clincal trials

• I, II, III ginkobiloba, ?-lipoic acid/ essential
  fatty acids, vit E/selenium
• II Zenepax (?-IL-2 R a subunit)
• III IVIg
• I M-T412 (?-CD4 mAb chimera)
• II CGP77116 (myelin-like protein)
• II Yoga

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Surprise Rx

• 3-Hydroxy-3-methhylglutaryl coenzyme A (HMG-CoA)
  reductase inhibitors, the so-called statins,
  atorvastatin, cerivastatin, fluvastatin,
  pravastatin, lovastatin and simvastatin, can
  induce relatively large reductions in plasma
  cholesterol levels and are established drugs for
  the treatment of hypercholesterolemia.

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Surprise Rx

• It has been demonstrated that statins decrease
  the secretion of the pro-inflammatory cytokines
  IL-6 and IL-8 but not tumor necrosis factor-
  (TNF-a), from activated macrophages, inhibit
  chemokines release such as MCP-1 and IP-10 by
  endothelial cells (ECs), inhibit adhesion
  molecules expression such as CD11 on monocytes or
  ICAM-1 on ECs.

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Surprise Rx

• Experiments demonstrated that statins inhibit
  MMPs activity and secretion, such MMP-1, MMP-3
  and MMP-9, by human and rabbit macrophages in
  vitro as well as in vivo.
• Furthermore, statins have effects on the
  coagulation process.

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Surprise Rx

• Recently, it has been demonstrated that statins
  act as direct inhibitors of induction of MHC-II
  expression by IFN-g and thus as repressors of
  MHC-II-mediated T cell activation Nat Med
  200061399 Swiss Med Wkly 200113141.
• This effect of statins is due to inhibition of
  the inducible promoter IV of the transactivator
  class II transactivator (CIITA). The CIITA is a
  master regulator of MHC class II expression.

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statins
Functional inhibition of MHC class II antigens
by statins on T lymphocytes activation.
3H-thymidine incorporation (a), and IL-2
release (b) measured in allogenic T lymphocytes
exposed to human ECs pre-treated for 48 h with
IFN- (500 U/ml) alone (1), or IFN- (500 U/ml)
with atorvastatin (10 M) (2).
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Surprise Rx

• Numerous other practical clinical applications
  for using statins as immunomodulators,
  particularly in diseases where aberrant
  expression of MHC class II molecules are
  implicated.
• This ranges from autoimmune diseases such as
• type I diabetes, multiple sclerosis and
  rheumatoid arthritis to psoriasis and chronic
  inflammatory diseases like atherosclerosis.
• The high degree of patient tolerance of statins
  makes them potentially a welcome addition to the
  limited current arsenal of immunosuppressive
  agents.

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