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Auto-immune diseases

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Auto-immune diseases Leonard H Sigal MD, FACP, FACR P.R.I.- CD& E- Immunology Bristol-Myers Squibb Princeton, NJ Clinical Professor of Medicine and Pediatrics – PowerPoint PPT presentation

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Title: Auto-immune diseases


1
Auto-immune diseases
  • Leonard H Sigal MD, FACP, FACR
  • P.R.I.- CD E- Immunology
  • Bristol-Myers Squibb
  • Princeton, NJ
  • Clinical Professor of Medicine and Pediatrics
  • UMDNJ Robert Wood Johnson Medical School
  • New Brunswick, NJ

2
Too little immunity is a problem
  • But, what about too much immunity?
  • Recall Critical to a proper immune response is
    being able to differentiate self from
    non-self- the entity from the attackers

3
Too much immunity
  • Allergy- one theory may be due to improved
    hygiene and lack of ambient bacterial exposures
    early in life
  • Auto-immunity- breakdown in tolerance- genetic
    predisposition plus environmental exposure as
    trigger

4
AUTO-IMMUNITY
  • Breakdown in ability to differentiate self
    from non-self
  • Tolerance is the ability to not
    immunologically react to self
  • Self-recognition (non-auto-aggressive behavior)
    is part of many normal immune and homeostatic
    mechanisms
  • 5 to 8 of the US population has an auto- immune
    disorder, may be more than one

5
AUTO-IMMUNITY
  • Tolerance starts in thymus and continues with
    active suppression in the periphery
  • Developing immunocytes are exposed to
    self-antigens and if their receptor recognizes
    self too well the cell is eliminated (negative
    selection) no recognition ? positive
    selection mid- ground survive but anergized or
    controlled peripherally.

6
AUTO-IMMUNITY
  • Organ-specific single or a few
  • Systemic
  • Auto-immunity of a single organ often means
    there is another organ affected
  • Family history is often positive

7
Self-recognition- salubrious examples
  • Idiotype network- regulation of antibody
    production
  • Antigen presentation MHC and cell-surface
    antigen receptors interact
  • Ligand-receptor interactions
  • Antigen-specific suppressor cells factors

8
Why auto-immunity?
  • There are auto-aggressive immune clones in
    your body right now
  • Under normal circumstances these are kept under
    control- breakdown in control leads to
    auto-aggressive behavior
  • A breakdown in tolerance can lead to
    auto- immunity
  • In both SLE and RA, auto-antibodies may be
    present for up to 9 years prior to disease

9
What Induces Autoimmunity?
CENTRAL (prenatal) and PERIPHERAL (later)
MECHANISMS
10
Aire- a key to tolerance induction in the thymus
  • Aire- auto-immune regulator protein expressed in
    the thymus that induces thymic medullary
    epithelial cells to express 200 to 1200
    non-thymic proteins, seemingly to allow
    intra-thymic processing and presentation of these
    proteins to lead to tolerance
  • Defect of Aire expression associated with APECED
    autoimmune polyendocrinopathy candidiasis
    ectodermal dystrophy

11
FOXp3
  • Mouse strain scurfy develops an X-linked
    recessive auto-immune disorder with multiple
    organ-specific inflammation, hypergammaglobulinemi
    a, wasting and a lymphoproliferative disorder-
    due to uncontrolled activation and proliferation
    of CD4 T-cells.
  • Similar human disease phenotype
  • X-linked autoimmunity, allergic dysregulation
    syndrome (XLAAD)
  • Immune dysregulation, polyendocrinopathy,
    endocrinopathy, X-linked syndrome (IPEX).

12
T-regs CD4 CD25
  • GITR, CD62L, CTLA4 or ?E/?7 integrin might be
    better markers than CD25

13
non T-reg T regulators
  • CD4 TH1 cells (secreting gamma interferon)
  • CD4 TH2 cells (secrete IL-4)
  • CD4CD25 TH3 cells (IL-10 and/or TGF?)
  • CD4 TR1 cells (secrete IL-10)
  • intraepithelial CD8 ?/?cells (IL-10)
    and natural killer T-cells (IL-4).

14
Adaptive/Acquired Immunity Activation of
Effector T cells
Antigen Presenting Cell
Foreign antigen
Viral antigen Self antigen
Processing Loading
MHC class I
MHC class II
TGF? IL6
TGF?
CD4 Helper
CD4 Th17
CD8 Cytotoxic
CD4 CD25 Treg Foxp3
IL17 IL22
Effector T cells
Possible autoimmune activity
Antibodies Cytokines
Cytotoxic cell activity
TGF? IL10
Regulatory functions
15
CD4 cell populations of note
Th1
Th2 Th17
Intracellular Extracellular pathogens
Extracellular pathogens like
parasites bacteria
?IFN IL4 IL17A LT? IL5
IL17F TNF? IL6 IL6 IL2 IL9 IL1
0 IL13
Bacterial species implicated include 
Klebsiella pneumoniae, Bordetella pertusis,
Citrobacter rodentium, and Borrelia burgdorferi
16
T Cells Orchestrate the Adaptive and Innate
Responses
Proliferate and differentiate to effectors
CD4 T-helper cell
Osteoclast
RANK-L
T cell
T cell
IL-2
IL-4, IL-10
T cell
T cell
B-cell
IFN-g, TNF-a
IFN-g IL-4 IL-5 TNF-a TGF-b
IL-3, IL-7, GM-CSF
Stem cell
B-cell proliferation B-cell differentiation cytok
ine production APC activity antibody production
TNF-a, IL-1, IL-6, IL-12
17
1. Genes
2. Abnormal Immune Response
4. Inflammation
5.Damage
C1q,C2,C4 HLA-D2,3,8 MBL
FcR 2A,3A,2B IL-10 MCP-1 PTPN22
Environment
Rash Nephritis Arthritis Leukopenia CNS
dz Carditis Clotting Etc
Renal Failure Atherosclerosis Pulm
fibrosis Stroke Damage from Rx Etc
3. Autoantibodies Immune Complexes
UV light Gender EBV Other Infe Others
Courtesy Bevra Hahn, MD
18
Auto-antibodies- receptor targets Receptor
Stimulate Block
  • TSH R. Graves Hashimotos
  • Insulin R. Hypo- Hyperglycemia
  • ACTH R. Addisons
  • Intrinsic Factor Pernicious anemia
  • ACh R. Myasthenia gravis

19
Auto-antibodies- other targets
  • Basement membrane Goodpastures syndrome
  • Uveal tract Sympathetic ophthalmia
  • Cardiac tissue Dresslers syndrome
  • Exocrine glands Sjogrens syndrome
  • Epidermal Bullous pemphigus hemidesmosomes
  • Blood cells Hemolytic anemia, AITP

20
TREATMENT OF AUTO-IMMUNITY
  • If hormonal deficiency- REPLACE
  • If organ inflammation- SUPPRESS Pulse
    corticosteroids Oral corticosteroids Cytotox
    ic agents Immunomodulatory agents Plasmaphere
    sis

21
TREATMENT OF AUTO-IMMUNITY
  • Neutralize inflammatory cytokines Solubilized
    receptor TNF
  • Monoclonal antibody TNF, BLyS
  • Antibody to receptor IL-6
  • Receptor antagonist IL-1
  • Suppress antigen-specific response
    Co-stimulation blockade CTLA4Ig
  • Counterbalancing cytokines

22
MP/DC
Clinical Trials
Treg
IFNa
Anti-IFNa
DR
Edratide
B7
LJP394
Peptide
CD28
TCR
X
Y
Anti-CD20
BCR
CD20
Anti-CD22
CTLA4-Ig
CD22
B Cell
T Cell
CD28
B7
IMPDH
IMPDH
Inosinic acid
purines
Inosinic acid purines
BCMA APRIL
BLyS
Mycophenolate
Mycophenolate
Anti-BLyS TACI-Ig
Courtesy Bevra Hahn, MD
23
Molecular biology has given us a new therapeutic
world
  • Replace deficiencies- IVIG, ADA
  • Repair genetic defects- ADA
  • Stem cell transplants
  • Cytokines, receptors, antibodies- antagonist and
    agonist
  • Support patients until defect identified and
  • toxicity of therapy can be overcome

24
Abbreviations in common use
  • SUFFIX DESCRIPTION
  • -mab Monoclonal antibodies
  • -umab Human mab
  • -ximab Chimeric mab (mixture of mouse and
    human structures)
  • -zumab Humanized mab (very short murine
    sequences remain, solely in the
    antigen-binding regions)
  • -cept Receptor-antibody fusion protein, often
    Fc component of an IgG
  • -kinra Interleukin receptor antagonist
    (-kin is suffix for interleukin -ra for
    receptor antagonist)
  • -nakinra IL1 receptor antagonist
  • -tinib Inhibitor of a tyrosine kinase

25
SYSTEMIC INFLAMMATORY SYNDROMES
  • Systemic lupus erythematosus (SLE)
  • Rheumatoid arthritis (RA)
  • Juvenile rheumatoid arthritis (JRA)- aka
    Juvenile idiopathic arthritis (JIA)
  • Juvenile dermatomyositis
  • Kawasaki disease
  • Seronegative spondylarthropathies (SNSA)

26
SYSTEMIC LUPUS ERYTHEMATOSUS
  • Multi-system inflammatory disease
  • Episodic features in kidneys, brain, skin,
    joints, serosa
  • Broad range of severity
  • Steady improvement in outcomes with the
    evolution of better treatment
  • Poor outcome CNS or renal disease lower
    socio-economic status externalized locus of
    control

27
SYSTEMIC LUPUS ERYTHEMATOSUS-Criteria
  • Constitutional
  • Skin malar rash, discoid lesions,
    photosensitivity
  • Oral/nasal muco- cutaneous lesions
  • Joints and Muscle
  • Nephritis
  • Brain seizures, psychosis
  • Pleurisy/pericarditis
  • Cytopenias
  • Positive ANA
  • Immunoserologies dsDNA, Sm, anti- cardiolipin

Need 4 of the 11 criteria
28
SYSTEMIC LUPUS ERYTHEMATOSUS
  • Most common cause of death used to be
    active disease
  • Now, it is consequences of STEROIDS early
    infection late accelerated
    atherosclerosis
  • Consequences of cyclophosphamide
    malignancy
  • Consequences of dialysis, hypertension,
    etc. end-organ damage

29
IL-10
Ts
TGF?
TGF?
IFN?
Crow MK, AR, 2003
30
Treg (Foxp3 CD4 T) are Depleted in Patients with
Active SLE
Miyara et al, J Immunology, 2005
31
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32
TGF? in Normals

T
CD8
B
TGF?
IL-2
AB
NK
NK
Treg
CD4
33
Patients with SLE Make Abnormally Low Levels of
TGF?
TGF? pg/ml


Ohtsuka et al, JI 1998
Human cells stimulated with anti-CD2
34
SYSTEMIC LUPUS ERYTHEMATOSUS
  • Therapy tailored to the organ system(s)
    affected, severity/type of damage
  • NSAIDs
  • Hydroxychloroquine
  • Corticosteroids
  • Cyclophosphamide
  • Azathioprine
  • Biologics in trials- BLyS, CTLA4Ig

35
Rheumatoid arthritis
  • 1 of population seems to be decreasing in
    incidence
  • Synovitis, primarily of small joints of hands
    and feet
  • Symmetric- could this be neural input?
  • Rheumatoid factor
  • Anti-CCP (cyclic citrullinated peptide) prior to
    disease

36
Rheumatoid arthritis- focus?
  • T cell
  • Macrophage
  • Synoviocyte (fibroblastoid)
  • B cell
  • Genetics
  • Anti-CCP2

37
Rheumatoid arthritis- therapies
  • NSAIDs, COX2s
  • Corticosteroids
  • Methotrexate, leflunomide
  • Cyclosporine (T cell target)
  • Anti-CD3 total nodal irradiation
  • Anti-TNFs
  • Co-stimulation modulation
  • B cell assassination B cell activation blockade

38
JUVENILE IDIOPATHIC ARTHRITIS (JIA)-ILAR 1995
  • Seven categories
  • Systemic
  • Oligoarthritis
  • Polyarthritis (RF-)
  • Polyarthritis (RF)
  • Psoriatic arthritis
  • Enthesitis-related arthritis- related to SNSAs
  • Other arthritis

39
JUVENILE RHEUMATOID ARTHRITIS (JRA)/ IDIOPATHIC
ARTHRITIS (JIA)
  • Unknown etiology
  • Unknown immune focus in joints, eyes, etc.
  • Age lt 16 years at onset
  • Genetic pre-disposition
  • Multiple cytokines involved, e.g. TNF, IL-1,
    IL-6

40
Macrophage Activation Syndrome- complication of
systemic JRA
  • Acute onset- high fever, lymphadenopathy, acute
    hepatitis, profound cytopenias, DIC
  • Can be post-viral, NSAIDs, Methotrexate
  • Can mimic JRA flare
  • Hematophagocytosis by well-differentiated
    macrophages in bone marrow
  • Rx? steroids, IVIG, cyclosporin

41
Macrophage activation syndrome
  • Myelocyte within activated macrophage, and
    multiple adherent red blood cell and myeloid
    precursors.

42
Macrophage activation syndrome
  • Neutrophilic bands and metamyelocyte within an
    activated macrophage.

43
JUVENILE IDIOPATHIC ARTHRITIS- New management
  • Methotrexate
  • Etanercept
  • Infliximab
  • Adalimumab
  • Leflunomide
  • Abatacept (CTLA4-Ig)
  • Anakinra not very effective
  • Anti-IL-6 effective not yet approved

44
DERMATOMYOSITIS
  • Multi-system inflammatory disease
  • Adults and children
  • Acute and chronic inflammation of striated
    muscle and skin

45
SERONEGATIVE SPONDYLOARTHROPATHIES
  • Ankylosing spondylitis
  • Psoriatic arthritis
  • Psoriatic spondyloarthropathy
  • Inflammatory joint disease associated with
    inflammatory bowel disease
  • Reactive arthritis (no longer called Reiter
    syndrome)

46
SERONEGATIVE SPONDYLOARTHROPATHIES
  • No serum rheumatoid factor
  • Inflammation of spine and sacroiliac joints
  • Primary focus of inflammation is the enthesis
  • HLA-B27 independent linkage with aortic
    disease (and anterior uveitis)

47
SNSA- therapy
  • NSAIDs, COX2
  • Sulfasalazine
  • TNF blockade

48
SYSTEMIC INFLAMMATORY SYNDROMES-Vasculitis
  • Classified by size of vessel affected Large
    Takayasu Medium PAN Churg-Strauss
    Medium Wegener Goodpasture Small
    Henoch-Schonlein Purpura
  • Pathogenesis is unclear immune complex
    auto-antibody cellular reactivity

49
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50
COMBINATIONS OF FEATURES GREATLY ENHANCE
PROBABILITY OF VASCULITIS
  • Fever
  • Glomerulonephritis
  • Palpable purpura
  • Peripheral neuropathy
  • Established auto-immune disease
  • Ischemia, e.g. gut, heart, brain especially in
    young patients

51
DIAGNOSING VASCULITIDES
  • Based on collection of current findings
  • Consider historical features
  • May be overlap in syndromes
  • Always try to substantiate diagnosis by biopsy
    of affected tissue(s)

52
RESULTS OF VASCULAR INFLAMMATION
  • STENOSIS OCCLUSION
  • ISCHEMIA / INFARCTION
  • DILATATION RUPTURE
  • TURBULENT FLOW / BLEED

53
VASCULITIDES OF OLDER PEOPLE
  • Giant cell arteritis
  • Polyarteritis nodosa (PAN)
  • Wegener granulomatosis
  • Cryoglobulinemia
  • Leukocytoclastic vasculitis

54
SIGNS AND SYMPTOMS OF GCA
  • gt 50 years of age 100
  • ESR       gt100 60
  • Headache 70
  • Tenderness of arteries 50
  • Jaw claudication 50
  • Bruits 40
  • Visual symptoms   10-15
  • Diplopia           Vision loss           Ultim
    ate blindness
  • Weight Loss 40
  • Fever 20

55
POLYMYALGIA RHEUMATICA
  • Shoulder and hip girdle pain
  • Perceived weakness, but normal strength
  • Morning stiffness, but not obvious synovitis
  • Over age 50
  • Dramatic and rapid response to steroids
  • Overlap with GCA up to 40 of PMR have GCA (may
    be delayed) and up to 65 of GCA have PMR
  • Recent studies suggest the shoulder and hip pain
    is due to a mild synovitis of those joints

56
GIANT CELL ARTERITIS
Disrupted internal elastic lamella
57
Not merely temporal arteritis
ANEURYSMS
58
  • Classical Polyarteritis Nodosa
  • Medium-sized vessel involvement.
  • Absence of vasculitis of arterioles, venules
    and capillaries. Renal disease may occur, but
    not
  • glomerulonephritis.
  • Microscopic Polyangiitis
  • Involvement of "microscopic" vessels
    (arterioles, venules, and capillaries), with or
    without medium-size vessel involvement.
  • Glomerulonephritis is common and pulmonary
    capillaritis may occur.
  • Few or no "immune deposits," no granulomas -
    distinct from HSP, cryoglobulinemic
    vasculitis, lupus, serum sickness.

59
Polyarteritis Nodosa
  • Skin Small (purpura) and medium (gangrene)
    vessels, subcutaneous nodules, livedo
    reticularis, ischemic atrophy
  • Renal Rapid renal failure as a consequence of
    multiple infarcts
  • Gastrointestinal abdominal pain, bleeding, bowel
    perforation, and malabsorption.
  • Cardiac and pulmonary Cardiomegaly,
    pericarditis, coronary artery involvement leading
    to ischemia and infarction,
  • Reproductive Orchitis in males.

60
WEGENER'S GRANULOMATOSIS
  • Idiopathic systemic inflammatory disease
  • with an unusual propensity to affect the
  • respiratory tract and kidneys.
  • Small and medium-sized vessels.
  • Tissue damage often associated with necrosis and
    granuloma formation.
  • Active disease is often associated with
  • antibody formation to proteinase 3 (Pr3).

61
Wegener Granulomatosis
62
Wegener Granulomatosis
63
ANCA anti-neutrophil cytoplasmic antibodies
WG
MPA CG UC
Myeloperoxidase, Lactoferrin, Proteinase-3 elasta
se, cathepsin C
64
Cryoglobulinemia
  • Immunoglobulin and other molecules associate in
    blood immune complexes then settle on blood
    vessel wall and cause inflammation.
  • Linked to underlying abnormality of plasma cells-
    making antibody that self-associates, causing
    complexes
  • Can be associated malignancy or underlying
    inflammatory disease, e.g. Sjogren syndrome
  • BUT, idiopathic is common and no clear
    explanation until a few years ago discovery of
    association with Hepatitis C infection
  • Now known that essentially all of these
    idiopathic cases are due to Hepatitis C
    infection

65
Cryoglobulinemia
66
BEHÇET SYNDROMEAdamantiades-Behcet
  • May have been described first by Hippocrates in
    the 5th century BC, in his 3rd Epidemion.
  • First modern formal description published in
    1922 by Hulusi Behçet, Turkish dermatologist.
  • Sometimes called "Adamantiades syndrome" or
    "Adamantiades-Behçet syndrome".
  • Malesfemales 11 more female in US, Japan,
    Korea, the West
  • Increasing prevalence with increased awareness
  • Turkey 300/100,000 US/EU 10-17/100,000

67
BEHÇET SYNDROME
The Silk Road
  • HLA-B51

68
BEHÇET SYNDROME
  • Mucosal lesions- very painful aphthous ulcers
  • Cutaneous lesions- erythema nodosum, acneiform,
    folliculitis
  • Ocular- panuveitis, anterior uveitis, retinal
    vasculitis
  • Arthritis/arthralgia
  • CNS and PNS disease- meningomyelitis, brainstem,
    organic confusional syndromes, changes of
    personality, psychosis
  • GI inflammation- intestinal ulcerations
  • Deep vein thrombosis/superficial thrombophlebitis
  • Other organs lungs, kidneys, epididimytis

69
BEHÇET SYNDROME
70
BEHÇET SYNDROME
Hypopyon
71
BEHÇET SYNDROME
72
BEHÇET SYNDROME
  • Pathergy sign

73
VASCULITIDES OF YOUNGER PEOPLE
  • Takayasu aortitis
  • Henoch-Schonlein purpura (HSP)
  • Leukocytoclastic vasculitis (LCV)
  • Kawasaki syndrome
  • Serum sickness-immune complex-mediated
  • Goodpasture syndrome

74
TAKAYASU ARTERITIS
  • Young women
  • Disease of aorta and its first branches
  • Loss of pulse (Pulseless disease), stroke,
    hypertension
  • Can affect pulmonary circulation, as well
  • Progression in up to half of patients even though
    thought to be in remission may occur silently
  • Even when thought to be quiescent 40 of
    patients still have active inflammation at surgery

75
Takayasu arteritis
76
HENOCH-SCHONLEIN PURPURA
  • Palpable purpura
  • Glomerulonephritis
  • Arthritis
  • Abdominal pain
  • Malesfemales mean age 5 yrs.
  • Preceding URI in 2/3 (1-3 weeks).

77
HENOCH-SCHONLEIN PURPURA
  • Small vessels, esp. Post-capillary venules.
  • All lesions about same stage in evolution.
  • Bx with i.F. TYPICALLY IgA deposits in skin
    and kidney
  • Usually single episodes lt 4 weeks duration.
  • 40 recurrence rate after period of
    wellness.
  • May be permanent renal damage

78
Henoch-Schonlein purpura
79
KAWASAKI DISEASE- Criteria
  • Fever 100 5 days or more, remittent
  • Conjunctivitis 85 Bilateral
  • Lymphadenopathy 70 Cervical gt1.5 cm
  • Lips/oral mucosa 90 Strawberry tongue
    Dry, red vertical fissures Red
    oropharynx
  • Extremities 70 Erythema of
    palms/soles Convalescent fingertip
    desquamation

80
KAWASAKI DISEASE-other features
  • Cardiac- most serious complication Pericarditis,
    arrhythmias, infarction Myocarditis- Heart
    failure, aneurysms
  • CNS- irritability is almost universal consider
    aseptic meningitis, focal lesions, seizures-
    CNS vasculitis

81
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82
Goodpasture Syndrome
  • Typically young men presenting with
    pulmonary-renal syndrome hemoptysis AND renal
    failure
  • Caused by auto-antibodies that uniquely bind to
    basement membranes of lung and kidney, causing
    alveolitis and glomerulonephritis
  • Serum from patients can cause a similar syndrome
    to develop in serum-recipient monkeys

83
Goodpasture Syndrome
84
Goodpasture Syndrome
anti-GBM antibodies directed against
noncollagenous (NC1) globular domain of the ?3
chain of type IV GBM collagen
85
VASCULITIS- Treatment
  • Which organ system?
  • How severe?
  • Rate of damage?
  • Potential reversibility?

86
VASCULITIS- Treatment
  • Corticosteroids Daily or Pulse
  • Cytotoxic agents, e.g. Methotrexate
    Azathioprine Cyclophosphamide
  • Immunomodulatories Mycophenolate
    mofetil Cyclosporine

87
Immunomodulation General Principles
  • If we accept the premise that many systemic
    inflammatory diseases are auto-immune,
    manipulation of the immune response may help
    control the disease
  • Identification of which immune mechanism is
    causative/contributory is crucial

88
Immunomodulation-
Immediate control of disease
  • Pulse IV corticosteroids can be very useful in
    getting some diseases under control immediately
  • Plasmapheresis has limited usefulness
    auto-antibody- (Goodpasture) or
    immune-complex-mediated (systemic JRA?)
    diseases
  • IVIG- ITP, dermatomyositis

89
Immunomodulation Present
  • IVIG Regulatory idiotypes vs. Saturating
    Fc receptors? vs. Induction of IL-10
  • Steroids Lympholysis
  • Cytotoxics Kill inflammatory cells
  • Pheresis Removal of effector cells and
    evil humors

90
MOLECULAR BIOLOGIC AGENTS
  • Interfere with TNF Soluble receptor-
    Etanercept
  • Interfere with TNF Monoclonal
    antibody- Infliximab Adalimumab
  • Interfere with IL-1 Receptor antagonist-
    Anakinra
  • Interfere with T cell costimulation Abatacept

91
Immunomodulation Future
  • Interfere with antigen-specific responses-
    costimulation blockade
  • Regulatory anti-inflammatory cytokine
  • Monoclonal antibody and soluble receptors for
    effector molecules
  • Receptor antagonists

- Abatacept- BMS -please recall my conflict of
interest
92
Immunomodulation Future
  • Enzyme blockade- e.g. TACE, ICE
  • Kinase blockade, e.g. p38 MAP kinase-
    intracellular messengers to nucleus
  • Induce tolerance- oral tolerance is the Holy
    Grail

TNF or IL-1 activating-converting enzyme- frees
TNF or IL-1 from membrane-bound form- makes it a
circulating pro-inflammatory cytokine
93
Molecular biology has given us a new therapeutic
world
  • Repair immunodeficiencies- IVIG, ADA
  • Repair genetic defects- on hold for now
  • Stem cell transplants
  • Cytokines, receptors, antibodies- antagonist and
    agonist
  • Support patients until defect identified and
  • toxicity of therapy can be overcome

94
Confused?
  • leonard.sigal_at_bms.com
  • JCR Journal of Clinical Rheumatology
  • Basic Science for the Clinician
  • Immunology Today
  • Nature Immunology Reviews
  • Science- introductory pieces
  • Annual Review of Immunology
  • Current Opinions in Immunology

95
Auto-immune diseases
  • Leonard H Sigal MD, FACP, FACR
  • P.R.I.- CD E- Immunology
  • Bristol-Myers Squibb
  • Princeton, NJ
  • Clinical Professor of Medicine and Pediatrics
  • UMDNJ Robert Wood Johnson Medical School
  • New Brunswick, NJ
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