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Vaccination (continued) bearing receptors for processed forms of the antigens. The development and propagation of the immune response also involves diverse subtypes of T cells and B lymphocytes, natural killer and lymphokine-activated killer cells, neutrophils, and eosinophils. The communications between these immune and inflammatory cells are mediated in large part by small proteins (about 20 kilodaltons) named cytokines. The cytokines include the interleukins (IL-1 to IL-18), gamma interferon, granulocyte- macrophage colony stimulating factor (GM-CSF), tumor necro- sis factor, and transforming growth factor beta. The cytokines have various actions; for example, IL-1 is involved in T- and B-cell maturation, gamma interferon is involved in helper T cell 1 (Th1) upregulation and enhanced major histocompatibility complex (MHC) expression, IL-2 is involved in Th1 upregula- tion, IL-4 is involved in Th2 upregulation, IL-10 is involved in suppression of inflammatory cytokines and enhancement of B-cell proliferation, GM-CSF is involved in comigratory signals for dendritic cells, and IL-12 is involved in stimulation of Th1 differentiation. Cytokines are species-specific and expensive, and there are concerns regarding their stability, toxicity, and potential autoimmunity. These issues have limited their use as vaccine components. Immunomodulation refers to the ability of many adjuvants to modify the cytokine network and, hence, the immune response. Adjuvants can target macrophages of the Peyer's patches (lymph nodules of the intestine) to induce mucosal im- mune responses, or they can allow antigens to associate direct- ly with class I MHC molecules on the cell surface to elicit class I– restricted CD8+ cytotoxic T-lymphocyte responses. Particulate antigens tend to target macrophages, and macrophages can be recruited to the site of antigen deposition through the action of cytokines. Freund's complete adjuvant and lipopolysaccharide- based adjuvants drive the responses of Th1 subtype CD4+ helper cells, whereas alum salt, cholera toxin, and pertussis adjuvants drive the responses of Th2 subtype CD4+ helper cells. The Th1 responses are associated with interferon gamma, IL-2, and IL-12 secretions. Th1 cells also secrete tumor necrosis factor, thereby enhancing B-cell responses that elicit IgG2a (the antibody subclass most efficient in binding the serum comple- ment proteins that enhance antigen-antibody reactions). The Th2 cells secrete the IL-4, IL-5, and IL-10 that activate the pro- duction of high levels of IgG1, IgA, and IgE by B cells. Selection of the appropriate immunoregulatory adjuvant not only leads to an enhanced immune response, but also determines the iso- type of IgG, how much CD4+-directed cell-mediated immunity is generated, and which other immunoglobulins are made. Recombinant viral vectors and chimeric viruses Another option is the use of recombinant viruses for the delivery of vaccine antigens. Although foreign antigens may be expressed in these recombinant viruses and used as inac- tivated subunit vaccines, live-attenuated-viral-based vectors as vaccines have decided advantages. This is because a single vaccination without adjuvants can suffice for immunization by the live-virus vaccine. Replication of the viral-based vector within the host amplifies the amount of foreign antigen being expressed, thereby often increasing both cell-mediated and hu- moral immune responses to the foreign antigen. The process- ing and posttranslational modifications of the foreign antigen within infected eukaryotic cells more closely resemble those occurring during natural infection with the pathogen from which the foreign antigen was derived. In addition, presenta- tion of the antigen may be optimized. Attenuated bacteria, such as Salmonella, as well as many different virus families have been used as vectors, including adenoviruses, herpesviruses, papovaviruses, retroviruses, and picornaviruses. However, the most extensively developed and exploited vector has been vaccinia virus, a member of the Poxvirus family. Vaccinia is a very large virus; about 5% of its DNA either is redundant or encodes genes that are not abso- lutely essential for virus replication in cultured cells. Thus, the capacity of vaccinia recombinants to accommodate foreign DNA is very large. Experimental vaccinia-based-vector vaccines include those with foreign DNA inserts derived from hepatitis B virus, influenza, malaria, Epstein-Barr virus, genital herpesvirus, respiratory syncytial virus, Lassa fever virus, human T-cell leuke- mia virus, and HIV. One of the most interesting of the vaccinia- based viral vectors is the recombinant that expresses the rabies virus glycoprotein gene. The vaccinia/rabies recombinant was incorporated in bait as an oral vaccine and is presently being used for the immunization of wildlife. Although vaccinia is a comparatively safe vaccine virus, immunosuppressed people can become systemically infected and die with generalized vaccinia infection. Therefore, it is difficult to imagine vaccinia being used in humans in view of the global AIDS epidemic. An additional problem arises from the induction of vaccinia antibodies during the initial usage of the vaccinia vector so that it becomes difficult to use the vectorial vaccine twice. Recombinant DNA techniques also have made it possible to construct poliovirus type 1/type 3 antigenic hybrid viruses in cell cultures to elicit both type 1 and type 3 neutralizing antibodies. Three poliovirus serotypes are known, and each se- + ward ' s science