The long term aims of this project are designed to elucidate how microbial mitogens can influence host susceptibility to disease or to participate in disease, and to apply this knowledge to the development of immunoregulatory substances which might be of benefit in the treatment of human disease based upon immunological dysfunction. The immediate specific aims for the current grant period are: 1. to determine the structural features of the M. arthritidis T cell mitogen (MAM) that are important for interaction with I-E protein accessory cell surface receptor and for biological activity in respect to: a)further develop procedures for production of homogeneous MAM; b) determination of the primary amino acid sequence of MAM; c) identification of active moieties of MAM by means of; i) specific residue derivatization, and ii) biologic and I-E binding activities of proteolytic or chemically derived oligopeptides from MAM. 2. Mechanism (s) of MAM-induced inhibition of T cell responses to mitogens in respect to: a) changes in cell populations in vivo following injection of MAM; b) cytokine production in vivo in response to MAM; c) MHC restriction of suppression; d) identification of the effector cell responsible for inhibition (i.e. is, cytolytic or natural killer cells or macrophages; e) role of soluble factors in suppression; f) effectiveness and potential toxicity of multiple doses of MAM on T cell function. 3. Effects of MAM on various parameters of immune function in respect to: a) inhibition of T cell responses to foreign antigens in vivo: b) inhibition of the in vitro response of node T cells and T cell hybridomas to antigens; c) inhibition of humoral antibody responses to T cell dependent and independent antigens; d) inhibition of the mixed lymphocyte reaction to mixtures of disparate MHC or Mls determinants: e) prolongation of allograft survival with a view to practical use of MAM as a new immunomodulator.
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