Page 420 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 27 Host Defenses to Extracellular Bacteria 401

at mucosal surfaces. Enhancement of these immune mechanisms squalene. Cytokines, such as IL-1, IL-2, IL-12, IL-18, and
can provide protection even in immunocompromised individuals granulocyte macrophage–colony-stimulating factor (GM-CSF),
(although immune responses are diminished in these individuals). also modify and enhance immune responses to vaccines. IL-12,
For example, vaccination with meningococcal capsular vaccines for example, induces strong Th1 shifts, and GM-CSF is a comigrat-
protect patients with hereditary complement deficiencies by ing signal for DCs and stimulates antigen processing and presenta-
enhancing opsonophagocytic activity. However, vaccines have tion. Antigen recognition and processing in macrophages is critical
limitations in terms of long-lived immune responses, safety issues, to determining T-cell responses and can be manipulated by
and poor responses in certain populations (extremes of age) selected adjuvants. Immune modulation is being evaluated not
when infections with extracellular bacteria are most common. only for the enhancement of bacterial vaccines but also as adjunct
Advances in genetic engineering, immunology, molecular patho- therapy for serious bacterial infections, such as sepsis. Vaccines
genesis, vaccine adjuvants, and delivery systems are resulting and specific immunotherapeutic approaches, such as cytokines,
in the development of new vaccines and vaccine approaches may also find use against chronic tissue-damaging inflammatory
that enhance the immune response to extracellular bacterial reactions created by persistent extracellular bacteria (e.g., Heli-
pathogens (e.g., protein–polysaccharide conjugate vaccines for cobacter) and autoimmune reactions that may be induced by
Hib, S. pneumoniae, and N. meningitidis). cross-reactive bacterial antigens (e.g., C. jejuni and Guillain-Barré
The conjugation of bacterial polysaccharides to carrier proteins, syndrome).
such as diphtheria or tetanus toxins, has been a major advance
in stimulating immune responses to saccharide bacterial antigens. TRANSLATIONAL RESEARCH OPPORTUNITIES
Polysaccharide capsules, for example, when used alone, are
“T-independent” antigens; they do not require the presence of An important challenge for the next decade will be to take the
T cells to induce an immune response, and generate IgM as the rapidly expanding basic discoveries in innate immunity, systems
dominant antibody produced (Chapter 6). Failure to induce biology, and response to bacterial antigens into clinical applica-
memory and failure of affinity maturation follow polysaccharide tions. The design and use of bacterial vaccines through the
immunization. Thus polysaccharides are poorly immunogenic assessment of innate immune molecular signatures after vaccina-
in infants, older adults, and those with impaired antibody tion, both for general use and for subpopulations of nonre-
production—groups most susceptible to encapsulated bacterial sponders, is one example. A second is the continued development
pathogens. Covalent linkage of the polysaccharide to a carrier of small-molecule inhibitors or enhancers that specifically target
protein converts the polysaccharide to a thymus-dependent innate immune pathways to modulate bacterial immune responses.
antigen generating IgG anticapsular antibodies and memory B A third is the control of mucosal immune responses to prevent
cells. Because these vaccines induce vigorous mucosal immune or eliminate colonization by bacterial pathogens. A fourth is the
responses, they also provide “herd” protection. A major (and understanding of role of the microbiome in shaping the immune
unanticipated) result of vaccination with the Hib, meningococcal, response to pathogens and vaccines and its therapeutic potential
and pneumococcal conjugate vaccines is the interruption of for both infections and noninfectious diseases. Fecal microbiota
mucosal carriage, decreased transmission, and herd protection. transplantation for C. difficile colitis is an early example of
These vaccines are now used as part of the routine immunization therapeutic use of the microbiome. Finally, the development of
series in all age groups. new therapies for acute bacterial sepsis may be based on improved
The presentation to CD4 T cells of an antigen by MHC class understanding and control of the immune responses in sepsis. 36
II molecules is critical for an immune response and influences
the amount of antibody, the affinity of that antibody, and the
duration of response. CD4 T cell subsets influence the qualitative ON tHE HORIZON
and quantitative features of an immune response to vaccines • Tailoring vaccine design based on assessment of innate immune
and bacterial antigens. As new subsets of CD4 T cells are described, molecular signatures
research is necessary to determine their role in existing vaccines • Small molecule inhibitors or enhancers specifically targeting innate
and strategies to exploit them in new preparations (Chapter immune pathways
38
16). Mucosal vaccination is an attractive strategy for protection • Identification of immune responses that prevent or eliminate mucosal
bacterial pathogen colonization
against extracellular bacteria as mucosal colonization often • Development of new therapies modulating immune response in sepsis
precedes invasive disease. The hope is to generate effective immune • Defining microbial community and metagenome changes after antibiotic
responses at the mucosa and avoid the need for parenteral treatment
39
injection. In addition, recent advances in the application of • Managing disease based on the human microbiome
systems biology to define molecular signatures that correlate
with and predict vaccine immunity have greatly enhanced our
understanding of immune responses to vaccination. 40 Please check your eBook at https://expertconsult.inkling.com/
Considerable progress is being made in the development of for self-assessment questions. See inside cover for registration
new vaccine adjuvants and immune modulators (see Chapter details.
90 for updated information). Aluminum salts, used since the
1930s in many vaccines against bacteria, induce a >90% Th2
response. As noted above, bacterial toxins as conjugates can be REFERENCES
used to enhance immunogenicity. In addition, saponin adjuvants, 1. Silva MT. Classical labeling of bacterial pathogens according to their
liposomes, CpG DNA repeats, and TLR agonists are in use or lifestyle in the host: inconsistencies and alternatives. Front Microbiol
under development as adjuvants. Monophosphoryl lipid A (MPL), 2012;3:71.
long known to be an effective adjuvant in animal models, is now 2. Medzhitov R. Recognition of microorganisms and activation of the
approved for human use, as an oil-in-water emulsion containing immune response. Nature 2007;449:819–26.