Induction of pathogenic vs. regulatory T cells depends on APC /T cell interactions

CD-80CD-86CD-80CD-86

CD-28CD-28

CTLA-4CTLA-4MHCMHC

TCRTCR

MHCMHC

TCRTCRAg

AgCD40CD40

CD40LCD40L

IL-10IFNIL-10

IFNIL-12,18, 23

IL-12,18, 23

IL-10TGFIL-10TGF

IFNIL-17IFNIL-17 TH1, 17TH1, 17

TR1, TH3

Treg

TR1, TH3

Treg

Antigen presenting cells (APC)process and present bacterial

antigens, are activated by bacterial adjuvants

CD-80CD-86CD-80CD-86

CD25CD25

TGF

Effector (microbial clearance, inflammation) Regulatory (homeostasis)

Pro-inflammatoryPro-inflammatory

Anti-inflammatoryAnti-inflammatory

TNFIL-1IL-6

IL-12 / 18 / 23IL-4,

IFNIL-ILIL-21

TNFIL-1IL-6

IL-12 / 18 / 23IL-4,

IFNIL-ILIL-21

IL-10TGF

IL-1Ra, IL-11IFN

PGE2, PGJ2

IL-10TGF

IL-1Ra, IL-11IFN

PGE2, PGJ2

Loss of tolerance(Inflammation)

Loss of tolerance(Inflammation)

Tolerance(Homeostasis)

Tolerance(Homeostasis)

Mediator BalanceMediator Balance

Aggressive early onset Crohn’s disease in IL-10 receptor deficient families

•Immune cells from these patients were hyper-responsive to bacterial products and did not respond to IL-10 suppression

•One patient with refractory disease had complete remission with a bone marrow transplant from a sibling who lacked this gene (corrected genetic defect in immune cells)

Glocker, NEJM 2010

Pro-inflammatoryPro-inflammatory

Anti-inflammatoryAnti-inflammatory

TNFIL-1IL-6

IL-12 / 18 / 23IL-4,

IFNIL-ILIL-21

TNFIL-1IL-6

IL-12 / 18 / 23IL-4,

IFNIL-ILIL-21

IL-10TGF

IL-1Ra, IL-11IFN

PGE2, PGJ2

IL-10TGF

IL-1Ra, IL-11IFN

PGE2, PGJ2

Loss of tolerance(Inflammation)

Loss of tolerance(Inflammation)

Tolerance(Homeostasis)

Tolerance(Homeostasis)

Selective Correction of Mediator Selective Correction of Mediator ImbalanceImbalance

Therapeutic Manipulation of Intestinal Bacteria (individual profile): Selectively Alter Beneficial vs. Detrimental Species

Injurious Pro-inflammatory

Bacteroides vulgatus, B. thetaEnterococcus faecalis

E. coli - enteroadherent / invasive

Klebsiella pneumoniaeBifidobacterium animalis

Fusobacterium variumIntestinal Helicobacter species

Lactobacillus sp.Bifidobacterium sp.

E. coli NissleSaccharomyces boulardii

Bacteroides thetaiotaomicron Faecalibacterium prausnitzii

Clostridium subsets

ProtectiveProbiotic

Improving current techniques to restore a healthy microbiome

• Select approach and targets based on analysis of an individual’s microbiota pattern (customized approach)

• Concentrate on protective resident species that have good chance to colonize and function in the intestine

• Refine bacteriotherapy and determine its effectiveness in IBD – will require long term longitudinal studies in carefully characterized patients

• Determine if dietary approaches can alter composition and function of enteric microbiota in therapeutic / preventive manner

• Test the promise of genetically engineered bacteria

Harnessing translational research to improve clinical outcomes

• Identifying clinically relevant pathways to develop new drugs or repurpose existing agents

• Predicting natural history of disease in an individual

• Predicting which patient will respond to a given therapy

• Correcting abnormal pathways- cures and preventions

Where do we need to go with IBD treatment?

Current vs. optimal

(individualized treatment)

AZA/6-MP/MTX

Systemic corticosteroids

Antibiotics (Crohn’s colitis)

ASA (colitis)

Topical or rapidly metabolized corticosteroids

Surgery

Bowel rest (SB)

TNF antagonist

Cyclosporine, Natalizumab

TNF antagonists ( early intervention?)

ASA, aminosalicylates; AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate

Current Paradigm for the Sequential Treatment of Crohn’s Disease and UC (“Bottom up”)

Moderate

Severe/refractory

Mild

Steroids

AZA / MTX

Combination

The concept of Top-Down Therapy

Infliximab

Why not treat every IBD patient with the most aggressive therapy at diagnosis?

• Most patients have a benign course and don’t need aggressive therapy- < 50% of Crohn’s disease pts need systemic steroids, smaller number anti- TNF

• Aggressive immunosuppression increases risk of infections and tumors

• We don’t know long term toxicities of newer medications

• New therapies are expensive!

New paradigms of treatment

• Match the aggressiveness of treatment with the (potential) aggressiveness of disease

• Treat disease correctly the first time!

AZA/6-MP/MTX

Systemic corticosteroids

Antibiotics (Crohn’s colitis)

ASA (colitis)

Topical or rapidly metabolized corticosteroids

Surgery

Bowel rest (SB)

TNF antagonist

Cyclosporine, Natalizumab

TNF antagonists ( early intervention?)

ASA, aminosalicylates; AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate

New Paradigm for Treating Subsets of IBD patients: Match the aggressiveness of treatment with the predicted

aggressiveness of disease

Moderate

Severe/refractory

Mild

Predicted diseaseactivity

Get it right the first time!

Contrasting current approaches to treating IBD and cancer

IBD

• Assess location and extent of disease

• Treat all patients the same (bottom up or top down), with some variation for aggressiveness

Generic approach (30-40% remission rate, no cure)

Cancers

• Check genotype (prognosis, treatment guide and family screening)

• Clinical, imaging assessment of extent (aggressiveness, clinical pattern)

• Analyze tissue for receptor expression, enzyme levels, histologic grade of aggressiveness/differentiation, depth of extension (results determine which therapy used, prognosis)

Targeted /individualized approach expectations of cures

IBD1 IBD2 IBD3 IBD4

CDUC

Disease behavior, mechanisms

Names vs. Mechanistic subsetsNames vs. Mechanistic subsets

Defining IBD: current vs. future

From Dermot McGovern

Individualizing therapy for IBD subtypes: Different mechanisms, different features, different therapies

Genetic Genetic mutationsmutations

NOD2

ATG16L1

IL-23R

Gene (s) IV

ClinicalClinicalPhenotypePhenotype

CD I-aggressive SB dz

SB dz?

course

CD II

CD IVfistula

Immunologic Immunologic response to response to

bacterial antigenbacterial antigen

ASCA, OmpC,

I2+

?

?

Flagellin

ClinicalClinical

IBD I-aggressive SB dz

IBD IIIMild

SB dz

IBD II-UC-like

IBD IV?

ClinicTreatment

Rx 1?defensinsAntibiotic

GM-CSFAntibx?

Anti- IL-23(?)

Therapy 4

How to predict which patient will:

• Have an aggressive course?• Respond to a potential treatment?• Have complications of disease or therapy?

Understand mechanisms of disease in an individual at time of diagnosis

Genetic, microbial, immunologic profiles and clinical phenotype

Pediatric Research Network• Investigating unique needs of children and adolescents with IBD• 28 centers have enrolled 1800 newly diagnosed patients with IBD

(2/3 Crohn’s disease)• Goals: identify serum biomarkers, immune markers, fecal

bacteria, genes and clinical features that predict at the time of diagnosis which child will develop severe, complicated vs. mild Crohn’s disease and which individual will respond to each medication

Clinical Implications: When a patient is diagnosed, initiate treatment with a medication that will almost certainly work well, prevent complications with aggressive therapy in patients with high risk of aggressive disease courses and complications, but use nontoxic drugs for low risk pts: minimize drug toxicity and cost

2 patients with Crohn’s disease, 2 different

treatments (2020)Patient A:• Tissue shows low F. prausnitzii, high AI E. coli• Genotype – NOD 2 polymorphism• Treatment: Ciprofloxacin x 1 month, F. prausnitzii probiotic

weekly, daily plantain extract (prevent AIEC binding) (backup- early resection and prevent recurrence with F. prausnitzii probiotic )

• No clinical symptoms or Rx complications for 15 yearsPatient B:• Genotype IL-23R polymorphism• Treatment: prolonged administration anti- IL-23 antibody

(backup: bone marrow transplant from sibling without IL-23R gene defect)

• No further Crohn’s disease symptoms for 15 yrs

What needs to be done to cure a patient with IBD?

1. Understand mechanisms of disease in an individual Genetic, microbial, immunologic profiles and clinical phenotype

2. Fix the problem

• Correct underlying defective pathway

OR

• Permanently block inflammatory response

Nontoxic medication that induces a sustained, complete remission

Correct underlying defective pathway• Gene: replace abnormal gene (gene therapy, bone

marrow transplant) or correct abnormal function (replace defective protein, block abnormal function)

• Microbiome: permanently alter microbiota (fecal transplant, eliminate aggressive bacteria, restore protective bacteria), change diet, effective probiotic

• Immunologic pathway: Block aggressive responses in sustained, nontoxic approach, permanently augment (restore) protective responses

•

CCFA Initiatives that can help develop new approaches to correcting causative IBD defects

• Genetics- Determine function of major IBD risk genes (now 163 total) and how the abnormal genes and pathways interact. Once abnormal mechanisms are identified, strategies to correct them with new or existing medications can be developed

• Microbiome: Identify key causative and protective bacterial species and infectious triggers. Once identified, realistic strategies to eliminate/ block detrimental species, augment concentration or function of protective species, and avoid triggering agents (? Immunization) can be developed

What needs to be done to prevent onset of IBD in a high risk individual?

1. Identify which person is at risk of developing IBD

Genetic, microbial, immunologic profiles

2. Fix the problem

• Correct underlying defective pathway

OR

• Eliminate environmental triggers

• Alter microbial profile

• Alter immune response

In 2014, we have built the foundation to better understand the role of microbiota in intestinal diseases.

Can we use this information to:

• Treat disease or prevent relapses by manipulating the environment (altering diet, environmental, triggers, bacteria, fecal transplant)?

• Deliver optimal individual treatment based on clinical features and genetic, microbial and immunologic profiles?

• Cure patients with disease by correcting defects or permanently normalizing responses?

• Prevent disease in susceptible individuals by manipulating their environment or correcting the underlying defect?

Individualizing therapy for IBD subtypes: Different mechanisms, different features, different therapies

Genetic Genetic mutationsmutations

NOD2

ATG16L1

IL-23R

Gene (s) IV

ClinicalClinicalPhenotypePhenotype

CD I-aggressive SB dz

SB dzPost-op

recur course

CD II

CD IVfistula

BacterialBacterialprofileprofile

Adh/inv

E. coli

Klebs

F. prausnit

Claustrid

ClinicalClinical

IBD I-aggressive SB dz

IBD IIIMild

SB dz

IBD II-UC-like

IBD IV?

ClinicTreatment

Rx 1 block piliAntibiotic

GM-CSFAntibx

Anti-IL-23

F. prausnitzi

ReplaceClaustrid

Sequential, safer approach to treating IBD: Maintain long term remission by alternative approaches

IL-1TNFIL-1TNF

IL-12IL-12IFN TNF

IFN TNF

Eliminate antigenic drive

Antibiotics, probiotics prebiotics, fecal

transplant, diet,block bacterial binding,enhance bacterial killing (stimulate

defensins, GM-CSF, hydroxychloroquin)

Restore mucosal barrier function SCFAs, probiotics fiber/prebiotics Growth factors,

trefoil factor, epithelial stem cells

Promote Promote regulatory cellregulatory cell

activity activity ((TRTR11, TH, TH33 , Treg, , Treg, B cells, DC) B cells, DC)

Rapamycin, Rapamycin, Omega 3 FAs, retinoic Omega 3 FAs, retinoic

acid, vit D acid, vit D Bacteroides fragilis PSA. Bacteroides fragilis PSA. Clostridium subsetsClostridium subsets, , F. prausnitziiF. prausnitzii, worms, worms

Promote Promote regulatory cellregulatory cell

activity activity ((TRTR11, TH, TH33 , Treg, , Treg, B cells, DC) B cells, DC)

Rapamycin, Rapamycin, Omega 3 FAs, retinoic Omega 3 FAs, retinoic

acid, vit D acid, vit D Bacteroides fragilis PSA. Bacteroides fragilis PSA. Clostridium subsetsClostridium subsets, , F. prausnitziiF. prausnitzii, worms, worms

Paralyze TH1, TH17, innate immune responses

Steroids, biologics

Paralyze TH1, TH17, innate immune responses

Steroids, biologics

How can PCORI help?

• Identify environmental triggers (dietary factors, allergens, infections, stress, etc)

• Provide biosamples (Blood, saliva, feces) for translational research

• recruit clinically defined subsets for clinical trials