This work seeks to further define the biologic importance and therapeutic potential of selected autocoids as immune modulators. The key data justifying this proposal include the facts that 1) Mediators of inflammation have been found to modulate murine and human models of immunity and 2) Congeners and conjugates of histamine have been found that affect only lymphocytes no other tissues. In the case of histamine derivatives, compounds with either pure Hl or mixed plus H2 effects have been constructed and tested in vitro and preliminarily tested in vivo. In the last years, we believe we and others have developed justification for focusing on histamine derivatives as immune modulators. The justification includes findings that receptors histamine are non-randomly distributed on murine and human lymphocytes that participate in immune response; the expression of histamine receptors is modulated on distinct subsets of murine and human lymphocytes by a variety of immunologically based stimuli (e.g., mitogens, the mixture of cell types in an MLR, the various lymphokines in the environment, and the stage of the immune response); the amine is stored in the tissues very frequently associated with immune responses; some lymphokines released during an immune response release histamine; a variety of immune-related stimuli release histamine; of the autacoids histamine alone releases HSF, and some chemoattractants and migration inhibitory factors; histamine effects in some human cells may relate to compartmentalized adenylate cyclase or CAMP; and histamine is capable regulating T cell surface antigens. In short, cellular responses to histamine seem exquisitely controlled by localized mechanisms of amine release as well as local factors that impact on receptor distribution and expression. The proposed study 1. primarily extends ongoing studies on the effects of histamine antihistamine on models of murine and human immune responses; 2. attempts to establish so the molecular mechanisms of the effects of Hl, H2, or Hl plus H2 stimulation in highly defined subsets of cells and immune circumstances and; 3. attempts to determine the in vivo setting mechanisms by which receptor and tissue specific congeners and conjugates of histamine antihistamines can modify models of T cell dependent and independent immune responses. Ultimately, we hope to determine the appropriateness and feasibility to transfer the compounds for testing their value as immune modulators in man.
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