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 selftolerance)
Decrease of immune responses may lead to an
immunodeficiency state
Shift in immune responses can lead to allergy
 Immunological Tolerance
History - Ehrlich, Owen, Burnet,
Billingham, Brent and Medawar
 Burnets Clonal Selection Model:
Central Tolerance
DEVELOPMENT MATURITY
Clonal
Deletion
Anti-self Self Ag
Lymphocyte
Activation
Differentiation

Anti-non-self Foreign Ag + second signal

Lymphocyte
 x

Medawars experiment demonstrating

neonatal tolerance induction (Nobel Prize)
 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
Central Tolerance
 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
Generation of immune repertoires
Bone Marrow Thymus

Central Tolerance
Self-reactive lymphocytes
Deleted by negative selection

Leakage of self-reactive
Peripheral Tolerance lymphocytes controlled

Wrong environment Wrong genes

(viral infection?)
Tolerance fails
or mutations

Autoimmune Diseases

Global Therapies Selective

Tolerance Exists in Both T and B Cells

However, the Kinetics and Waning of Tolerance Induction

Differs in T and B Lymphocytes
 Pathways to Peripheral Tolerance
Proliferation & differentiation Activated
Normal
Response T cells
CD28 B7
Antigen Recognition
without co-stimulation

Anergy Functionally
CTL4-B7 interaction Unresponsive

CTLA4 B7

Activation Fas Fas-FasL interaction

induced cell Apoptosis
death
FasL
Cytokine-mediated suppression Inhibition of
Cytokine proliferation &
regulation effector action
cytokines
The Two Signal Hypothesis for T-cell Activation

Signal 1

TCR
MHC II
Mature
Dendritic Activated
TH
cell Tcell
H cell
APC B7 CD28

Signal 2
Hypothetical mechanism of tolerance in mature T cells

Signal 1

Resting Tolerant
B-cell T H0 cell
APC T cell

CD28

Tolerance (anergy or apoptosis)

from lack of signal 2
 Summary: Lack of co-stimulation
can lead to tolerance (anergy)

Normal
Response Proliferation &
differentiation

CD28 B7

Anergy

Antigen Recognition
without co-stimulation
 Regulation by CTLA-4

CTLA4
CTLA4-B7 interaction

B7

Functionally
Activated T cell Unresponsive (Anergic) T cell
 Regulatory T cells

Production of IL-10 or TGF-

Functionally
Regulatory Unresponsive T cell
T cell
Pathways to Peripheral Tolerance
 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

B cells
FcRII
T cells
CTLA4
NK cells
KIR (killer cell Ig-like receptors),
 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
Idiotype/Anti-idiotype network
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., TNF)
 Cytokine Regulation via TH1 TH2
Balance
High affinity
Th2 Between TCR and
APC

High [Antigen]
IFN-g

IL-4 IL-10 & TGF- IL-12

IL-18
Low affinity
Between TCR and
APC
Th1
Low [Antigen]
 Th1 versus Th2 Balance
Disease Th1 Th2

Experimental Cure Progression

Leishmaniasis

Experimental autoimmune Progression Prevention

encephalomyelitis

Tuberculosis Cure/Prevention Progression

Atopy Prevention? Progression

Type 1 Diabetes (NOD) Progression Prevention

 CNSImmune System Interactions
Cytokines
CNS
Antibodies
Hypothalamus

Cytokines Sympathetic
Activated Pituitary nervous system
Immune cells
Adrenal gland
NE

Immune System
NE
2AR

APC B cell Th1 Th2 CTL

 Immunosuppression (adapted from Roitt)
Anti-TCR, -CD3,
CD4/8, CD45RB,
LFA-1, ICAM-1 Anti-IL2

IL2R

G0 G0 G1 S G2/M G1/0

Steroid
Cyclosporin Rapamycin Azathoprine X-rays
CTLA-4-Fc-
FK506 Methotrexate
fusion peptide Cyclophosph.-
Steroid amide
UV etc
And now for a clinical case.
 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
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?

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.