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Autoimmunity III. Therapeutics of Autoimmune Diseases. General Ag-specific Gene therapy IVIg Plasmapheresis BMT. Specific SLE RA MS. Autoimmune Therapeutics. Antigen-specific Therapy. Induce tolerance Determined by Form and purity of Ag Dose Route of administration

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autoimmunity iii

Autoimmunity III

Therapeutics of Autoimmune Diseases

autoimmune therapeutics
General

Ag-specific

Gene therapy

IVIg

Plasmapheresis

BMT

Specific

SLE

RA

MS

Autoimmune Therapeutics
antigen specific therapy
Antigen-specific Therapy
  • Induce tolerance
  • Determined by
    • Form and purity of Ag
    • Dose
    • Route of administration
    • Co-stimulation
  • Systemic or mucosal
gene therapy anti cytokine
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
intravenous immunoglobulin ivig
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
plasmapheresis
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
slide9

Cearlock, D.M.

2000. MLO.

plasmapheresis10
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.
bone marrow transplant
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
slide12
SLE
  • Goals: treat active phase w/out causing long-term damage
    • Limiting corticosteroid, immunosuppressive exposure
    • Combinations of drugs
    • Treat organ/system manifestations
slide14
SLE
  • Clinical Trials:
    • Regulation of CD154 (CD40L)
    • SELENA (Safety of Estrogens in SLENational Assessment) – Phase III
      • OCP: Ortho-Novum 777 (oral contraceptive)
      • HRT: Premarin and Provera (replacement)
    • II: Dehydroepiandrosterone (GL701)
    • UV A-1 light therapy
goals of therapy for ra
Goals of Therapy for RA
  • Relieve pain and Inflammation
  • Prevent joint destruction
  • Maintain function
slide18
RA
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Glucocorticoids
slide19
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
slide20
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
slide21

Newer drugs in the treatment of RA

  • DMARDs
      • Etanercept (Enbrel)
      • Infliximab (Remicade)
      • Leflunomide (Arava)
etanercept
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.
etanercept25
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.
etanercept26
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.
etanercept27
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.
etanercept study
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 > 2.0 mg/dL, or morning stiffness for = 45 minutes.
etanercept study29
Etanercept - STUDY
  • Doses of 10 mg or 25 mg ENBREL® or placebo were administered SC twice a week for 6 consecutive months.
etanercept study30
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.
heart failure
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).
infliximab pharmacology
Infliximab: Pharmacology
  • A chimeric IgG1 antibody against TNF-α, composed of human constant and murine variable regions
  • Binds specifically to human TNF-α
  • Binds both to soluble and transmembrane forms, thus inhibiting binding of TNFα with its natural receptors
leflunomide
Leflunomide
  • Reduce pain and inflammation
  • Retards structural damage erosion and joint space narrowing
  • Inhibit pyrimidine nucleotides formation
  • Hepatotoxicity and gastrointestinal toxicities
ms rr
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
slide36
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
ms rr37
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
ms other
MS – Other
  • RR
    • Relapses: Glucocorticoids
    • Symptom specific therapy
  • Chronic-Progressive
    • IFN-1a, -1b, cyclophosphamide, mitoxantrone, plasma exchange
mitoxantrone
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.
ms clincal trials
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
surprise rx
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.
surprise rx42
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.
surprise rx43
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.
surprise rx44
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 2000;6:1399; Swiss Med Wkly 2001;131:41].
  • 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.
statins
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).

surprise rx46
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.