PART 1 Overview the present state of veterinary vaccine

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Vaccine manual 5,uct of irn unity by veteir,irn Un pro p ylactic. W I Morrison, Infectious disease continues to be one of developments in the application of DNA. the most important constraints on the technology now provide a strong con. efficient production of farm livestock in ceptual framework for the rational devel. both developing and developed countries opment of new vaccines. While vaccination and the therapeutic or This chapter will consider recent de. prophylactic use of drugs both play an velopments in immunology that are. important role in animal disease control pertinent to understanding how the. vaccination is increasingly being viewed immune system controls infections. as the more sustainable option This view and will discuss their implications for. is influenced not only by the potential that contemporary approaches to vaccine. vaccination offers for greater economic development. efficiency but also by the concerns that, have been raised about the selection of APPROACHES TO VACCINE DEVELOPMENT. drug resistant pathogens and the potential Most of the current veterinary vaccines are. harmful effects of drug residues in animal based on the use of either killed organisms. products and the environment Vaccination or their products or live attenuated. has had a major impact on the control of organisms The development of these. epidemic viral diseases of livestock such vaccines has not relied on knowledge of. as foot and mouth disease and rinderpest the immune responses that mediate. However there are many other important immunity Significant advances have been. diseases for which efforts to develop made primarily by the development of new. effective methods of vaccination have been culture techniques improved attenuation. unsuccessful procedures and better adjuvants While. The advent of recombinant DNA there is some scope for further efforts to. technology in the early 1980s created develop vaccines along these lines there. exciting new opportunities to produce are many diseases for which the more. vaccines based on the use of expressed empirical methods are unlikely to be. products of cloned genes However only a successful. few such vaccines have been successfully Two main approaches to vaccine design. developed In retrospect it can be seen can be considered using modern molecular. that the immediate expectations of the new technologies namely the production of. technology were unrealistically high given attenuated mutant organisms by deliber. the limited knowledge of the immunology ate molecular manipulation and the. of many of the target diseases and of how identification of antigenic components of. antigens are processed and recognized by pathogens that can be used to induce. the immune system In the intervening protective immune responses these. decade there have been major advances in components are known as subunit. immunology which coupled with further vaccines Unlike the traditional vaccine. 6 The induction of immunity by veterinary immunoprophylactics. strategies the ability to exploit these new Recognition of antigen by B and T. approaches to vaccine development is lymphocytes, dependent on an intimate knowledge of The antigen recognition structures on B. the molecular structure of the target and T lymphocytes namely immuno. pathogens and an understanding of the globulin Ig and the T cell receptor TCR. mechanisms of immunity are both generated by a process of gene. rearrangement whereby each of the two, PROCESSING AND RECOGNITION OF chains that make up the molecules is.
ANTIGENS produced by bringing together two or three. Immune effector mechanisms variable sequences from a pre existing. Studies in laboratory animal model library of variable genes with a constant. systems have demonstrated that the sequence to form a functional gene Cooper. immune system can respond in a number and Burrows 1989 Davis and Bjorkman. of different ways to control an infection 1988 This mechanism together with the. The type of response elicited by a pathogen further diversity created by a combination. depends largely on the nature of the of different variable regions in Ig heavy. organism and its site of replication within and light chains and TCR alpha and beta. the host In general organisms that chains facilitates the generation of a very. establish systemic infections and replicate large repertoire of B lymphocytes and. extracellularly are controlled by antibody T lymphocytes each with a unique antigen. responses recognition specificity, Secretory antibody responses also play Despite the similarity in structure of Ig. an important role in the control of infec and TCR molecules B and T lymphocytes. tions at mucosal surfaces By contrast cell differ fundamentally in the way they. mediated immune responses are generally recognize antigen Immunoglobulins. more important in controlling organisms whether on the surface of B lymphocytes. which replicate intracellularly The T lym or as secreted antibodies interact directly. phocytes that participate in cell mediated with foreign antigen usually in the form. immune responses may exert their effector in which it is initially encountered by the. function in a number of different ways host i e as an intact organism or as. They may kill infected cells or release molecules released from the organism. cytokines which inhibit growth of intra Recognition of antigens by antibody is. cellular organisms or which recruit and therefore often dependent on the con. activate accessory cells such as macro formational integrity of the molecules By. phages to perform these functions Indeed contrast T lymphocytes only recognize. a number of different mechanisms may antigens after they have been degraded. operate against the same organism Stimu and presented on the surface of other cells. lation of T lymphocyte responses is also Brodsky and Guagliardi 1991 These. essential to provide help again in the form antigen bearing cells rnay be cells infected. of cytokines for the production of antibody with foreign organisms or professional. by B lymphocytes Hence T lymphocytes antigen presenting cells such as macro. have a pivotal role in the induction of phages and dendritic cells which have. virtually all specific immune responses ingested antigen The processed antigen. The way in which antigen is processed which is in the form of short peptides of. and recognized by the immune system less than 20 amino acids is associated with. determines the type of T cell response that major histocompatibility complex MHC. is induced molecules on the surface of the antigen. Vaccine manual 7, presenting cell Bodmer 1984 The T cell although the antigenic peptides that. receptor does not react with antigen alone associate with class II are longer 13 to 17. but rather recognizes a combination of the amino acids than those bound to class I. antigenic peptide and the associated MHC eight to ten amino acids Much of the. molecule Townsend and Bodmer 1989 sequence polymorphism in MHC. molecules occurs in and around the, The special role of MHC molecules peptide binding region and although this. The MHC consists of a set of closely linked variation does not affect the overall. genes many of which encode molecules structure of the peptide binding groove it. involved in antigen processing and results in subtle differences that influence. presentation Trowsdale 1993 There are the nature of the peptides that each. two main types of MHC molecules namely molecule will bind Thus each individual. class I and class II The most striking class I molecule tends to bind a different. feature of these MHC molecules is the high repertoire of peptides Sette et al 1987. degree of polymorphism they display Rothbard and Gefter 1991 so that T cells. among individuals of a species Bodmer from animals expressing different MHC. 1984 Trowsdale 1993 Class I molecules molecules will often recognize different. are heterodimers composed of a poly epitopes from the same pathogen and in. morphic heavy chain and a non poly some cases these epitopes may be on. morphic light chain j32 microglobulin the different proteins. latter encoded outside the MHC They are Although this variation might be expect. expressed on most cells of the body Class ed to result in quantitative differences in. II molecules are also heterodimers both the immune response to pathogens and. polypeptides being encoded within the hence differences in susceptibility to. MHC but their expression in healthy disease there are relatively few well. animals is confined mainly to profes documented examples of strong asso. sional antigen presenting cells namely ciations of MHC with susceptibility to. macrophages dendritic cells and B lym infectious disease in outbred species This. phocytes In most mammalian species probably reflects the large number of. examined each class is encoded by two potential T cell epitopes in most pathogens. gene loci and in each instance both alleles and the fact that most animals in an. are expressed outbred population will be heterozygous. While it has been recognized since the and therefore will express several class I. early 1970s that class I and class II or class II molecules Variations in the. molecules are involved in presenting epitopes that are selected in individual. antigen to T cells the precise molecular animals may however affect the strain. and structural basis of presentation was specificity of the T cell response if some of. not elucidated until the late 1980s A key the epitopes vary between pathogen strains. event was the resolution of the structure of Vitiello and Sherman 1983. class I molecules by X ray crystallography As already indicated the TCR recognizes. Bjorkman et al 1987 This revealed a a combination of self MHC molecule and. prominent cleft in the membrane distal bound peptide Since the region of the. part of the molecule which subsequent MHC molecule recognized by the. studies have shown to be the site of antigen TCR i e the peptide binding groove is. binding A similar structure has been polymorphic each T cell will only re. described for class II MHC molecules cognize an antigenic peptide associated. Brown et al 1993 Stern et al 1994 with a particular MHC molecule This. 8 The induction of immunity by veterinary immunoprophylactics. phenomenon known as MHC restriction onstration that CD4 T cells recognize. Doherty Blanden and Zinkernagel 1976 antigen presented by class II MHC. has important practical implications for molecules whereas CDS T cells recognize. studies of T cell responses in outbred antigen presented by class I MHC. animals T cells from one animal molecules These interactions are. will recognize antigen presented on the accompanied by binding of the CD4 and. animal s own antigen presenting cells but CD8 molecules to conserved regions on. will not recognize the same antigen on the presenting class II and class I MHC. presenting cells from another animal of a molecules respectively CD4 T cells were. different MHC phenotype shown to mediate help for B cell responses. Until recently the capacity of a given and delayed type hypersensitivity. MHC molecule to bind a large number of reactions whereas CD8 T cells were. different antigenic peptides was difficult responsible for cell mediated cytotoxicity. to explain However studies carried out of virus infected cells However for some. over the last four years involving the time the factors that determined whether. isolation and sequencing of peptides an antigen was presented by class I or class. bound to class I molecules have helped to II MHC molecules were unclear This was. resolve this issue The heterogeneous resolved by studies which showed that. mixture of peptides isolated from an class I and class II molecules bind peptides. individual class I molecule were found to generated within different subcellular. be conserved at one or two residues compartments of antigen presenting cells. usually at positions 2 and 9 and these Antigens derived from organisms that. conserved amino acids were shown to be replicate in the cytoplasm of cells are. essential for binding the peptides to the degraded by proteases within the cytosol. respective MHC molecule Matsumura et and the resultant antigenic peptides are. al 1992 Rammensee Falk and Rotzschke transported into the endoplasmic reti. 1993 Thus the amino acids at these culum where they associate with newly. positions represent an MHC binding motif synthesized class I MHC molecules. the antigenic specificity of the peptide destined for the cell surface van Meek and. being determined by amino acids at other Nathenson 1992 By contrast organisms. positions Information on the binding motif or proteins taken into antigen presenting. of a particular MHC molecule can be used cells by phagocytosis or endocytosis. to predict possible T cell epitopes within undergo enzymatic degradation within. proteins of known amino acid sequences endosomes and associate within an. There is some evidence that similar endosomal compartment with newly. characteristics determine the binding of synthesised class II MHC molecules. peptides to class II molecules Rudensky transported from the Golgi apparatus. al 1992 although this has proved difficult before being expressed on the cell surface. to substantiate Brodsky 1992 Unanue 1992,These alternative routes of antigen. T cell subpopulations recognize antigen processing are known as the endogenous. processed in different subcellam and exogenous pathways respectively. Vaccine manual 5 strategies the ability to exploit these new approaches to vaccine development is dependent on an intimate knowledge of the molecular structure of the target pathogens and an understanding of the mechanisms of immunity PROCESSING AND RECOGNITION OF ANTIGENS Immune effector mechanisms Studies in laboratory animal model systems have demonstrated that the immune system can

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