Treating Infectious Diseases in a Microbial World Report of Two Workshops on Novel Antimicrobial Therapeutics (2006) / Chapter Skim
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Promising Approaches to the Development of Immunomodulation for the Treatment of Infectious Diseases: Report of a Workshop
Promising Approaches to the Development of Immunomodulation for the Treatment of Infectious Diseases: Report of a Workshop
Pages 37-62
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From page 37... ...
The success and low cost of broad-spectrum antibiotics have reduced the incentive to develop alternative antimicrobial strategies, such as augmenting host responses during infectious disease. The National Institute of Allergy and Infectious Diseases asked the National Research Council to convene a committee of experts, the Committee on New Directions in the Study of Antimicrobial Therapeutics: Immunomodulation, to organize a brainstorming workshop to explore novel ways of modulating the host immune system to treat infectious disease (biographical sketches of the committee members are found in Appendix D)
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From page 38... ...
The workshop concluded with a plenary discussion during which the breakout groups' conclusions were presented and discussed. This report describes the most interesting insights that came out of the workshop and the most promising avenues for future research on and development of immunomodulators to treat infectious diseases.
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. Some microbial diseases cause damage to the host because an overly vigorous immune response leads to excessive inflammation; others occur because immune responses are insufficient and require bolstering (Janeway et al.
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The availability of a variety of agents with the ability to fine-tune the immune response would provide clinicians with many new options in the treatment of infectious diseases. The development of more sensitive tools to determine immune status and host response will allow greater predictability of the effects of immunomodulators on different groups of patients, such as the immunocompromised.
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The assemblages occur on the skin and along the mucosal surfaces of the body. They make a critical contribution to human health by providing nutrients and mediating normal development and function of host tissues, including those of the immune system (Noverr and Huffnagle 2004)
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42 . niversity U d ,Stanfor Schneider David of tesy Cour system.
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; thus, therapeutics that work through the nervous system could have immunomodulatory effects and be effective in treating infectious diseases. Increasing awareness of the complexity of the human immune response may make the process of developing and testing immunomodulatory therapeutics daunting.
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Boosting Innate Immunity Research in the last 10 years has revealed that the human innate immune system includes a large array of pattern-recognition receptors (PRRs) , including scavenger receptors, complement receptor 3, mannose receptor, Nucleotide-binding and Oligomerization Domain-containing (NOD)
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From page 45... ...
The committee identified three potential boosters of innate immunity as having particular promise: TLR agonists and agents that modulate the TLR response pathway, cationic host-defense peptides, and direct expansion of the effector cells normally activated by the innate immune system. TLR agonists have already shown promise as immunomodulators.
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46 TREATING INFECTIOUS DISEASES IN A MICROBIAL WORLD FIGURE 3 View of the TLR4 pathway with the Cytoscape program. Each circle represents a particular protein, and the lines connecting them reflect known interactions (signal transduction, gene regulation, or physical protein-protein interaction)
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From page 47... ...
The numerous interlocking regulatory mechanisms, which ensure that the immune response is sufficient to clear the disease-causing microorganism and is then promptly turned off, are not well enough understood to support prediction of the activity of innate immune modulators. Experience indicates that attempts to modulate innate immunity can have unwelcome results.
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· I-1.4 Identification of biomarkers of innate immune status. Suppressing Inflammation Excessive stimulation of innate immunity by some host-microorganism interactions can produce proinflammatory mediators, such as TNF-, that promote host damage.
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because of its ability to suppress the induction of the proinflammatory cytokine TNF- by bacterial LPS; nevertheless, despite suppressing this component of innate immune responses, LL37 can also protect against infections (Leist and Jaattela 2002)
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Passive Antibody Therapy Passive antibody therapy is proven and immediately available for the treatment of infectious diseases. It involves the administration of an immunoglobulin molecule, or fraction thereof, to prevent or treat an infectious disease.
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The committee identified two potential applications of passive antibody therapy as particularly promising: the development of monoclonal antibodies for use as single reagents or cocktails to address the pressing problem of multiple-drug-resistant bacterial infections in hospitals and the development of antibody reagents that take advantage of normal antibody interaction with the innate immune system, for example, by inducing mediators of damage control (such as interleukin-10 and other cytokines) to serve as broad-spectrum stimulators or suppressors of immunity.
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Most available vaccines are used to prevent infectious diseases. However, the rabies vaccine is given after infection and induces a protective immune response before the onset of disease.
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From page 53... ...
Similarly, because current vaccination techniques do not perfectly mimic natural infection, the protection they provide is often not as long-lasting. Dendritic cell vaccination and the development of antigens that target dendritic cells were viewed as promising approaches to enhance vaccine effectiveness because dendritic cells are critical components of innate immunity that also initiate acquired immune responses.
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54 TREATING INFECTIOUS DISEASES IN A MICROBIAL WORLD nipulation of normal processes, such as interactions of the immune system with the normal microbiota, to ameliorate the effects of pathogens may offer novel, noninvasive, and inexpensive therapeutic strategies. The resident microbiota is essential to immune development in neonates and disturbances of the microbial community cause an imbalance in human health (Eckburg et al.
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From page 55... ...
The committee identified the development of probiotics as an approach to treating infectious diseases that could yield results more quickly than other interventions based on manipulating the normal microbiota. It recommends the following three applications as particularly promising: · I-5.1 The displacement of pathogens from a niche, such as the skin or the oral cavity.
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From page 56... ...
. Learning how interactions between pathogenic microorganisms and hosts can persist without causing disease and identifying the conditions that promote disease are critical for an improved understanding of microbial pathogenesis.
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Such studies could take the form of prospective sampling of patients entering hospitals to look for markers predictive of susceptibility to infectious diseases or response to treatment. Another promising approach would be to look for patterns of immune markers that correlate with particular infectious agents, stages of infection,
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Nonhuman primates offer alternative models that are potentially more predictive, but experiments with them are expensive and are constrained by ethical considerations. The development of infectious disease models that use severe combined immunodeficiency (SCID)
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THE NEAR AND FAR HORIZON Treatment regimens that modulate the immune response have the potential to revolutionize how infectious diseases are treated. Such immunomodulatory therapies would be important additions to the current arsenal, especially because they would be expected to act synergistically with conventional antimicrobial therapies that target disease-causing organisms directly (Tzianabos and Kasper 2002)
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(2005) Natural regulatory T cells in infectious disease.
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(2003) Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases.
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(2005) Dissecting innate immune responses with the tools of systems biology.
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