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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 UMDNJ – Robert Wood Johnson Medical School New Brunswick, NJ. “Too little immunity” is a problem.

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auto immune diseases

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

too little immunity is a problem

“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

too much immunity
“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
auto immunity
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
auto immunity5
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.
auto immunity6
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
self recognition salubrious examples
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
why auto immunity
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
what induces autoimmunity
What Induces Autoimmunity?

CENTRAL (prenatal) and PERIPHERAL (later) MECHANISMS

aire a key to tolerance induction in the thymus
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
foxp3
FOXp3
  • Mouse strain “scurfy”: develops an X-linked recessive auto-immune disorder with multiple organ-specific inflammation, hypergammaglobulinemia, 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).
t regs cd4 cd25
T-regs: CD4+ CD25+
  • GITR, CD62L, CTLA4 or E/7 integrin might be better markers than CD25
non t reg t regulators
non T-reg T regulators
  • CD4+ TH1 cells (secreting gamma interferon)
  • CD4+ TH2 cells (secrete IL-4)
  • CD4+CD25+ 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).
slide14

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

cd4 cell populations of note
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

IL10

IL13

* Bacterial species implicated include : Klebsiella pneumoniae, Bordetella pertusis, Citrobacter rodentium, and Borrelia burgdorferi

slide16

Macrophage

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

cytokine production

APC activity

antibody production

TNF-a, IL-1, IL-6, IL-12

slide17

DC

DC

Chr. inflam

Tcell

Tcell

Ag

Ag

Chr. oxid.

Bcell

Bcell

C3

Suppressive

networks

Suppressive

networks

C3a

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

auto antibodies receptor targets receptor stimulate block
Auto-antibodies- receptor targets:Receptor Stimulate Block
  • TSH R. Graves Hashimoto’s
  • Insulin R. Hypo- Hyperglycemia
  • ACTH R. Addison’s
  • Intrinsic Factor Pernicious anemia
  • ACh R. Myasthenia gravis
auto antibodies other targets
Auto-antibodies- other targets:
  • Basement membrane Goodpasture’s syndrome
  • Uveal tract Sympathetic ophthalmia
  • Cardiac tissue Dressler’s syndrome
  • Exocrine glands Sjogren’s syndrome
  • Epidermal Bullous pemphigus hemidesmosomes
  • Blood cells Hemolytic anemia, AITP
treatment of auto immunity
TREATMENT OF AUTO-IMMUNITY
  • If hormonal deficiency- REPLACE
  • If organ inflammation- SUPPRESS Pulse corticosteroids Oral corticosteroids Cytotoxic agents Immunomodulatory agents Plasmapheresis
treatment of auto immunity21
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
slide22

MP/DC

Clinical Trials

Treg

IFNa

Anti-IFNa

Edratide

DR

B7

LJP394

Peptide

CD28

TCR

X

Y

Anti-CD20

BCR

CD20

Anti-CD22

CTLA4-Ig

CD22

T Cell

B Cell

CD28

B7

IMPDH

IMPDH

Inosinic acid

purines

Inosinic acidpurines

BCMA

APRIL

BLyS

Mycophenolate

Mycophenolate

Anti-BLyS

TACI-Ig

Courtesy Bevra Hahn, MD

molecular biology has given us a new therapeutic world
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

abbreviations in common use
Abbreviations in common use
  • SUFFIXDESCRIPTION
  • -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
systemic inflammatory syndromes
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)
systemic lupus erythematosus
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”
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

SYSTEMIC LUPUS ERYTHEMATOSUS-Criteria

Need “4 of the 11” criteria

systemic lupus erythematosus28
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
slide29

IL-10

Ts

TGF

TGF

IFN

Crow MK, A&R, 2003

tgf in normals
TGF in Normals

T

CD8

B

TGF

IL-2

AB

NK

NK

Treg

CD4

patients with sle make abnormally low levels of tgf
Patients with SLE Make Abnormally Low Levels of TGF

TGF

pg/ml

*

*

Ohtsuka et al, JI 1998

Human cells stimulated with anti-CD2

systemic lupus erythematosus34
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
rheumatoid arthritis
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
rheumatoid arthritis focus
Rheumatoid arthritis- focus?
  • T cell
  • Macrophage
  • Synoviocyte (fibroblastoid)
  • B cell
  • Genetics
  • Anti-CCP2
rheumatoid arthritis therapies
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
juvenile idiopathic arthritis jia ilar 1995
JUVENILE IDIOPATHIC ARTHRITIS (JIA)-ILAR 1995
  • Seven categories:
    • Systemic
    • Oligoarthritis
    • Polyarthritis (RF-)
    • Polyarthritis (RF+)
    • Psoriatic arthritis
    • Enthesitis-related arthritis- related to SNSAs
    • Other arthritis
juvenile rheumatoid arthritis jra idiopathic arthritis jia
JUVENILE RHEUMATOID ARTHRITIS (JRA)/ IDIOPATHIC ARTHRITIS (JIA)
  • Unknown etiology
  • Unknown immune focus in joints, eyes, etc.
  • Age < 16 years at onset
  • Genetic pre-disposition
  • Multiple cytokines involved, e.g. TNF, IL-1, IL-6
macrophage activation syndrome complication of systemic jra
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
macrophage activation syndrome
Macrophage activation syndrome

Myelocyte within activated macrophage, and multiple adherent red blood cell and myeloid precursors.

macrophage activation syndrome42
Macrophage activation syndrome

Neutrophilic bands and metamyelocyte within an activated macrophage.

juvenile idiopathic arthritis new management
JUVENILE IDIOPATHIC ARTHRITIS- New management
  • Methotrexate
  • Etanercept
  • Infliximab
  • Adalimumab
  • Leflunomide
  • Abatacept (CTLA4-Ig)
  • Anakinra not very effective
  • Anti-IL-6 effective; not yet approved
dermatomyositis
DERMATOMYOSITIS
  • Multi-system inflammatory disease
  • Adults and children
  • Acute and chronic inflammation of striated muscle and skin
seronegative spondyloarthropathies
SERONEGATIVE SPONDYLOARTHROPATHIES
  • Ankylosing spondylitis
  • Psoriatic arthritis
  • Psoriatic spondyloarthropathy
  • Inflammatory joint disease associated with inflammatory bowel disease
  • Reactive arthritis (no longer called Reiter syndrome)
seronegative spondyloarthropathies46
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)
snsa therapy
SNSA- therapy
  • NSAIDs, COX2
  • Sulfasalazine
  • TNF blockade
systemic inflammatory syndromes vasculitis
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
combinations of features greatly enhance probability of vasculitis

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

diagnosing vasculitides
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)
results of vascular inflammation
RESULTS OF VASCULAR INFLAMMATION
  • STENOSIS & OCCLUSION
  • ISCHEMIA / INFARCTION
  • DILATATION & RUPTURE
  • TURBULENT FLOW / BLEED
vasculitides of older people
VASCULITIDES OF OLDER PEOPLE
  • Giant cell arteritis
  • Polyarteritis nodosa (PAN)
  • Wegener granulomatosis
  • Cryoglobulinemia
  • Leukocytoclastic vasculitis
signs and symptoms of gca
SIGNS AND SYMPTOMS OF GCA
  • > 50 years of age 100%
  • ESR:       >100 60%
  • Headache 70%
  • Tenderness of arteries 50%
  • Jaw claudication 50%
  • Bruits 40%
  • Visual symptoms:   10-15%

Diplopia           Vision loss           Ultimate blindness

  • Weight Loss 40%
  • Fever 20%
polymyalgia rheumatica
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
giant cell arteritis
GIANT CELL ARTERITIS

Disrupted internal elastic lamella

slide58
Classical Polyarteritis Nodosa :

Medium-sized vesselinvolvement.

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.

polyarteritis nodosa
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.

slide60

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).
anca anti neutrophil cytoplasmic antibodies
ANCA: anti-neutrophil cytoplasmic antibodies

WG

MPA

CG

UC

Myeloperoxidase, Lactoferrin, Proteinase-3

elastase, cathepsin C

cryoglobulinemia
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
beh et syndrome adamantiades behcet
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".
  • Males:females = 1:1; more female in US, Japan, Korea, “the West”
  • Increasing prevalence with increased awareness
    • Turkey 300/100,000; US/EU 10-17/100,000
beh et syndrome
BEHÇET SYNDROME

The Silk Road

  • HLA-B51
beh et syndrome68
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
beh et syndrome72
BEHÇET SYNDROME
  • Pathergy sign
vasculitides of younger people
VASCULITIDES OF YOUNGER PEOPLE
  • Takayasu aortitis
  • Henoch-Schonlein purpura (HSP)
  • Leukocytoclastic vasculitis (LCV)
  • Kawasaki syndrome
  • Serum sickness-immune complex-mediated
  • Goodpasture syndrome
takayasu arteritis
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
henoch schonlein purpura
HENOCH-SCHONLEIN PURPURA
  • Palpable purpura
  • Glomerulonephritis
  • Arthritis
  • Abdominal pain
  • Males~females; mean age 5 yrs.
  • Preceding URI in 2/3 (1-3 weeks).
henoch schonlein purpura77
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 < 4 weeks duration.

40% recurrence rate after period of wellness.

May be permanent renal damage

kawasaki disease criteria
KAWASAKI DISEASE- Criteria
  • Fever 100% 5 days or more, remittent
  • Conjunctivitis 85 Bilateral
  • Lymphadenopathy 70 Cervical >1.5 cm
  • Lips/oral mucosa 90 Strawberry tongueDry, red vertical fissures Red oropharynx
  • Extremities 70 Erythema of palms/soles Convalescent fingertip desquamation
kawasaki disease other features
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
goodpasture syndrome
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
goodpasture syndrome84
Goodpasture Syndrome

anti-GBM antibodies directed against noncollagenous (NC1) globular domain of the 3 chain of type IV GBM collagen

vasculitis treatment
VASCULITIS- Treatment
  • Which organ system?
  • How severe?
  • Rate of damage?
  • Potential reversibility?
vasculitis treatment86
VASCULITIS- Treatment
  • Corticosteroids Daily or Pulse
  • Cytotoxic agents, e.g. Methotrexate Azathioprine Cyclophosphamide
  • Immunomodulatories Mycophenolate mofetil Cyclosporine
immunomodulation general principles
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
immunomodulation immediate control of disease
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
immunomodulation present
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”
molecular biologic agents
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
immunomodulation future
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

immunomodulation future92
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

molecular biology has given us a new therapeutic world93
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

confused
Confused?
  • leonard.sigal@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
auto immune diseases95

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