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Developing Immunotherapy for Autoimmune Diseases

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Developing Immunotherapy for Autoimmune Diseases. Premkumar Christadoss, M.B.B.S. Department of Microbiology and Immunology University of Texas Medical Branch 301 University Blvd. Galveston, Texas 77555-1070 [email protected] Generalized Myasthenia Gravis. MG.

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slide1

Developing Immunotherapy for Autoimmune Diseases

Premkumar Christadoss, M.B.B.S.

Department of Microbiology and Immunology

University of Texas Medical Branch

301 University Blvd.

Galveston, Texas 77555-1070

[email protected]

neuromuscular junction nmj
Neuromuscular Junction (NMJ)

Conti-Fine, B.M. et al. J. Clin. Invest. (116) 2843-22854, 2006

slide5

Normal

MG

NMJ in MG

slide6

Electronmicroscopy Study of NMJ of an MG Patient

Engel et al.

Mayo clinic proc. 52:267, 1977

slide7

AChR is a transmembrane glycoprotein formed by five homologous subunits in thestoichiometrya2bgdora2bed. The molecular weights of the subunits range between 45 and 55 kDa.

Theasubunit is Considered to be the highly immunogenic region.

slide8

EAMG induction

AChR Source

Primary immunization: 20 microgram AChR/CFA

28-30 days

Boost: 20 microgram AChR/CFA

28-30 days

Monitor for clinical EAMG

Immunopathological evaluation

slide9

MG in Mice

Normal

MG

slide10

Molecular Mechanisms of EAMG

AChR-Ab

Plasma cells

Complement activation

Class II

Peptide

(a146-162)

CD4

TCR

IFN-g

IL-18

NK

B7

CD 28

Proliferation and Differentiation

IL-10, TNF-a, IL-6,

IL-12, IL-18

APC

CD4

CD40L/CD40

AChR

IL-1, IL-12

AChR-specific memory B cells

AChR-specific memory T cell

C’

C’

Damage to the neuromuscular junction

B

slide11

COMPLEMENT PATHWAYS

CLASSICAL PATHWAY

C1

C4b

C2a

MASP1

MASP2

MBL

C3

C5

MAC

(C5bC9)

MBL PATHWAY

C3b

C3bBb

Bb

ALTERNATIVE PATHWAY

slide12

AChR-immunized C3-/- and C4-/- mice

are resistant to clinical EAMG

Tuzun -Christadoss.

J. Immunol. 171:3847, 2003

slide13

Serum anti-AChR antibody levels of

AChR-immunized mice

Tuzun- Christadoss.

J. Immunol. 171:3847, 2003

slide14

IF Studies Reveal IgG Deposits But Not C3 or MAC Deposits at the NMJs of Mice with C3 or C4 Deficiency

C4+/+

C4-/-

C3-/-

C3

MAC

IgG

Tuzun –Christadoss

J. Immunol. 171:3847, 2003

RED -bungarotoxin binding (NMJ)

GREEN C3, MAC or IgG deposits

slide15

Antigen/organ specific

Disease specific

I. AChR T cell epitope tolerance

II. AChR B cell epitope tolerance

I. Anti-Proinflammatory Cytokine

a. Soluble TNFR (etanercept)

b. IL1-Ra

c. Anti-IL-6

II. Blocking classical complement pathway

a. Anti C1q/C2/C4

Immune Intervention

slide17

Anti-C1q Administration Suppresses EAMG

Tuzun-Christadoss, J.Neuroimmunol.174:157-167, 2006

slide18

Dual Effect of Anti-C1q

Tuzun-Christadoss, J.Neuroimmunol.174:157-167, 2006

slide19

Anti-C1q Ab Treats EAMG

B6

RIII

Tuzun-Christadoss, J.Neuroimmunol, 182: 167-176, 2007

slide20

Anti-C1q Ab Treatment Suppresses AChR

and Dominant Peptide Specific

IL-6 Production

slide21

Effect of Cytokine Deficiencies in

Clinical EAMG

Normal

IL-4

IL-10

Gene Depletion

IFN-g

Anti-AChR Ab

Disease

IL-12

IL-18

IL-6

TNF-a p55p75

0

20

40

60

80

100

120

% clinical disease and anti-AChR antibodies

slide22

IL-6 and TNF in EAMG

TNF

TNF

AChR

specific

IL6

IL-6

Th

Th

GC formation

Activation of B cells and generation of effector B cells.

Potentiates production of IgG anti-AChR antibodies (pathogenic)

B

B

Activates C3

Promotes EAMG pathology

slide23

Targeting ProinflammatorCytokines

A. Soluble Recombinant HumanTNFR (Etanercept)

slide24

Soluble TNFR (Etanercept) Treats EAMG

Christadoss and Goluszko

J. Neuroimmunol, 122:186, 2002

slide25

Etanercept Treatment Fails to Suppress Serum Anti-AChR Ab

Christadoss and Goluszko, J. Neuro. Immunol. 122:186, 2002.

a pilot trial of etanercept in the treatment of steroid dependent mg
A pilot Trial of Etanercept in the Treatment of Steroid-Dependent MG *+
  • Mean change in QMG score from basline at 6 months was - 2.9 (p=0.041).
  • Mean change in MMT at 6 months was - 8.4 (p=0.020).
  • Mean decrease in prednisone dose from baseline to end of study was 17.5 mg/48 hr dose (p=0.0084).
  • Etanercept was well tolerated, and no severe adverse reaction observed
  • + 11 patients enrolled; 8 completed, and 2 patients withdrawn due to disease worsening.
immunological effect of etanercept
Immunological Effect of Etanercept
  • No reduction in plasma anti-AChR antibody.
  • Peripheral blood CD4 and B cell (CD19+) counts rose steadily during the 24 week study.
  • Patients who had higher increases in their cytokine levels had a worse outcome.
slide29

Targeting ProinflammatorCytokines

b. Recombinant Human IL1-Ra

slide31

IL-1Ra treatment

stopped

IL-1Ra treatment

stopped

IL-1Ra Treatment Prevents Clinical EAMG

Yang –Christadoss, J. Immunol.

175:2018, 2005

slide32

IL-1Ra Treats EAMG

Yang –Christadoss, J. Immunol.

175:2018, 2005

P<0.05

P<0.05

P<0.05

slide33

Possible Consequence of Down Regulating IL-1 by IL-1Ra in Mice with Clinical EAMG

IL-1

IL-1Ra

CD40L, OX40 Expression on T cells

Anti-AChR IgG , IgG1 and C3

Inflammatory cytokines

IFN-g, IL-2, IL-1, IL-6, TNF-a

Anti-AChR antibodies and complement

mediated NMJ pathology

slide34

IL-6 in MG: Multiple Hit

AChR Specific

NMJ

CD4

IL-6

B

IgG2b -C1q

C4-C3-

C5-9

C3

il 6 a danger molecule in eamg
IL-6–ADanger Molecule in EAMG !

1. IL-6 deficient mice are resistant to EAMG and produce less C3

2. C3 and FCγRIII deficient mice are resistant to EAMG and produce less IL-6

3. Amelioration of EAMG following anti-C1q treatment is associated with reduced IL-6

slide39

Classical Complement Pathway and IL-6 in EAMG Pathogenesis

anti-AChR antibody production

T helper

B cell

Antigen presenting cell

AChR

IL-6

C3

Immune complex formation

AChR

C1q

C1r

C1s

C1q

FcγRIII activation

Classical complement pathway activation

Stimulation of

IL-6, C1q and C3 production

Membrane attack complex formation

slide40

Balancing the Immune System to Treat Autoimmune Disease (MG)

Disease

IL-6, TNF

C3-C5b-C9

Anti-AChR IgG

IL-6, TNF-normal level

Healthy

Suppress anti-AChR

and C5b-C9

slide41

Targeting IL-6 and Classical Complement Pathway

Suppressed anti-AChR antibody production

T helper

B cell

Antigen presenting cell

AChR

IL-6

C3

Immune complex formation

AChR

C1q

C1r

C1s

C1q

Classical complement pathway activation

FcγRIII activation

Stimulation of

IL-6, C1q and C3 production

Membrane attack complex formation

slide43

MG Lab - Galveston

Erdem Tuzun1,2

Shamsher Saini

Andrey Bednov

Ben Scott 3

Jing Li1

Iris Wingrow3

Huibin Qi

Xiarong Wu

Collaborators

Huan Yang

Bo Wu

Stephen Higgs

Tian Lin Xio

Galen Kaufmann

Mat Merigioli

Juli Rowin

1MG foundation Osserman/Sosin/McClure Post doctoral Fellows

1,2MDA Research Career Award Recipients

3 MG Foundation Henry Viets Fellow

Supported by NIH,MDA, AFM,and MG Foundation

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