Host Modulation

INDEX: HOST MODULATION
•Introduction
•Principle
•Host mediated pathogenesis of
periodontal disease
•Arachidonic acid metabolites
•Cytokines
•Matrix metalloproteinase
•Regulation of bone remodeling
•Conclusion

INDEX: HOST MODULATORY
THERAPY
Systemically administered
agents
 Nonsteroidal Anti-inflammatory drugs
 Bisphosphonates
Sub antimicrobial-Dose Doxycycline
 Locally administered agents
 Enamel matrix proteins, growth factors
and bone morphogenetic proteins

INDEX: HOST MODULATORY
THERAPY
• Emerging host modulatory therapies
• Comprehensive management of patients
with periodontitis
• Conclusion

HOST MODULATION
• Host is the
organism having
periodontal disease
• Modulation means
alteration of function
or response of
gingiva in response to
a stimulus like plaque
in periodontal disease

PRINCIPLE
OF
HOST MODULATION
IN PERIODONTITIS

• It has been observed that in some
patients, despite having very minimal
amount of plaque, deep pockets are
seen. The reason for this can be the
exacerbated host response to bacterial
challenge in these patients

• Periodontitis, though initiated by
bacteria, but most of the destruction in
periodontal tissues is due to
upregulated host immune-
inflammatory response characterized
by the excessive production of the
inflammatory cytokines, prostaglandins
(PG) and enzymes like the matrix
metalloproteinases (MMPs).

• The host response is protective but can
result in significant tissue damage
including breakdown of collagen fibers
and resorption of alveolar bone by
releasing excessive amount of some
host inflammatory mediators (MMPs,
Cytokines, PG)

• These host mediators cause major
destruction in periodontium during
periodontitis.
• Thus the principle is to limit the
destruction in periodontium by
modulating the host response.

• Modulating host response means
limiting release of excessive
inflammatory mediators and enhancing
endogenous anti-inflammatory agents by
giving drugs (Host modulation therapy)
(HMT)

HOST MODULATION :- means
modifying destructive aspects in the
periodontal tissues by lowering the
release of destructive enzymes released
by immune cells in response to bacteria
(plaque)

IMMUNO-
INFLAMMATORY
DESTRUCTION IN
PERIODONTITIS
(PATHOGENESIS)

HOST MEDIATED PATHOGENESIS OF PERIODONTAL
DISEASE
After accumulation of subgingival plaque bacteria, microbial substance such as
lipopolysaccharides (LPS) and other bacterial antigens, diffuse across the sulcular
epithelium into the gingival connective tissue.
Epithelial and connective tissue cells are thus stimulated to produce inflammatory
mediators resulting in an inflammatory response in the tissues.
The gingival vasculature dilates (vasodilation) and blood vessels become more
permeable to fluid and cells (increased vascular permeability)

Polymorphonuclear cells (PMNs) start migrating from the circulation
towards the source of the chemotactic stimulus (bacteria and their
products) in the gingival crevice through junctional epithelium to
engulf bacteria.
During the process of phagocytosis, PMNs release excessive
quantities of destructive enzymes and inflammatory mediators.
These enzymes include the matrix metalloproteinase (MMPs) such as
collagenases and gelatinases, which break down collagen fibers in
gingival connective tissues.

Macrophages are further recruited to the area
to kill pathogens as part of innate immune
system and are activated (by binding to LPS)
to produce prostaglandin (PGE2), interleukins
(IL-1α, IL-1β, IL-6), TNF-α and MMPs.
Interleukins and TNF-α bind to fibroblasts, that
are stimulated to produce additional quantities
of PGE2, interleukins, TNF-α and MMPs in
positive- feedback cycles.
MMP breakdown collagen fibers, disrupting
the normal anatomy of gingival tissues and
resulting in tissue destruction.

The inflammation extends apically and
osteoclasts are stimulated to resorb alveolar
bone by high levels of PGE2, interleukins and
TNF-α in tissues.
Macrophages perform antigen presentation
functions to induce adaptive immunity (i.e. T-
cells and B- cells) for periodontal protection, in
periodontitis.
IgG producing B- cells other than providing
initial immune protection, are strongly
associated with the progression of periodontal
bone loss.

POTENTIAL TARGETS FOR HOST MODULATION
1. Arachidonic acid metabolites (PGE2)
2. Matrix metalloproteinase (MMPs)
3. Proinflammatory cytokines (IL-1β, TNF-α)
4. Regulation of bone remodeling (M-CSF,
RANKL)

PGE2 induces inflammation by
mast cell activation. It increases
vascular permeability,
vasodilation and increases the
expression of vascular
endothelial growth factors,
osteoclastic bone resorption
Effects of prostaglandin E2 on immune and
inflammatory responses

It interacts synergistically with IL-1
and TNF-α to enhance bone
resorption in periodontitis. It induces
osteoclast formation by regulating
RANKL/OPG expression in osteoblasts.
A. actinomycetemcomitans LPS
induces an upregulation of TNF- α, IL-
6 and RANKL mRNA expressions
partially via the PGE2.

There is increased PGE2 release by hyper
secretory monocyte PGE2 trait (Mϕ) and this
trait is responsible for the more periodontal
destruction in Aggressive Periodontitis,
Refractory Periodontitis and Insulin Dependent
Diabetes Mellitus (IDDM) patients
Monocytes from these periodontitis
patients release more IL-1β and PGE2
MONOCYTE PROSTAGLANDIN E2 RELEASE
IN HIGH RISK PATIENTS

Leukotrienes are
generated through the
lipoxygenase (LO)
pathway
LTB4, potent
chemotactic
mediator, plays a
central role in the
recruitment of
PMNs and
monocytes to sites
of developing
gingival
inflammation
Leukotrienes are
potent stimulators
of osteoclastic
bone resorption, by
increasing
osteoclast number
LIPOOXYGENASE

Interleukins (proteins between leukocytes) refer to
a special subgroup of cytokines which carry
detailed messages or instructions between
leukocytes.
PMNs, Fibroblast, macrophages and T- cells secrete
active pro-inflammatory cytokines and mediators
including IL-1β, TNF-α, IL-6, IL-7, IL-11 and IL-17, as
well as PGE2 which regulate osteoclastic
development and activities.
CYTOKINES

Increase release
of PGE2
Stimulate
osteoclast
activity
and MMP
release
Increase
apoptosis
of matrix
producing
cells, so
limit repair
IL-1 and TNF-α

Pro- inflammatory Cytokines- IL-6, IL-8, IL-17, IFN-γ
 The interleukin-6 family of cytokines currently includes
interleukin-6, interleukin-11, leukemia inhibitory factor,
oncostatin M, ciliary neurotrophic factor, cardiotrophin-1,
cardiotrophin-2, cardiotrophin- like cytokine ⁄ novel
neutrophin-1 ⁄ B-cell stimulatory factor-3, neuropoietin and
interleukin-27.
Anti-inflammatory Cytokines- IL-4, 10, 13, 15, 23.
These antiinflammatory cytokines basically inhibits
osteoclast progenitor cells.

The elevation in the pro inflammatory or destructive
mediators in response to bacterial challenge are
counter balanced by elevations in anti inflammatory or
protective mediators such as cytokines,IL-4,IL-10,as
well as tissue inhibitors of MMPs.
But when disease is severe, pro-inflammatory
mediators predominates

The matrix metalloproteinases are an important family
of zinc - and calcium-dependent endopeptidases
secreted or released by a variety of host cells such as
polymorphonuclear leukocytes, macrophages,
fibroblasts, bone, epithelial and endothelial cells.
Four major subgroups are directly related with the
destruction of periodontium: collagenases,gelatinases,
stromelysins and membrane-type MMPs(MTMMPs).
MATRIX METALLOPROTEINASES

Inflammatory cells such as neutrophils and
macrophages produce matrix metalloproteinases,
with neutrophils being the major source of
collagenase(MMP-8) and gelatinase(MMP-9) in
inflammatory diseases such as chronic
periodontitis.
MMP-1 & MMP-2 are produced from resident cells
(fibroblast & epithelial cells). MMP-1 is
collagenase-1 which is usually seen in aggressive
periodontitis.

Matrix metalloproteinase-3 (stromelysin) is effective
at degrading proteoglycans and fibronectin.
Osteoblast-derived collagenase (MMP-13) seems to
be mainly responsible for degrading the non
mineralized osteoid layer covering bone surfaces,
exposing the mineralized matrix to osteoclasts.
Matrix metalloproteinase-9 (gelatinase-B) is also
found to be secreted by human osteoclasts in vitro.

REGULATION OF BONE REMODELLING
It has long been accepted that bone formation and bone resorption are
processes that are "coupled”. This coupling process entails that osteoclasts
resorb an area of bone, and osteoblasts are signaled to come in and replace
the lost bone.
There are 2 molecules considered essential and sufficient to support
osteoclastogenesis:
A] Macrophage colony-stimulating factor (M-CSF or CSF- I).
B] Receptor activator of nuclear factor kappa B ligand (RANKL).

Macrophage colony stimulating factor (M-CSF)
It is one of the earliest signaling molecules identified to play a
role in osteoclast development and activation. M-CSF is produced
mainly by osteoblasts, bone marrow stromal cells, activated T-
cells and blood vessel endothelium and binds to a receptor on pre-
osteoclasts known as cFMS, a member of the tyrosine kinase
receptor superfamily. The binding of M-CSF to cFMS results in
the activation of several transcription factors, which ultimately
results in the initiation of osteoclastogenesis.

It is a key mediator in the process of osteoclast
formation. This membrane-bound protein is a
member of the tumor necrosis factor
superfamily and is expressed by a variety of cells,
including osteoblasts, fibroblasts and T-cells.
The binding of RANKL to its receptor RANK on the
surface of pre-osteoblasts results in the activation
of c-jun terminal kinase and the subsequent
activation of nuclear factor-kappaB, leading to
osteoclast formation.
The production of RANKL is regulated in response
to the presence of inflammatory cytokines such
as tumor necrosis factor-α and interleukin-1.
Receptor Activator of Nuclear Factor kappa B
Ligand (RANKL)

M-CSF is a secreted factor but the
cell surface form of RANKL
requires a juxtacrine (cell to cell)
interaction.

 Bacterial biofilms have been shown to be the
primary etiological factor in the initiation of
gingival inflammation and subsequent destruction
of periodontal tissues.
 At the same time there is strong evidence that
destructive processes occurring as part of the host
inflammatory response are responsible for the
majority of the hard and soft tissue breakdown
leading to the clinical signs of periodontitis.
SUMMARY

 The precise nature of the host inflammatory
response is still an area of intense research, but it is
clear that host-derived pro-inflammatory mediators
and cytokines, together with proteolytic enzymes
such as matrix metalloproteinases (MMPs), play a
significant role for causing changes in connective
tissue and bone metabolism that lead to the
breakdown of periodontal ligament (PDL) and
alveolar bone resorption.
 Therefore, the successful long-term management
of this disease may require a treatment strategy by
integrate therapies that will address both causative
components.
SUMMARY

Host Modulatory Therapy (HMT)
Aim is to reduce tissue destruction and
even regenerating the periodontium by
downregulating the destructive aspects of
host response and upregulating the
protective or regenerative responses by
prescribing drugs

Host Modulatory Therapy (HMT)
It is the latest adjunctive therapeutic option
for treating periodontitis

 Systemically administered agents
 Bisphosphonates
Sub antimicrobial-Dose Doxycycline
 Locally administered agents
 Enamel matrix proteins, growth factors and bone
morphogenetic proteins
Hostmodulatorytherapy(HMT)

SYSTEMICALLY ADMINISTERED AGENTS
Nonsteroidal Anti-inflammatory drugs(NSAIDs)
►Includes- Salicylates (e.g. Aspirin), indomethacin, & propionic
acid derivatives (e.g. ibuprofen, flurbiprofen, naproxen)
►NSAIDs inhibit the formation of prostaglandins, mainly
prostaglandin E2 (PGE2) by COX-1 and COX-2 inhibition.

•On withdrawal of taking long term NSAIDs periodontal benefits are lost
with an acceleration of the rate of bone loss seen before NSAID therapy
known to as “rebound effect”.
•NSAIDs are presently not indicated as adjunctive HMTs in the treatment
of periodontal disease.

Nonsteroidal Anti-inflammatory drugs(NSAIDs)
►Selective COX-2 inhibitors are free of side effects such as GIT
disturbances and impaired hemostasis. Examples are Rofecoxib,
Colecoxib
►But these NSAIDS were later banned due to life threatening side effects

BISPHOSPHONATES
►Inhibit bone resorption by disrupting osteoclast activity &
interfere with the secretion of lysosomal enzymes.
►Bisphosphonates bind to hydroxyapatite crystals in bone and
prevent their dissolution.
►They also increase osteoblast differentiation and inhibit
osteoclast activation, and are used extensively in the
management of osteoporosis and other bone resorptive
conditions.

BISPHOSPHONATES-MECHANISM OF
ACTION
►Anti-resorptive agents
►Binds to hydroxyapatite crystals in bone
►Directly or indirectly inhibits osteoclasts
Pharmacologically active only while on exposed bone
surfaces.
- remains bound in the bone matrix for years

•Bisphosphonates have been
investigated as adjuncts in the
treatment of periodontal disease,
and in various studies the use of
Alendronate had shown significant
increase in bone density compared
with placebo.

DISADVANTAGE
• Several case reports have shown avascular necrosis of the
jaws, particularly the mandible, following bisphosphonate
therapy, with an increased risk of bone necrosis following
dental extractions. This has been termed “bisphosphonate-
associated osteonecrosis” and is a significant and clinically
serious complication of bisphosphonate therapy
• Reason is due to extensive bone formation with obliteration of
even blood vessels, reducing blood supply to bone.

SUBANTIMICROBIAL DOSE
DOXYCYCLINE
• Subantimicrobial dose doxycycline remains, at
present, the only systemic host response
modulator specifically indicated as an
adjunctive treatment for periodontitis.
• It is approved by the US Food and Drug
Administration.

SUBANTIMICROBIAL DOSE
DOXYCYCLINE
• Introduced under the trade
name Periostat 20-mg
doxycycline hyclate, twice
daily for period of 3–9
months as an adjunct to
root surface instrumentation

• Rationale for using SDD-
20mg dose exerts its effect by inhibiting MMPs,
cytokines, osteoclast activity; enhancing osteoblastic
activity and collagen formation
Minimal antibiotic effect, so minimal side effects

Inhibit production of epithelial
derived MMPs by inhibiting
cellular expression.
Inhibition of active MMPs by cation
chelation
Decreases expression of cytokines
like IL-I, IL-6, TNF-α and PGE2
Inhibits production of reactive
oxygen species (ROS) released by
PMNs.
Stimulates collagen production by
fibroblasts
Suppress osteoclast activity and bone
resorption.
Stimulates osteoblast activity and
hence bone formation.

LOCALLY ADMINISTERED AGENTS
Nonsteroidal Anti-inflammatory drugs
Topical NSAIDs have shown benefit in the
treatment of periodontitis. Many studies have
shown reduced GCF levels of PGE2 & reduced
bone loss
But has not been approved as local HMTs for
the management of periodontitis

ENAMEL MATRIX PROTIENS, GROWTH FACTORS AND BONE
MORPHOGENETIC PROTIENS
– used as adjunct to surgical procedures, improves
wound healing, stimulates regeneration of lost bone,
PDL & cementum.
 Included - enamel matrix proteins (Emdogain), bone
morphogenetic proteins (BMP-2, BMP-7), Growths
factors (PDGF, IGF), and tetracyclines.
The FDA approved local HMT for
adjunctive use during surgery is
Emdogain, Platelet derived growth factor-
BB (Trade name-GEM 21S) and BMP-2

Till date SDD is the most commonly used HMT
SDD

Chronic,
Refractory
Periodontitis
Aggressive
periodontitis
who is being
treated
nonsurgically
Periodontitis
patient having
Diabetes,
Smoking habit,
Osteoporosis,
Genetic
susceptibility
Indications of HMT
(SDD)

Indicated in periodontitis patients with heart
diseases and un-controlled diabetes. SDD
given for long period reduces the chances of
myocardial infarction and diabetes related
complications in these patients. Good results
are also seen in smokers patients with SDD
Indications of HMT
(SDD)

In all these patients SDD should be combined
with SRP, Local drug delivery or Surgical
treatment.
Indications of HMT
(SDD)

Patient
allergic to
tetracycline
Pregnant,
lactating
females
Children less
than 12
years of age
due to risk of
discoloration
of dentition
Contra- Indications of HMT
(SDD)

Reduce efficacy
of oral
contraceptives
Risk of
having
increased
sensitivity to
sunlight
(sunburns)
In gingivitis,
periodontal
abscess or
where
antibiotics
are indicated
Contra- Indications of HMT
(SDD)

SDD should be given to patients twice daily or
once daily (modified release SDD) for 3 months
to maximum of 9 to 24 months.
Rebound effect is seen if SDD is given for
1month
SDD

Patient should be well explained about the
benefits of SDD to get good compliance
SDD

EMERGING HOST
MODULATORY THERAPIES
Chemically modified
tetracyclines (CMTs)
Anticytokine Drugs
Resolvin E1

Chemically Modified Tetracyclines
(CMTs)
• Chemically- modified tetracyclines
(CMTs)- are the nonantibiotic
tetracycline molecules modified to
remove all antibiotic properties, but
retain host modulatory,
anticollagenolytic effects.

• CMTs are potent inhibitors of pro-
inflammatory mediators and increase levels
of antiinflammatory mediators such as
interleukin-10 (IL-10)

CMTs such as CMT-3 & CMT-8 (both lack
antibiotic activity but retain anti-MMP
activity) inhibit osteoclastic bone resorption
& stimulate bone formation, promote wound
healing & inhibit proteinases released by
periodontal pathogens.

Anti-cytokine drugs.
• TNF-α antagonists like Infliximab,
Etanercept have shown good results
in rhematoid arthritis patients. In future,
it can be used in periodontitis patients

Resolvin E1
• Resolving molecules may be used in
future as new therapeutic methods for
treating periodontitis

Resolvin E1
• These molecules reduce PMN
infiltration, promote phagocytosis of
apoptotic neutrophils, prevent
connective tissue and bone loss ; and
promote regeneration of lost soft tissue
and bone

COMPREHENSIVE MANAGEMENT OF PATIENTS WITH
PERIODONTITIS
►Patient education and motivation, including oral hygiene
instructions and detailed explanation of rationale for any
adjunctive treatment.
►SRP (Scaling and Root planing)
►Site-specific anti-bacterial treatment with local drug
delivery systems.
►Host-response modulation by HMT
►Risk factor modification
►Periodontal surgery

SRP for bacterial
reduction
Risk factor
modification
(Smoking, Diabetes)
Local drug delivery,
surgical pocket
reduction
Host modulatory
therapy
(SDD)
Best
treatment

CONCLUSION
►In the future a range of HMTs targeting different breakdown events in the
periodontal tissues are likely to be developed as adjunctive treatments for
periodontitis.
►The ultimate goal is to maximize the treatment response by reducing
inflammation & inhibiting destructive processes in the tissues, which will
result in enhanced periodontal stability after SRP.
►Currently SDD is the only approved HMTs used systemically and has
shown good results especially in smokers, uncontrolled diabetic patients,
genetic susceptible patients

Host Modulation

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