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Concept of Immune Regulation. Immune responses are tightly regulated complex interaction of cells & mediators, and by mechanisms to prevent anti-self reactivity Failure of regulatory control can occur…

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concept of immune regulation
Concept of Immune Regulation
  • Immune responses are tightly regulated complex interaction of cells & mediators, and by mechanisms to prevent anti-self reactivity
  • Failure of regulatory control can occur…
    • Enhancement of immune responses or infection can generate autoimmune reactions (loss of self–tolerance)
    • Decrease of immune responses may lead to an immunodeficiency state
    • Shift in immune responses can lead to allergy
immunological tolerance
Immunological Tolerance
  • History - Ehrlich, Owen, Burnet,
    • Billingham, Brent and Medawar
burnet s clonal selection model central tolerance
Burnet’s Clonal Selection Model:Central Tolerance

DEVELOPMENT MATURITY

ClonalDeletion

Anti-self

Lymphocyte

Self Ag

Activation

Differentiation

Anti-non-self

Lymphocyte

Foreign Ag + second signal

slide4

x

Medawar’s experiment demonstrating

neonatal tolerance induction (Nobel Prize)

immunological tolerance1
Immunological Tolerance
  • Definition and Properties
    • Specific unresponsive state induced by exposure to antigenic epitopes
    • Tolerance to self is initially induced during embryonic life, and is maintained by antigen
    • Tolerance occurs in both T and B cells
    • Multiple mechanisms of tolerance exist
mechanisms of immunological tolerance overview
Mechanisms of Immunological Tolerance - Overview
  • Central Tolerance through Clonal Deletion
    • Clones of cells that have receptors for self-antigens are deleted during development
  • Peripheral Tolerance
    • Clonal Anergy-failure of APC to deliver a second signal during antigen presentation (example: B7-CD28 interaction)
    • Suppression of responses may occur by production of regulatory T cells that inhibit immune response to self-antigen (example: TGF-, IL10 and Th1 vs. Th2 cytokines)
    • Ignorance to some self antigens may also exist
tolerance establishment and failure
Tolerance: Establishment and Failure

Generation of immune repertoires

Bone Marrow

Thymus

Central Tolerance

Self-reactive lymphocytes

Deleted by negative selection

Leakage of self-reactive lymphocytes controlled

Peripheral Tolerance

Wrong environment

(viral infection?)

Wrong genes

or mutations

Tolerance fails

Autoimmune Diseases

Global

Therapies

Selective

slide9

Tolerance Exists in Both T and B Cells

However, the Kinetics and Waning of Tolerance Induction

Differs in T and B Lymphocytes

slide10

Pathways to Peripheral Tolerance

Proliferation & differentiation

Activated T cells

NormalResponse

B7

CD28

Antigen Recognitionwithout co-stimulation

FunctionallyUnresponsive

Anergy

CTL4-B7 interaction

CTLA4

B7

Fas

Activation induced cell death

Fas-FasL interaction

Apoptosis

FasL

Inhibition of proliferation &

effector action

Cytokine-mediated suppression

Cytokine regulation

cytokines

the two signal hypothesis for t cell activation

TCR

MHC II

B7

CD28

The Two Signal Hypothesis for T-cell Activation

Signal 1

Mature

Dendritic

cell

APC

Activated

TH cell

TH

cell

Signal 2

hypothetical mechanism of tolerance in mature t cells

Resting

B-cell

APC

TH0 cell

CD28

Tolerance (anergy or apoptosis)

from lack of signal 2

Hypothetical mechanism of tolerance in mature T cells

Signal 1

Tolerant

T cell

slide13

Proliferation &

differentiation

B7

CD28

Anergy

Antigen Recognitionwithout co-stimulation

Summary: Lack of co-stimulation can lead to tolerance (anergy)

Activated T cells

NormalResponse

slide14

CTLA4-B7 interaction

FunctionallyUnresponsive (Anergic) T cell

Regulation by CTLA-4

CTLA4

B7

Activated T cell

slide15

Regulatory T cells

Production of IL-10 or TGF-b

FunctionallyUnresponsive T cell

RegulatoryT cell

inhibition by antibody feedback
Inhibition by Antibody Feedback
  • Passively administered antibody can prevent an antibody response
  • Antibody produced during an immune responses leads to elimination of antigen (stimulus)
    • Less antigen available to stimulate specific cells
    • Immune complexes can bind to inhibitory receptors

Application: RhoGam for Erythroblastosis Fetalis

major immune inhibitory receptors
Major Immune Inhibitory Receptors
  • B cells
    • FcgRII
  • T cells
    • CTLA4
  • NK cells
    • KIR (killer cell Ig-like receptors),
anti idiotypes and immune regulation
Anti-Idiotypes and Immune Regulation
  • Definition
    • anti-idiotype response-antibody produced against immunoglobulin or TCR idiotypes that serve to down-regulate immune response
    • The epitope for an responsive anti-idiotype molecule (antibody, BCR, or TCR) is the internal image formed by the CDR region of the respective epitopes antigen receptor
cytokines and immune regulation
Cytokines and Immune Regulation
  • Definition
    • Soluble mediators
    • Made by a variety of cells
    • Multifunctional proteins and peptides
      • Involved in initiating immune response
      • Involved in turning off immune response
      • Some serve as direct effector molecules (e.g., TNFa)
cytokine regulation via t h 1 t h 2 balance
Cytokine Regulation via TH1 – TH2 Balance

High affinity

Between TCR and APC

High [Antigen]

Th2

IFN-g

IL-12

IL-4

IL-10 & TGF-b

IL-18

Low affinity

Between TCR and APC

Low [Antigen]

Th1

th1 versus th2 balance
Th1 versus Th2 Balance

Disease Th1 Th2

Experimental Cure Progression Leishmaniasis

Experimental autoimmune Progression Preventionencephalomyelitis

Tuberculosis Cure/Prevention Progression

Atopy Prevention? Progression

Type 1 Diabetes (NOD) Progression Prevention

cns immune system interactions
CNS–Immune System Interactions

CNS

Hypothalamus

Pituitary

Adrenal gland

Cytokines

Antibodies

Sympathetic

nervous system

Cytokines

Activated

Immune cells

NE

Immune System

NE

b2AR

APC

B cell

CTL

Th1 Th2

immunosuppression adapted from roitt
Immunosuppression (adapted from Roitt)

Anti-TCR, -CD3, CD4/8, CD45RB, LFA-1, ICAM-1

Anti-IL2

IL2R

G0

G1

S

G1/0

G2/M

G0

Steroid

CTLA-4-Fc-g fusion peptide

UV

Cyclosporin

FK506

Steroid

Rapamycin

Azathoprine

Methotrexate

etc

X-rays

Cyclophosph.-amide

patient presentation
Patient Presentation
  • 6 year old male, ER with unexplained bruising associated with minor trauma
  • Patient has minimal clotting activity
    • FVIII levels <1% of normal
  • Patient given i.v. FVIII concentrate i.v. and released but returns in two weeks with same problem
    • Repeated FVIII treatment
  • However, FVIII is ineffective.
issues
Issues
  • Coagulation factor inhibitors (anti-FVIII activity)
    • Basis?
      • Lack of tolerance. Why?
    • Prevalence/impact
      • 20-30% FVIII, less FIX
    • Treatment/problems
      • FVIII concentrate or rFVIII
        • Inhibitors develop that neutralize FVIII
        • Therapy?
          • Porcine FVIII with less cross-reactivity
          • Tolerance (high dose)
          • Gene therapy
what are inhibitors
What are Inhibitors?
  • IgG; commonly subclass 4, mixed 1 & 4
  • Occur in
    • Congenital factor deficiency = alloimmune
    • Previously unaffected = autoimmune
      • Associated with pregnancy, autoimmunity, malignancy, multi-transfusion, advanced age etc.