Immunobiology of Dental Caries

Dr. Noel K. Childers

Department of Pediatric Dentistry
4-3230
nkc@uab.edu
 Colonization of Oral Cavity

Sterile at Birth
• S. mitis and S. oralis very early
(within 24 hours)
• S. Sanguis by 9 months of age
• S. mutans and S. sobrinus 18-24
months “window of infectivity”
 Mechanisms involved in S. mutans
colonization and pathogenesis

• Sucrose-independent attachment (Ag I/II)

• Sucrose-dependent reaction (glucosyltransferase)

• Bacterial metabolic activities with lactic acid

production
 Potential Means of Controlling
Dental Caries

• Increase resistance of teeth (e.g., fluoride, sealants)

• Improve diet

• Alter microflora
mutant strains
mechanical (remove niche)
antimicrobial/antibiotic
alter salivary components - specific and non-specific
Common Mucosal Immune System

GALT: gut associated lymphoreticular tissue

Others: BALT - bronchial …

NALT - nasal …
DALT - ductal …
SALT - salivary …
 Function of Salivary IgA
• Inhibition of adherence of microorganisms on
epithelial surfaces (or teeth, i.e., AgI/II)

• Neutralization of toxins or enzymes (e.g., GTF)

• Viral neutralization (e.g., polio virus)

• Antigen trapping and antigen exclusion

• Interaction of S-IgA with non-specific defense

mechanisms (e.g., mucins, lactoferrin, lysozyme,
lactoperoxidase)
Immunologic Means to Obtain
Caries Immunity

1. Natural Immunity

2. Active immunity
• Local immunization
• Systemic immunization
• Oral/Mucosal Immunization

3. Passive Immunization
Natural Immunity to Dental Caries

• Maternal Protection

• Ontogeny of Mucosal Immunity

• Natural Caries Immunity

 Unique Aspects of Infancy

•Teeth are erupting

•Oral cavity is being colonized

•Breast feeding is discontinued

•Immune system is developing

 Obstacles Encountered in Demonstrating
Caries Protective Role of IgA
• Dental caries is a chronic, slow process
• Dental caries may not be active when antibody
activity is assessed
• Absorbance of antibodies by oral micro-organisms
• Determination of local antibodies in the microbial
environment
• Cross reacting antigens between cariogenic and non-
cariogenic organisms
 Questions arising from findings of
negative correlation between
anti-S. mutans and dental caries

• Why don’t some individuals respond to the obvious

challenge?
• Do individuals with caries and decreased antibodies
have the ability to respond?
• Can the response in “non-responsive” individuals be
induced?
 Pitfalls in the Development of a
Caries Vaccine
• Identification of virulence antigens of S. mutans
• Lack of understanding of the mechanism of immune
protection
• Mechanisms involved in the induction and
regulation of protective immunity
• Possibility of immunopathological complications to
immunization
• Approval to test candidate vaccine in young
population
Steps in Development of Caries Vaccine

• Identify virulence antigens

• Design a means to induce protective

responses

• Animal model

• Human tests (Phase 1,2,3)

Caries Vaccine Response Requirements

• Interfere with early colonization.

• Not necessarily bactericidal.

• Non-inflammatory response.

• Persistent response.

• Site directed response (oral cavity).

Pathologic Consequences of Local Injection

• Local injection impairs normal gland functions.

• Many exocrine glands are inaccessible for purpose of
immunization.
• A potential exists to induce autoimmune antibodies,
e.g., group A streptococci.
• Possibility for induction of IgE antibodies resulting
in Type I hypersensitivity.
 Phases of Clinical Studies
• Phase 1: 20-80 Subjects (Safety)
– Pharmacology, metabolism, side effects
– Early evidence of effectiveness
• Phase 2: 100-300 Subjects (+Scientific quality)
– Controlled clinical studies
– Effectiveness, short term side effects
• Phase 3: 300-3000 Subjects (+Marketing potential)
– Randomized Clinical Trial (Field Trial)
– Effectiveness and Safety
Caries Vaccine Strategies
•orally administered vaccines
•topically applied vaccines
•intranasal
•palatine tonsil
•salivary glands
•adjuvants
•cholera toxin B subunit
•monophosphoryl lipid A
Clinical Approach to Develop a
Caries Vaccine

• Adult Phase 1 studies

• Pre-adolescent Phase 1 studies
• Pre School Children Phase 1
studies
• Infant Phase 1,2,3 studies
 Dentition Eruption Table
Primary Permanent
Central incisors, mand. 5-9 mo 7-8 yr
Central incisors, max. 8-12 mo 7-8 yr
Lateral incisors, max. 10-12 mo 7-8 yr
Lateral incisors, mand. 12-15 mo 7-8 yr
First molars 12-18 mo 6-7 yrs
Canines 16-20 mo 12-14 yr
Second molars 20-30 mo 12-15 yr
 Rationale for Approach
• Dental caries vaccine must be administered to
young children/infants to be effective
• Safety issues much more stringent in children
• Stepwise approach maybe necessary for FDA
approval
• Most adults have already experienced dental
caries
• Senescence of some of the mucosal immune
system (e.g., tonsils)
 Barriers to
“A vaccine for tooth decay”
• FDA approvals
– Safety concerns
• Funding
– NIH limited resources
– Patent-ability issues for private funding
• Efficacy studies
– Chronic disease
– Long-lasting immune responses
Immunologic Means to Obtain
Caries Immunity

1. Natural Immunity

2. Active immunity
• Local immunization
• Systemic immunization
• Oral/Mucosal Immunization

3. Passive Immunization
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