Overview Components of Innate Immunity

Innate immunity is the first line of defense against infections. The phylo-genetically ancient, phagocyte-based effector mechanisms of innate immunity exist in their mature state prior to microbial exposure and infection does not alter the intrinsic specificity of the system components. This is in sharp contrast to the more recently evolved mechanisms of adaptive immunity in which the microbial encounter leads to gene rearrangements that alter the intrinsic properties of the system components, e.g., following infection, microbe-stimulated antibody gene rearrangements lead to production of antibodies of greater affinity for the microbe. Mechanisms of innate immunity are either constitutively active or are activated very rapidly after infection (prior to development of adaptive immune responses) and serve three very important functions. First, as the initial host response, innate defenses limit or prevent infection by rapidly eliminating microbes (clearance). Second, the effector components of innate immunity interact and work together with components of adaptive immunity to synergistically augment microbial clearance. Third, innate immunity stimulates and can reprogram adaptive immune mechanisms to optimize clearance of specific types of microbes. Although viral clearance has been traditionally thought to be due to lymphocyte-mediated clearance of infected cells, recent data have demonstrated the important role for phagocyte-mediated clearance of recombinant, replication-deficient adenoviral vectors administered to the lung and systemic circulation. In this chapter we will review data regarding the interaction between adenovirus and host innate immune mechanisms and discuss the implications for use of recombinant adenoviral vectors for in vivo

ADENOVIRAL VECTORS FOR GENE THERAPY Copyright 2002, Elsevier Science (USA). All rights reserved.

gene transfer. The discussion will be focused on pulmonary innate immune responses because much of our information comes from preclinical and clinical studies done in an effort to an develop adenoviral vector-based in vivo gene therapy for the clinical manifestations of cystic fibrosis lung disease. A brief review of innate immunity is useful prior to discussing data related to adenovirus.

Components of the innate immune system are found, presumably, in all Mesozoic organisms in contrast to adaptive immunity which is present only in cartilaginous and bony fish, amphibians, reptiles, birds, and mammals. Coevolution during the 400 million years since appearance of lymphocyte-based adaptive immunity accounts for the close interconnection between innate and adaptive immune mechanisms. Innate immunity is composed of a set of constitutive and inducible components including physical and biochemical barriers, circulating or mobile effector cells and proteins, and proinflammatory and chemotactic cytokines (Table I). The principal effector components of innate immunity involved in clearance of microbes during in vivo infection include phagocytic and natural killer (NK) cells, cytokines, and complement.

Phagocytic cells are the primary effectors of microbial clearance in vivo and consist of tissue macrophages and circulating monocytes and neutrophils. Tissue macrophages are derived from circulating monocytes that enter the various organs and differentiate into morphologically, histochemically and functionally distinct phagocyte populations [1, 2]. Macrophages, which are normally resident in tissues and phagocytically competent prior to infection, provide a constitutive mechanism for primary clearance of microbes in tissues and organs. Neutrophils, normally abundant in blood and also phagocytically competent prior to infection, are not normally present in tissues but are recruited in response to localized release or generation of chemotactic factors at the site of infection. Thus, neutrophils provide a potent, inducible mechanism for secondary clearance of microbes in tissues and organs. Both macrophages and neutrophils are capable of internalizing and destroying a variety of microbial pathogens and secrete a number of potent inflammatory mediators in response to infection. NK cells normally constitute 5 to 20% of the blood mononuclear cells and are primarily involved in clearance of viruses and some other intracellular pathogens. NK cells are activated and lyse virally infected host cells by three incompletely understood mechanisms: (1) binding to microbe-specific antibody molecules attached to infected host cells, (2) binding to adhesion molecules whose expression is upregulated on infected host cells, and (3) binding by an unknown mechanism to host cells lacking class I major histocompatibility complex (MHC) molecules (reviewed in [3]).

Cytokines constitute a group of soluble protein components of innate immunity that serve critical proinflammatory and chemoattractive functions (reviewed in [4]). These functions include augmentation of inflammation (e.g., by TNFa, interleukin (IL)-l), induction of resistance to viral infection within

Table I

Components of Innate Immunity In the Lung

Class

Type

Effector

Principal function

Presence

Barriers

Physical

Epithelium

Block microbe entry

Constitutive

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