skin immune system (8). They are in a unique posi- tion to capture exogenous antigens. Upon exposure to antigens, they migrate as veiled cells to lymph nodes.
Immunoprophylaxis of bovine dermatophytosis Roar Gudding, Arve Lund
Abstract
Introduction
The literature on immunoprophylaxis as control method for ringworm in cattle is reviewed. Scientific papers on immune response to dermatophyte antigens and vaccination against ringworm were obtained from personal files and computerized search in 4 relevant databases. Vaccines with antigens of Trichophyton verrucosum stimulate a humoral and cellular immune response. In animals vaccinated with inactivated vaccines, some protection is observed after challenge. However, the protective immunity is inadequate in most cases. Vaccination with live vaccines elicits an immune response that prevents the development of clinical disease. The protective immunity is based mainly on the cellular branch of the immune system. The efficacy and safety of live dermatophyte vaccines have been demonstrated in both challenge experiments and field trials from different countries. Effective control of ringworm in cattle has been achieved in regions implementing systematic vaccination.
Dermatophytosis, or ringworm, is an infection of the superficial, keratinized structures of the skin and hair of animals and humans. The disease is caused by a group of keratinophilic, filamentous fungi, called dermatophytes, belonging to the genera Trichophyton, Microsporum, and Epidermophyton. The dermatophytes are molds, characterized morphologically by hyphae forming a mycelium when grown on suitable media. In infected skin, these dermatophytes exist in a parasitic form, characterized by hyphae that may fragment into arthrospores (1). Several species of Trichophyton and Microsporum may cause clinical infections in animals (2,3). In cattle, dermatophytosis is most often caused by T. verrucosum. Ringworm denotes the clinical entity characterized by
Resume Immunoprophylaxie contre la dermatophytose bovine Cet article presente une etude de la documentation sur l'utilisation de l'immunoprophylaxie comme m'thode de controle pour la teigne chez les bovins. Les donnees scientifiques sur la reponse immunitaire aux antigenes dermatophytes et a la vaccination proviennent de dossiers personnels et de quatre bases de donnees obtenues par recherche sur ordinateur. Les vaccins a bases d'antigenes de Trichophyton verrucosum produisent une reponse immunitaire humorale et cellulaire. Les animaux inocules avec des vaccins inactives ont demontret une certaine protection lors d'un test de provocation; toutefois, la protection immunitaire etait inadequate dans la majorite des cas. L'inoculation avec des vaccins de souches vivantes de dermatophytes produits une reponse immunitaire suffisante pour prevenir l'apparition de signes cliniques. Cette protection immunitaire est surtout d'origine cellulaire. Les vaccins de souches vivantes ont ete eprouves dans plusieurs pays pour leur efficacite' et leur siurete par des essais experimentaux de provocation et des etudes cliniques sur le champ. Les regions qui ont etabli un programme d'immunisation ont obtenu un controle efficace contre la teigne chez les bovins. (Traduit par Docteure Therese Lanthier) Can Vet J 1995; 36: 302-306
Central Veterinary Laboratory, P.O. Box 8156 Dep (Gudding, Lund), Department of Large Animal Clinical Sciences, the Norwegian College of Veterinary Medicine, P.O. Box 8146 Dep (Gudding), N-0033 Oslo, Norway 302
annular skin lesions. Although it is a superficial skin infection, ringworm in cattle may have a significant impact on management and economics in affected herds. Once the disease is introduced into a herd, it spreads easily from one animal to another. Spores may survive in the environment for 2 to 3 y, and calves or purchased animals introduced into the herd are likely to contract infection. The inflammation of the skin is associated with unthriftiness and general discomfort in affected animals. In addition, secondary bacterial infections may occur. Ringworm is a zoonosis. According to a Swedish and a Swiss study, 29% and 74%, respectively, of dairy farmers had experienced ringworm (4,5). Furthermore, a positive correlation was observed between herds with ringworm and people with ringworm (4). Dermatophytosis also has important economic significance, as apparently healed skin lesions reappear after the tanning process (6). Consequently, a national vaccination program was advocated by the Swedish hide industry (7). In Norway and a few other countries, ringworm in cattle is a notifiable disease. Restrictions on sale of breeding animals and on the access of livestock to common pastures are imposed on affected herds. Treatment of clinical ringworm in cattle is expensive and time-consuming. There is definitely a need for effective prophylaxis against the disease as hygienic and other preventive measures often fail. The main purpose of this paper is to review the literature on vaccination against ringworm in cattle, with particular emphasis on immunoprophylaxis as a control method. Relevant information on immunological aspects of dermatophyte infections in man and animals is also presented. The literature reviewed has been compiled from personal reference files collected over recent years, supplemented with computer-aided searches of the following databases: CAB (Commonwealth Agricultural Bureaux) from 1984 to 1994, Agricola from 1979 to 1994, Medline from 1985 to 1994, and Biosis from 1985 to 1994. Can Vet J Volume
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importance of neutrophils in the host' s defense against dermatophytes is further supported by the dense infiltration of these cells in infected areas of the skin, in both The skin is continuously exposed to exogenous antigens, natural and experimental infections. so this extensive organ has specific immunological The elimination of dermatophytes is also supported by defense mechanisms. Upon exposure to foreign antigens, enhanced epidermopoiesis due to contact sensitivity to such as dermatophytes, the following sequence of events fungal elements (21). This leads to an increased turnover is presumed to be initiated in the skin. of the epidermis, with subsequent elimination of the Antigen presentation fungal cells from the skin surface. The antigens are trapped in the epidermis by Langerhans' An antibody response can be demonstrated in cattle cells, which are prominent antigen-presenting cells of the and experimental animals by different methods, in spite skin immune system (8). They are in a unique posi- of the superficial location of the antigens (22). Although tion to capture exogenous antigens. Upon exposure to the protective role of antibodies in dermatophytosis antigens, they migrate as veiled cells to lymph nodes has been questioned, a contribution to host defense by draining the skin, where the antigens are presented to opsonization or other mechanisms cannot be excluded T-lymphocytes in a major histocompatibility complex (23). A study in calves indicated that a combination (MHC) class II-restricted fashion (9). Migration of of cell-mediated and humoral responses is required for antigen-presenting cells is probably initiated by cytokines. immunity and clearance of T. verrucosum infection However, the type of cytokine and the mechanisms (13). Fungal elements in infected areas did not decrease involved have not been determined. One of the candidates until after both humoral and cellular responses had is granulocyte macrophage-colony stimulating factor been established. (GM-CSF), which has been shown to have a stimulatory The cellular branch of the immune system is crucial effect on Langerhans' cells, including potentiation of for protective immunity against dermatophyte infectheir antigen-presenting capacity (10). Different cytokines tions (24-27). Studies with T. quinckeanum in mice produced by keratinocytes create favorable conditions showed that fungal antigens activated T-helper cells. The in the skin for specific immunological activity (11). significance of these cells for protection was demonAs Langerhans' cells have poor phagocytic capacity, strated in an in vivo cell transfer system (28). macrophages may have a role in the uptake and degradation of the fungi into smaller fragments. It has also Vaccines, immune response, and been proposed that keratinocytes, which are able to protection phagocytize and degrade antigens, may process antigens Cell-wall antigens, as well as metabolites secreted by that can be transferred to Langerhans' cells and directly growing fungal cells, constitute the major antigens prepresented to T cells (12). sented to the infected host (23,27). The outer layer of the cell wall contains mainly glycoproteins. Dermatophytes Recruitment of cells In calves experimentally infected with T. verrucosum, an also produce several proteinases, among which keratiincrease in the number of lymphocytes and other inflam- nase has a significant role in pathogenesis. matory cells in the dermis has been demonstrated; these Inactivated dermatophyte vaccines include macrophages, CD4+ and CD8+ lymphocytes, Vaccines for cattle containing formalin-inactivated and y8 T cells (13). The CD4+ T helper cells were cells of strains of T verrucosum have been examined for the most numerous. The increase in y1 T cells in dermis immunogenicity and protective ability in experimental and epidermal tissue during the course of infection is and field trials (29,30). Vaccination stimulated a cellular noteworthy, particularly since their function is not immune response, as assessed by a skin test and a known in detail. In ruminants, 9y1 T cells are especially leukocyte migration inhibition test. In the experimental prominent and associated with epithelial surfaces (14). trial, some protection was observed after challenge In some skin diseases, yb T cells are selectively recruited with a virulent strain of T. verrucosum on depilated to sites of active inflammation, for example, orf viral and scarified skin. The design of the field trial with infection in sheep (15). vaccination of already infected animals was, however, A dense infiltration of neutrophils has been observed suboptimal for the evaluation of any prophylactic effect in infected areas of the skin in calves experimentally of the vaccine preparation. challenged with T. verrucosum (16). Dermatophyte An inactivated vaccine with adjuvant containing antigens were also chemotactic for human neutrophils in conidia and mycelial elements of 2 strains of T. equinum in vitro assays (17). In mice experimentally infected with was used for immunization of horses (31). The relative dermatophytes, a dense infiltration of neutrophils and protection was 75% and 87% in the exposure and the pen macrophages in skin was demonstrated before the peak contact studies, respectively. Also, when infection did of infection (18). occur, the lesions in vaccinated animals were less severe The elimination process than those observed in nonvaccinated animals. The The effector mechanisms involved in the elimination of results were further confirmed by a field study involvdermatophytes are not fully understood. In mice, ing approximately 3500 horses (31). The incidence of T. quinckeanum and T. rubrum were highly susceptible ringworm dropped from a prevaccination level of 40% to in vitro killing by components of the hydrogen to essentially 0% following systematic vaccination. peroxidase-halide system (19,20). These studies Vaccines against ringworm must be capable of eliciting suggested that phagocytosis and oxidative products of the both humoral and cellular immune responses, of which respiratory burst of neutrophils and macrophages par- the cellular response is crucial for protection. Adjuvants ticipated in the killing of dermatophytes in vivo. The are important in inactivated vaccines in order to
Theory for antigen presentation and elimination of dermatophyte infection
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Figure 1. Mean antibody response assessed by an enzyme linked immunosorbent assay in 5 rabbits vaccinated 2X with a Trichophyton verrucosum vaccine and in 2 control rabbits. aOD=optical density * p
