Passive immunity against human pathogens using bovine antibodies.

Abstract

The control and treatment of infectious diseases is increasingly complicated by the development of antibiotic-resistant organisms, the emergence and rapid dissemination of new pathogens, and the growing incidence of opportunistic infections. Identification and commercialization of new anti-microbial agents has always been a time-consuming and expensive process, and development of new strategies to control disease are therefore clearly warranted. The immune system has evolved to help combat various types of infections. As most pathogens enter through mucosal surfaces, the local immune defence may be of particular importance and evolutionary pressure has led to the development of a specialized immunoglobulin class in secretions—IgA. Patients with primary immunodeficiencies involving IgA are known to be highly susceptible to respiratory and gastrointestinal (GI) tract infections (for review see [1]), supporting the notion of a crucial role for antibodies in the mucosal defence. Infection-prone IgA-deficient patients are currently treated with human IgG given systemically [2]. However, a proportion of these patients still suffer from mucosal infections which necessitates development of additional forms of therapy, and human IgG in high doses has previously in fact been given orally, without adverse effects, to healthy volunteers [3] and to patients suffering from a variety of GI infections (for references see [4]). However, from a theoretical point of view human IgG is expected to be less effective than human IgA due to its comparatively low proteolytic stability, and it may also, due to its interaction with complement and phagocytosing cells, provoke an inflammatory reaction. Human breast milk, which contains secretory IgA, is known to protect against diarrhoea in infants. Oral administration of purified human immunoglobulin has previously also been suggested to exhibit a prophylactic effect against development of necrotizing enterocolitis in prematurely born children [5] and a therapeutic effect in Campylobacter jejuni [6] and Clostridium difficile [7] induced diarrhoea in immunodeficient patients as well as chronic diarrhoea of unknown aetiology in normal infants [8]. However, the titre against most human pathogens is rather low in the IgA-containing gammaglobulin preparations, and vaccination of volunteers for preparation of hyperimmune products is not feasible. Furthermore, there is always a risk of transmission of infectious agents when using human plasma as a starting material and since the cost for these preparations is high, alternative sources of antibodies must be sought. The common dairy cow may be one such alternative, as bovine antibodies are actively transported from plasma to milk in cows and are present in high concentrations in colostrum. The antibodies protect the calves from GI infections during the neonatal period and are of major importance for their survival. Bovine immunoglobulin preparations against rotavirus and Escherichia coli have previously been shown to be effective as prophylaxis against infections and have been commercially available for use in farm animals for decades. During the past few years, bovine immunoglobulin preparations have also been shown to protect against natural infection or challenge with a variety of different microorganisms in man. The effect of therapeutically administered bovine antibodies has not been as well documented, but successful intervention has been demonstrated in Helicobacter pylori, rotavirus and cryptosporidial infections (for references see [4,9]). Interaction between bovine antibodies and the human immune system is limited [10] and the preparation can be given without risk of serious adverse events. The titre of antibodies against many human pathogens is low in colostrum from non-immunized animals [4], and although a therapeutic effect has been suggested by oral administration of high doses of non-specific bovine immunoglobulins to patients with chronic diarrhoea [11–14], it is likely that a future product will have to be derived from immunized animals [10]. In this review, we will summarize published data on the use of bovine immunoglobulin-containing preparations for prophylaxis and therapy against selected mucosal infections in man and suggest directions for its future use.