Immune response toward

Raising the pi of macromolecules also can significantly alter the immune response toward them upon in vivo administration. Cationized proteins (those modified with diamines to increase their net charge or pi) are known to generate an increased immune response compared to their native forms (Muckerheide et al., 1987a, b Apple et al., 1988 Domen et al., 1987 Domen and Hermanson, 1992). The use of cationized BSA as a carrier protein for hapten conjugation can result in a dramatically higher antibody response toward a coupled hapten (Chapter 19). 

This chapter describes the design, preparation, and use of hapten-carrier conjugates used to elicit an immune response toward a coupled hapten. The chemical reactions discussed for these conjugations are useful for coupling peptides, proteins, carbohydrates, oligonucleotides, and other small organic molecules to various carrier macromolecules. The resultant conjugates are important in antibody production, immune response research, and in the creation of vaccines. 

Some synthetic carriers actually are designed to have low immunogenicity on their own to minimize the potential for antibody production against them. When a hapten is coupled to these molecules, the immune response is directed principally toward the modification, not at the carrier. This design approach guides most of the immune response toward the desired target and minimizes the production of carrier-specific antibodies. 

The hypothesis of the existence of T cells that specifically regulate immune responses towards self and allogeneic antigens has been formulated since 25 years ago [21]. However, phenotype and functional properties of Treg have been at least partially defined only in the last few years. 

Immunotoxicity of this type can result from faulty recognition of not self or an overreaction. Alternatively, an unwanted or exaggerated immune response toward a harmless antigen may occur and could be severe (e.g., fatal anaphylactic shock in response to peanuts). 

IgG or IgM antibodies direct the immune response toward the antigen located on a cell (e.g., a red blood cell or thrombocyte). Macrophages, NK cells, and neutrophils are recruited by the antibodies to the site of the antigen on the cell surface and destroy the cell by phagocytosis or lysis. Additionally, complement activation will damage the cell (Fig. 6.32). The result, for example, where red cells are the targets is hemolytic anemia. 

An intriguing question concerns the immune response elicited by allergen extracts at the mucosal surface. Some studies, in animal models, provided interesting information the dendritic cells of oral mucosa act as efficient antigen-presenting cells and produce IL-12, which directs the immune response towards a Thl profile away from pro-IgE-Th2 profile [6-8],... 

A -THC, like morphine, has been shown to suppress in vitro antibody formation by mouse spleen cells (Kaminski et al., 1992 Kaminski et al., 1994). Interestingly, A -THC is reported to increase IgGl responses to Legionella pneumophila in drug-treated animals, presumably by polarizing the immune response towards a Th2 phenotype (see below under T cell responses) (Newton et al., 1994). 

Thl/Tli2 subclasses of T helper cells that are distinguished by their cytokine profiles. Thl cells are characterized by production of IFN-g. Thl cells are characterized by production of IL-4. Th2 cells polarize the immune response towards cellular immunity and Th2 cells polarize towards antibody formation. 

The pattern of proinflammatory cytokines produced has implications for the character of the adaptive immune response, which will occur if the host is exposed to a foreign antigen. A T-helper type 1 (Thl) cytokine profde polarizes the immune response towards a cellular immune response, whereas a T-helper type 2 (Th2) profde favors antibody responses (Mos-mann and Coffman, 1987). IFN-y is a marker of a Thl response, and lL-4 is indicative of a Th2 response. There is evidence that morphine given in vivo biases the immune response toward a Th2 response (Roy et al., 2004). The consequences of this apparent shift toward Th2-type immunity are not clear, since other studies show that antibody production is suppressed in animals treated simUarly with morphine (Bus-siere et al., 1993). These results wUl be discussed in greater detaU below. 

There are striking parallels between the effects of opioids and cannabinoids on cytokine production. A -THC has also been shown to suppress proinflammatory cytokines crucial in host defense, such as TNF-a (Fischer-Stenger et al., 1993). Further studies showed a biphasic dose response to cytokine production by A -THC on human PBMCs, but it was the opposite of that observed with morphine, with low doses inhibiting TNF-a, lL-6 and lL-8, and high doses increasing these cytokines (Berdyshev et al., 1997). In a mouse model of Legionnaires Disease, A -THC blocked IFN-y, lL-12, and lL-12 receptor expression and increased lL-4 levels, reflecting a polarization of the immune response towards a Th2 phenotype (Perez-Castrillon et al, 1992 Klein and Cabral, 2(X)6). Similar... 

Despite this initial clinical setback, Ap-directed active vaccination continues to warrant further assessment via careful step-wise refinement and testing of novel immunotherapeu-tic approaches. It is clearly important to evaluate the antibody isotypes that are induced by candidate vaccine constructs, as well as determining the types of CD4 and CDS T cell immunity that are elicited. This information will undoubtedly facilitate the design of safer active vaccination strategies to direct the resultant immune response towards more desired effector functions. 

Immune responses can be divided into type 1 and type 2, based on the pattern of cytokine secretion and functional outcome of the immune response. Type 1 immune responses are characterized by secretion of IFN-gamma, production of IgG2a in mice, and activation of macrophages, NK cells, and cytotoxic T-cells. Type 2 responses are characterized by secretion of IL-4, IL-5, and IL-13 and by IgGl and IgE production. The responses are reciprocally regulated. How the polarization of the immune response toward type 1 or type 2 is determined is not exactly understood. IL-12 is an important factor that drives the type 1 response, and IL-4 is implicated in the type 2 response. Microbial products such as LPS and bacterial DNA stimulate the secretion of IL-12 by dendritic cells and preferentially induce type 1 immune responses. 

Protection from mbercnlosis is characterized by effective Mycobacterium-specific Thl responses and it has been hypothesized that co-infections with helminths will prevent the necessary Thl response by either disturbing the Thl/Th2 balance, or by driving the immune response towards a more anti-inflammatory status. Early observations showed that the incidence of lepromatous leprosy was twice as high in areas where onchocerciasis was endemic (Prost et al. 1979). 

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