HOST

MODULATION

DR. KRITIKA JANGIDMDS- PERIODONTICS

HOST MODULATION

HOST RESPONSE

HOST MODULATION

• Defined as‘the organism from which a parasite obtains its nutrition’

Or‘the individuals that harbours these pathogens’

HOST

• Refers to the response of the body of a living organism i.e. animal or plant against invading or threatening factors.

HOST RESPONSE

HOST RESPONSE MODULATION• Refers to the modulation of the immune

responses to suppress unwanted reactions to protect an organism against infectious disease.

CHANGING PARADIGMSOF

PATHOGENESIS OF PERIODONTITIS

In 1960s

Microbial challenge

Clinical signs of disease initiation and progression

In 1962- Glickman & Smulow

Bacterial plaque

Calculus formation

Periodontal pocket

formation

Bone loss

Occlusal trauma

• All bacteria on tooth surface are harmful.• Untreated periodontitis progresses slowly, steadily in a linear fashion over time.

Loe et al in 1970-1986

• Ivanyi and Lehner (1970)

Peripheral blood lymphocytes isolated from subjects with periodontitis >> lymphocytes from healthy subjects.

• Goodson (1972)

Prostaglandins were in the periodontal tissues and were likely important in the alveolar bone destruction of periodontal disease.

• Horton et al. (1972)

Human peripheral blood leukocytes from subjects with periodontitis produced a substance, termed osteoclast activating factor, which induced bone resorption.

• Clark et al. (1977)

Subjects with aggressive periodontitis had a neutrophil chemotactic defect.

In 1970s

Microbial challenge

Host immuno-inflammatory

response

Clinical signs of disease

initiation & progress

• Smoking as a risk factor

Preber H et al. 1984, 1986

Haber 1993

Bergstrom 1983• Diabetes as risk factors

Bissada et al. 1982

Emrich LJ 1991

Genco, Papapanaeu 1996

Risk factors

In 1980s

• Mechalowicz et al in 1991

Studies on monozygotic and dizygotic twins reared together and reared apart

Added genetic component linked to pathogensis

Genetics

Microbes

Occlusion

Host immune factors

Environmental factors

Genetics

Page and Kornman 1997

HOST MODULATION

“ There are compelling data from studies in animals and humans indicating that pharmacologic agents that modulate host response may be efficacious in slowing down the progression of periodontitis”

• Treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or down-regulating destructive aspects of host response and up-regulating protective or regenerative responses.

(CARRANZA)

What is?

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

NSAIDs

• COX-1 is expressed ‘constitutively’

• Known as a "housekeeping" enzyme. Functions include

1. gastric cytoprotection2. vascular homeostasis3. platelet aggregation 4. and kidney function

• COX-2 is usually undetectable in most tissues.

• Inducible during states of inflammation

• Upregulated by pro inflammatory cytokines, endotoxin.

VANE 1972NSAID’S BLOCK

COX

LPSNeutrophils

Macrophages

Fibroblasts

PGE2

Nyman et al 1979 Canine experimentalPeriodontitis model

Systemic indomethacin Suppressed alveolar bone resorption &Gingival inflammation

Williams et al 1988 Naturally occurring periodontitis in dogs

Topical flubiprofen propylene glycol gel

71% suppression in radiographic bone loss

Williams et al 1991 Naturally occurring periodontitis in beagles

Peroral flubiprofen Decreased rate of radiographic bone loss at 3,6,9 & 12 months

Howell et al 1991 Naturally occurring periodontitis in beagles

Peroral naproxen Decreased rate of radiographic bone loss by 61% when compared to controls

Howell et al 1991 Naturally occurring periodontitis in beagles

Topical piroxicam Decreased gingival & bleeding indices after 2 & 4 weeks

Li et al 1996 Spontaneous & experimental periodontitis in rhesus monkeys

Topical ketoprofen(1%) Clinical improvement in gingival inflammation but no significant decrease in PGE2 & LTB4 levels

Paquette et al 1997 ExperimentalPeriodontitis in beagle dogs

Ketoprofen Decrease in gingival inflammation & bone loss at 2 months

Waite et al 1981 Prevalence ofPeriodontal status in subjects taking NSAID’s

NSAID’s Lower gingival index scores & periodontal pockets

Williams et al 1989

44 adult periodontitis subjects monitored for 3 years

Systemicflurbiprofen

Lower bone loss rates at 12 & 18 months

Jeffcoat et al 1988

15 refractory periodontitis patients

Systemicflurbiprofen

Decreased bone loss over 2 months compared to placebo

Jeffcoat et al 1991

7 RPP subjects7 controls

Systemic naproxen

Decreased bone loss 3 months relative to placebo

• GIT upset• Gastrointestinal

hemorrhage (decreased platelet aggregation)

• Renal impairment• Hepatic impairment• Rebound

Phenomenon

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Blocking of MMP’S Bisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

MMP

Inhibit the synthesis and/or release of these enzymes

Block the activation of precursor (latent) forms of these MMPs (pro-MMPs)

Inhibit the activity of mature MMPsStimulate the synthesis of endogenous tissue

inhibitors of MMPs; or Protect the host’s endogenous inhibitors from

proteolytic inactivation

MMP Inhibitors

Sites of action

Drug Developmentof

Synthetic MMP Inhibitors

• CONHOH• Marimastat• Ilomastat, Batimastat-

1st to be tested in pts.

– Broad spectrum inhibitors (No selectivity)

– Muscular and skeletal pain (Toxicity)

1st Gen Hydroxamate Inhibitors

• Hydroxamate

New Gen Hydroxamate Inhibitors

• Sulfonamide• Substituted aryl• Stearic Hinderance

• Cipemastat- MMP-1, 3, 9• Excellent oral efficiency in

animal model of osteoarthritis

• RSH• Selectivity- MMP that

release TNFα, L-selectin, IL-1RA, IL6 are not inhibited

Severe Hepatotoxicity

New Gen Thiol Based MMP Inhibitors

• Pyramidine based– Selective for MMP-2,

8, 9, 13• Hydroxypyrone based– Selective MMP-3

inhibitor• Phosphorous based– Selective MMP-8

inhibitor

Other MMP Inhibitors

• Tetracyclines were found to directly inhibit collagenases from a wide variety of cells including PMN’s, macrophages, osteoblasts, osteoclasts, chondrocytes, and malignant melanoma cells (Golub et al 1987)

Tetracycline Based MMP Inhibitors

MMP 13 is more sensitive to tetracycline inhibition than MMP 8 and MMP 1 is least sensitive (Golub et al 1995)

MMP 2 (Gelatinase A)&MMP 9 (Gelatinase B) and other types of MMPs are also inhibited

TC’s do not inhibit serine proteinases (PMN elastase,plasminogen activator) and acid proteinases (cathepsins B & L)

TETRACYCLINES INHIBIT CONNECTIVE TISSUE BREAKDOWN: PLEIOTROPIC MECHANISMS(Golub & Ryan 1998)

• Mediated by extracellular mechanisms

• Mediated by cellular regulation

• Mediated by pro-anabolic effects

Mediated by extracellular mechanisms

• Direct inhibition of active MMPs

• Inhibition of oxidative activation of pro-MMPs

• Promotes excessive proteolysis of pro-MMPs into enzymatically inactive fragments

• Inhibition of MMPs protects α1-proteinase inhibitor

Mediated by cellular regulation

• Decrease cytokines, iNOS, phospholipase A2, prostaglandin synthase

• Effects on protein kinase C, calmodulin

Mediated by pro-anabolic effects

• Increase collagen production

• Increase osteoblast activity and bone formation

Golub et al (J Periodont Res  1985). reported that the semisynthetic compound (e.g., doxycycline) was more effective than the parent compound tetracycline in reducing excessive collagenase activity in the GCF of chronic periodontitis patients.  

SDD• Not used as monotherapy, Used as an adjunct to SRP

• Taken as 20mg twice daily for 3 months and up to a maximum of 9 months

• Three month prescription fits well with the typical maintenance recall of 3 months.

Effects of SDD

• History of allergy or hypersensitivity

• Pregnant and lactating women

• Children under 12yrs of age

• May reduce the effectiveness of oral contraceptives

Contraindications

Safety Data• 20mg twice daily was well tolerated (Caton et al

2000, Preshaw et al 2002)

• Most frequently reported adverse effects were headache(0.1%), common cold & influenza like symptoms, rash(0.1%), dyspepsia(0.2%)

• No typical side effects of tetracycline group of antibiotics were noted

• 4-dedimethylamino tetracycline

• Tetracyclinonitrile

• 6-deoxy-6-demethyl-4-de-dimethylaminotetracycline

• 7-chloro-4-de- dimethylaminotetracycline

Chemically Modified Tetracyclines

•Tetracycline pyrazole

•4-dedimethyl amino. 4-hydroxytetracycline

•12-deoxy-4-dedimethyl amino tetracycline

•4-dedimethylamino doxycycline)

• The anti collagenase activity of CMTs is ‑specific against the collagenase produced from neutrophils but not the fibroblasts.

• Does not affect the normal collagen turnover required to maintain the tissue integrity.

[Golub et al 1991]

• CMT 8 is the most potent inhibitor of periodontal breakdown

• CMT 8, 1, 3, 4, 7 and doxycycline ‑ ‑ ‑ ‑ ‑inhibited TNF α, IL 1, IL 6 and MMPs in ‑ ‑ ‑descending order.

• The CMT 1 and 3 also inhibit gingipains produced by P. gingivalis.

• Inhibition of inducible nitric oxide synthase (iNOS) expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) activity.

• CMT 3 and CMT 8 have shown maximum inhibitory effect ‑ ‑on the iNOS, CMT 1 and 2 had intermediary effect while ‑ ‑CMT 5 was ineffective.[Trachtman et al 1996] ‑

• Inhibition of proinflammatory mediators-IL 1β, IL 6, IL 8, ‑ ‑ ‑TNF–α and PGE2 from LPS stimulated host immune cells by suppressing phosphorylation of the nuclear factor κ–B cell signalling pathway.

• CMT 1, CMT 3, CMT 6, 7 and 8 were effective inhibitors ‑ ‑ ‑ ‑ ‑of osteoblastic collagenase in culture. CMT 8 was the most ‑potent[Rifkin et al 1994]

Other Roles of CMT

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

BISPHOSPHONATES• Bisphosphonates are analogs of

pyrophosphate(P-O-P) in which the oxygen is replaced by carbon with various side chains.

• It binds to the hydroxyapatite crystals of bone and prevents their dissolution by interfering with osteoclasts function

• Known as bone sparing agents

FIRST GENERATION

(alkyl side chains)

• Etidronate

SECOND GENERATION

(amino terminal group)• Alendronat

e• Pamidrona

te

THIRD GENERATIO

N (cyclic side chains)• Risedronate

•The antiresorptive properties of bisphosphonates change according to their side chains •Their potency increases from first to third generation

Activities of Bisphosphonates on Osteoclast Function

Tissue Level Cellular Level Molecular Level

↓ bone turnover due to ↓ bone resorption ↓ number of new bonemulticellular unitsNet positive wholebody bone balance

↓ osteoclast recruitment↑ osteoclast apoptosis↓ osteoclast adhesion↓ depth of resorption site↓ release of cytokines bymacrophages↑ osteoblast differentiationand number

Inhibit mevalonate pathway(can result in perturbatedcell activity and inductionof apoptosis)↓ post-translational prenylationof GTP-binding proteins

Tenenbaum HC et all 2002

•Alendronate treatment of humans with progressive moderate to severe periodontitis.• All subjects had SRP at baseline and were then treated with either 20 mg of alendronate daily for 6 months or placebo. •All subjects were monitored for 9 months.

Jeffcoat et al 1996

Alendronate

Placebo

• Probing depth reduction (Rocha et al 2004; Lane et al 2005)

• Clinical attachment gain (Lane et al 2005, Rocha et al 2001)

• Alveolar bone gain (Jeffcoat et al 1996, Rocha et al 2001,2004) and

• Increase in bone mineral density (El-Shinnawi et al 2003, Rocha et al 2004)

• The long-term use of bisphosphonates has been related to osteonecrosis of the jaw (Marx et al 2003)

• Clinically, ONJ is essentially exposed bone in the maxilla or mandible that does not heal within 8 weeks of identification (Wang HL et al 2007)

BRONJ

Osteonecrosis of Jaw

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

STATINS

• NATURAL(FUNGAL)• Lovastatin• Pravastatin• Simvastatin

• SYNTHETIC• Atorvastatin• Fluvastatin• Rosuvastatin

• Evaluation of anti-inflammatory effect of statins in chronic periodontitis.

• GCF IL-1β levels in generalized chronic periodontitis patients who are on statin medication (Group-I) were lower than the generalized chronic periodontitis patients without statin medication (Group-II).- statin users indicate that statins have anti-inflammatory effect on periodontal disease.

Snophia Suresh et al J Ind Pharmacol 2013

• Clinical efficacy of subgingivally delivered 1.2-mg simvastatin in the treatment of individuals with Class II furcation defects: a randomized controlled clinical trial.

• Locally delivered SMV provides a comfortable and flexible method to improve clinical parameters and also to enhance bone formation.

AR Pradeep et al J Periodontol 2012

Efficacy of subgingivally delivered simvastatin in the treatment of patients with type 2 diabetes and chronic periodontitis: a randomized double-masked controlled clinical trial.

Greater decrease in mSBI and PD and more CAL gain with significant IBD fill at sites treated with SRP plus locally delivered SMV in patients with type 2 diabetes and CP.

Pradeep AR et al J Periodontol 2013

• Risk of diabetes• Cognitive loss• Neuropathy• Pancreatic and hepatic

dysfunction• Sexual dysfunction.

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

ANTI CYTOKINE THERAPYNeutralization of cytokinesNormal interaction

Inflammatory signals

Suppression ofinflammatorycytokines

Anti-inflammatorycytokine

Inflammatory cytokine

Receptor blockadeActivation of

anti-inflammatory pathways

Cytokine receptor

Soluble receptor

Monoclonal antibody

Monoclonal antibodyReceptor antagonist

No signal

No signal

Monoclonal A/b to TNFα

Soluble form of TNF receptor

ANTICYTOKINE THERAPY & PERIODONTITIS

• Anti-cytokine agents have shown to significantly reduce loss of clinical attachment, loss of alveolar bone & slowing down the progression of experimental periodontal disease in animal studies

Assuma et al 1998, Graves et al 1998, Delima et al 2001, Oates et al 2002, Zhang et al 2004

• The effect of IL-6 receptor inhibition has been analysed in patients with periodontitis and a significant decrease in the gingival index, bleeding on probing, probing depth was noted.

Kobayashi 2014

• Subcutaneous injection rhIL-11in experimental periodontitis in dogs showed significant reduction in the rate of clinical attachment and radiographic bone loss after an 8-week period.

Martuscelli et al 2000

• Infliximab– Allergic reactions like swelling of

the lips– Difficulty in breathing – Lowered blood pressure.

• Etanercept– Infections– Hypersensitivity

• Anakinra– Infections– Immunogenicity– Malignancies – Decrease in the total white blood

cell and platelet count

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

NO INHIBITORS

MERCAPTO ETHYL GUANIDINE

• Blocks iNOS• Inhibits COX• Scavenges

peroxynitrate

Lohinai et al 1998 - found a reduction of alveolar bone loss and gingival inflammation after the use of a selective iNOS inhibitor - mercaptoethylguanidine

• Effect of quercetin (a flavonoid found in apples, onions, tea, and red wine) on the production of NO by murine macrophages activated with LPS from P. intermedia

• Quercetin significantly inhibits iNOS-derived NO production in murine macrophages activated by P. intermedia LPS.

Cho YJ et al

2013

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins, Growth factors,

BMP’s

HOST MODULATORY AGENTS

ANTAGONISTS TO CELL ADHESSION MOLECULES

• ICAM- 1 & E- selectin expressed on endothelial cell is responsible for PMN rolling & extravasation

• ICAM – 1 & E – selectin inhibitors – Tepoxalin, Sodium Cromoglycate, BMS-190394 have shown promise in inflammatory models (Hoshino et al 1997, Wilson et al 1998)

• AWAIT TESTING IN PERIODONTAL DISEASE MODELS

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

INHIBITION OF RANK/RANKL INTERACTION

• Dinosumab– Infections

of urinary and respiratory tracts

– Cataracts– Constipation– Rashes– Joint pain– Eczema

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

DISRUPTION OF CELL SIGNALLING PATHWAYS

• Within periodontal resident cell types - tissue macrophages and other periodontal cells, MAPKs are activated chiefly by LPS, IL-1 & TNF-α.

• Activation of p38 induces synthesis of pro-inflammatory cytokines, such as TNF-α, IL-1,IL--6 &IL-8

p-38 inhibitors

• p-38 inhibitors are known cytokine suppressive anti-inflammatory drugs (CSAIDs)

• BIRB-796 and SCIOS-469 are in phase III for the treatment of psoriasis and rheumatoid arthritis, respectively.

• Studies of VX-702, a newer p38 inhibitor which does not pass through the blood-brain barrier, are currently underway

Compound SD 282

LPS induced periodontal disease, inflammatory cytokine expression, osteoclastogenesis, and alveolar bone loss were reduced in rats model

Rogers JE et al J Periodontol 2007

The NF-κB pathway

LPS, IL-1,TNF,MMP’S,COX-2,iNOS present in large quantities in periodontal diseased tissues, can also activate NF-κB.

• In vitro studies have established that both P. gingivalis and other periopathogenic bacteria can activate NF-κB in periodontal tissues (Sugita N et al. Inflammation 1998).

• Activation of NF-ĸb(p50/p65) is significant in periodontally diseased tissues(Ambili R, Nandakumar et al JP 2005)

NF-κB Inhibitors

• Proteasome inhibitors block NF-κB activation

• Bortezomib (Velcade®) was tested in multiple myeloma with highly promising results (Richardson P 2003).

• BMS-345541 - decreased both synovial inflammation and joint destruction in an arthritis model (McIntyre et al 2003).

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

AGENTS THAT PROMOTE RESOLUTION

LIPOXINS

• Signals the initiation of resolution of inflammation (Serhan 1994; 1988)

• LXA4 is shown to effectively inhibit P. gingivalis induced aggregation and ROS production in whole blood

Borgeson et al 2011

RESOLVINS

• Generated from DHA

• Functions – stop PMN infiltration – reduce cytokine expression and – Improved wound healing in mouse models.

PROTECTINS

• Hasturk H, et al 2006– On application of ResolvinE1 in rabbit model for treating

periodontitis, histologically revealed no inflammatory changes, osteoclast formation or bone loss and temporal shift in the microflora in oral biofilm were also observed

• El-Sharkawy H,:– SRP followed by 900mg of EPA/DHA with 81mg

aspirin daily for 6 months for treating periodontitis- improved signs

• Macrophage mediated resolution of inflammation

• Potent up regulation of efferocytosis

MARESINS

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS

AGENTS THAT AID IN REGENERATION

• Enamel matrix proteins(EMDOGAIN)

• Bone morphogenetic proteins(INFUSE)

• Growth factors(GEM 21S)

Nonsteroidal anti-inflammatory

drugs (NSAID’s)

Anti- proteinase blocking of

MMP’SBisphosphonates Statins

Anti cytokine therapy NO inhibitors

Antagonists to cell adhesion

molecules

Inhibitors to RANK/RANKL

interaction

Disruption of cell signaling pathways

Agents that promote

resolution

Matrix proteins,growth

factors,BMP’s

HOST MODULATORY AGENTS