abul abbas keynote lecture

8/17/2019 Abul Abbas Keynote Lecture

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Determinants of Immunogenicityand Tolerance

Abul K. Abbas, MDDepartment of Pathology

University of California San Francisco

EIP Symposium Feb 2016



Why do some people respond totherapeutic proteins?

• Characteristics of the protein – Conformation, post-translational modifications, etc

•

Features of the host – Genes that influence immune activation vs tolerance:

largely unknown

– The immune “background” of the host

–

Defective control/tolerance mechanisms

• Environmental factors



Critical questions

•

Requirements for antibody response to aprotein

•

Why do some individuals produce antibodies

when exposed to a “self” protein? – Why does tolerance to the protein fail?

•

How can tolerance be restored?

•

What assays need to be developed to betterunderstand the loss and restoration oftolerance?



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Antibody production: activation of B cells



Naïve T cells:

Can recognizeantigen butincapable of any

functions

APC

+ antigen

Differentiation

+ a n t i g e n

CD4+ helperT cells

CD8+ CTLs

Cytokine

secretion

Cellkilling

Effector T cells

T cell responses

Proliferation



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Sites of microbe entry:skin, GI tract, airways(organs with continuousepithelia, populatedwith dendritic cells).Less often -- colonizedtissues, blood

Sites of lymphocyteactivation: peripherallymphoid organs (lymphnodes, spleen), mucosal

and cutaneous lymphoidtissues

Antigens and T cells come together in the same organs

Capture and presentation of antigens by dendritic cells

Abbas, Lichtman and Pillai. Basic Immunology, 5 th edition, 2016, Elsevier



Schematic model of T cell recognitionof antigen: what antigens do T cells see

MHC molecules are the peptide display molecules of the immune system

Human MHC: HLA (human leukocyte antigens)



Costimulation: the second signal for Tlymphocyte activation

Costimulation: signal(s)

in addition to antigenthat are needed tostimulate adaptive immuneresponses

Costimulators are inducedon APCs by microbes andby adjuvants administeredin vaccines

Self antigens and otherharmless substances failto induce costimulators,do not elicit immunereactions and may inducetolerance



Role of costimulation in T cell activation

Abbas, Lichtman and Pillai. Basic Immunology, 5 th edition, 2016 c Elsevier



APC

TCR

Naïve

T cell

Immunogenicantigen

(microbe,vaccine)

Tolerogenicantigen (e.g.self)

Effector andmemory cells

Tolerance: functional

inactivation or cell death,or sensitive to suppression

Antigen (peptide + HLA):signal 1

Costimulation(signal 2)

Costimulation determines the choiceof activation vs tolerance



0

100000

200000

300000

400000

500000

0 0.001 0.01 0.1 10

100000

200000

300000

400000

500000

0 0.001 0.01 0.1 1

Naïve CD4 T cells Memory CD4 T cells

P r o l i f e r a t i o n ( C P M )

Antigen ( !g/ml)

Naïve T cells are more dependent on B7costimulation than are memory cells

wild type (normal; positive control) B7.1/2-/-

None (negative control)

APCs



Costimulation

• Required for initiating T cell responses

(activation of naïve T cells)

• Ensures that T cells respond to microbes

(the most potent inducers of costimulators)and not to harmless antigens

– Source of costimulation during responses totumors, transplants, proteins given without

adjuvants ?

• Memory cells are less dependent oncostimulation than are naïve T cells



Possible host determinants of antibodyresponses to a biological

•

Size of antigen-specific T cell pool – Pre-existing pool of naïve T cells – High number of memory cells induced by cross-

reactive environmental antigens

•

Inheritance of HLA alleles that present theantigen –

Unlikely to be a key issue in an outbred population(many different HLA alleles present)

• High level of costimulation – Source? Unlikely to be provided by antigen itself – Activation state of dendritic cells?



Exploiting absence of costimulation toinhibit immune responses

• Costimulatory blockade (blocking B7-CD28,CD40 pathways)

• Peptide administration (repeated low doses,modeled after desensitization for allergies) –

Peptide-coupled PBLs (spleen cells in mice)



Activation

Normal: reactionsagainst pathogens

Tolerance,regulation

No response to self andother harmless antigens

The immunological equilibrium: balancinglymphocyte activation and control



Where is tolerance induced?

Central tolerance Peripheral tolerance



Best defined mechanisms of peripheral

T cell tolerance

• Engagement of inhibitory receptors

• Suppression by regulatory T cells (Tregs)



Inhibitory receptors of the immune system

• One mechanism by which the systemmaintains a balance between activationand inhibition is to use different

receptors for different outcomes

• Inhibitory receptors are present in NK

cells, T cells and B cells – Best defined activating and inhibitory

receptors of T cells are members of theCD28 family



21

APC TCR

CD28

NaïveT cell

B7

B7-CD28interaction

B7-CTLA-4interaction

CTLA-4

Proliferation,differentiation

Functionalinactivation

The opposing functions of CD28 and CTLA-4

Knockout of CTLA-4 in mice and mutation in humansresults in immune dysregulation (lymphoproliferation,multi-organ inflammation)



Engaging inhibitory receptors forinducing tolerance

• Can inhibitory immune receptors betriggered to shut off immune responses? –

Problem of reliably producing agonisticantibodies against cellular receptors

•

Blocking inhibitory receptors hasrevolutionized cancer immunotherapy – “Checkpoint blockade” stimulates anti-tumor

immune responses



Regulatory T cells

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8 th edition, 2014, Elsevier

CD4+, highCD25 (IL-2

receptor),Foxp3transcriptionfactor



The significance of Foxp3+ Tregs

• Genetic evidence: Foxp3 mutations -->autoimmune disease (IPEX); in mice,disease can be corrected by providingnormal Foxp3+ cells

• Do defects in Foxp3+ Tregs orresistance to Treg-mediated suppressioncontribute to common autoimmunediseases? – Inconsistent and variable data

– By definition, any abnormal immune responsereflects an imbalance of activation vs control



The therapeutic potential ofregulatory T lymphocytes

• Cell transfer of autologous Tregs tosuppress immune responses–

Grow up patient’s Tregs ex vivo

–

Ongoing clinical trials in graft rejection, T1Dshow it is safe

– Very little efficacy data



The therapeutic potential ofregulatory T lymphocytes

•

Cell transfer of autologous Tregs to suppress immuneresponses

•

Challenges:– Technically difficult, individualized

• Administer antigen or antigen mimic in

ways that preferentially induce Tregs?– Weak stimulus (peptide antigen, anti-CD3); +

IL-2?

F i f I l ki 2 h d



Functions of Interleukin-2: the dogma



The unexpected biology of IL-2

• Interleukin-2 is the prototypic T cellgrowth factor (TCGF), required forinitiating clonal expansion of T cells inresponse to antigen

• BUT: knockout of IL-2 or the or

chain of the IL-2R results not in immunedeficiency but in systemic autoimmunityand lymphoproliferation



Dual roles of IL-2 in T cell responses

Surprising conclusion from knockout mice: the non-redundant

function of IL-2 is in controlling immune responses



Therapeutic potential of IL-2: arevision

•

IL-2 was originally used to boost immuneresponses in cancer, HIV infection(promoting effector and memory T cells)

• Inconsistent clinical results

• IL-2 treatment can increase number andfunctional activity of Tregs

•

Low-dose IL-2 to treat steroid-resistantchronic GVHD, vasculitis•

More recent clinical trials ongoing in type 1diabetes, SLE, graft rejection



Antigen-specific lymphocytes

• Are antigen-specific T (and B) cells present

before treatment? Are they altered bytreatment? – Frequency of naïve T cells predicts magnitude of

response following antigen exposure

• What are the phenotypic and functionalcharacteristics of antigen-specific

lymphocytes?

Need for more sophisticated analyses of

antigen-specific lymphocytes



Strategies for restoring tolerance

•

Administration of antigen in tolerogenic form – Repeated doses of peptides without adjuvants

•

Blocking costimulation

•

Engaging inhibitory receptors

•

Treg targeted therapies: – Treg cell transfer

– IL-2

abul abbas keynote lecture

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