The skin is the largest organ of the human body, with a surface area of about 2 m2. It is composed of an outer epidermis, an inner dermis, and the underlying subdermal tissue. For more details on skin structure, refer to Chapter 8. The physiologically active epidermis contains keratinocyte antigen-expressing cells as the predominant cell type. These cells can only express antigens for a few days before sloughing off with the normal sloughing of the epidermal layers of the skin. However, this relatively short-term expression can raise long-term immune responses.
The skin also has other cell types that represent the nonkeratinocytes. These include melanocytes (pigment formation), Merkel cells, and Langerhans cells. The Langerhans cells are dendritic-shaped cells located in the basal parts of the epidermis (they are also found in mucous membranes).
The skin performs a complex defense function that may be described as immunological. The immunological environment of the skin, including the humoral and cellular components, is given the acronym SIS (skin immune system). Dysregulations of this system can manifest as immunodermatolog-ical diseases, including atopic eczema, psoriasis, cutaneous lupus erythematosus, scleroderma, and autoimmune bullous disease.40-42
It is known that Langerhans cells (dendritic cells in the epidermis) reside in the skin and express a high level (in response to external aggression) of MHC class II molecules and strong stimulatory functions for the activation of T lymphocytes. The Langerhans cells comprise only about 1% of the cell population of the viable epidermis but cover nearly 20% of the surface area through their horizontal orientation and long protrusions, which form a meshwork that can uptake antigens they encounter. These cells are also found in the lymph nodes and act on antigens and present them to lymphocytes, thus providing immune surveillance for the body. The concept of skin-associated lymphoid tissue (SALT) has evolved in which Langerhans cells in the epidermis are believed to act as antigenic traps, and the antigen-laden cells then migrate into dermal lymphatic channels to present the information to T lymphocytes in lymph nodes. The Langerhans cells continuously leave the epidermis and are constantly replaced by circulating stem cells from the bone marrow. When allergens penetrate into the skin, they can in some cases lead to allergic contact dermatitis. Although dendritic cells are critical for induction of immunity, other cells such as the keratinocytes, CD4+ helper T cells, and B cells also play a role.
Taken together, these cells make the skin an excellent site for vaccine administration.43,44 Noninvasive vaccination onto the skin has the potential to be a simple, economical, painless, and safe process widely applicable to many disease settings. Relatively recent literature relevant to transcutaneous immunization has been reviewed extensively.45,46 The skin of hairless guinea pig is more similar to human skin than to the skin of normal-haired guinea pig and other rodents; therefore, the hairless guinea pig may be a useful animal for such studies.47 However, many of the relevant immune reagents are available for the mice model only, which has been extensively used. Among larger animals, swine skin has the closest similarity to human skin.
Bacterial products such as heat-labile enterotoxin from Escherichia coli (LT) and cholera toxin (CT) have been used as adjuvants to enhance the immune responses to vaccine components. These products most likely take advantage of the defense mechanisms in the body that resist invasion by bacteria by recognizing structural elements. The safety and immunogenicity of LT in a skin patch has been evaluated in human subjects in a graded-dose trial and no adverse reactions were observed, either systemically or at the site of immunization. Biopsy samples also confirmed that no inflammation was seen after the immunization.48 Similarly, CT was tested on mice skin and was reported to stimulate immune response without causing any adverse reactions.4950
Because Langerhans cells are believed to be the only APCs in uninflamed skin, they are likely to be involved in transcutaneous immunization.51 Transcutaneous immunization has also been reported to induce antigen-specific T-cell responses in the spleen and draining lymph nodes of mice, using tetanus toxoid as a model antigen with a variety of adjuvants. An oligonu-cleotide DNA sequence as well as several cytokines and lipopolysaccharides also exhibited adjuvant activity. These are structurally dissimilar compounds, and their adjuvant activity therefore suggests that the enzyme function of CT or LT is not essential for transcutaneous immunization. Both systemic and mucosal antibody responses are produced by transcutaneous immunization.51-53 These studies with LT and CT were apparently done using intact skin, and hydration or related factors were attributed to possible permeation of these large molecules through the skin. Another study suggested that topical gene transfer is dependent on the presence of normal hair follicles54; again, other groups showed a wider pattern of dermal and epidermal gene expression.55
It has been suggested that small molecular weight synthetic peptides formulated with an adjuvant may be directly applied to bare skin to induce both humoral and cellular immune responses.56 However, typically enhancement methods may be needed to be able to deliver macromolecules into the skin. Protein antigens that can be delivered directly to the cytosol of the Langerhans cells may elicit both cellular and antibody responses. An investigation achieved this by delivering antigens on 1.5- to 2.5-^m gold particles to the epidermis using a needle-free powder delivery system.31 Such particle-mediated immunization is discussed in Section 10.4.2.
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