This grant proposes to pursue the potential utility of the interleukin, Lymphocyte Chemoattractant Factor (LCF) as a therapeutic agent for selective immune reconstitution of human CD4+ T cells and to develop competitive inhibitors of LCF function for use as therapy in inflammatory lung diseases characterized by CD4+ cell accumulation and CD4+ cell leukemias. Identification of CD4 as LCF's receptor; demonstration that LCF induces functional IL-2Rs, identification of mouse and rat homolog proteins (which express chemotactic activity for human T cells); and the presence of LCF in high concentrations in BAL and lung tissue of patients with Sarcoidosis and Asthma suggest avenues by which these goals can be accomplished:
The first aim will characterize regions of LCF and CD4 essential for function by: A. sequencing and cloning homologs for identification of regions of high homology in order to direct synthesis of inhibitory peptides and LCF analogs; B. identification of the binding region on CD4 in order to develop inhibitory rsCD4's or looped CD4 peptides capable of inhibiting LCF function; and C. Determine the second messengers involved in the CD4 dependent growth and chemotactic signals and functions.
The second aim will determine CD4's role in T cell growth by: A. exploring the role that CD4 plays as a growth factor receptor in the growth of CD4+ lymphoma lines in response to autocrine or paracrine stimulation by LCF. Since the vast majority of T cell lymphomas are CD4+ this will have potential therapeutic implications in development of selective therapeutics; B. exploiting LCF's use of CD4 as its receptor to induce functional IL-2 receptors to selectively expand specific subsets of CD4+ blood T cells in vitro for immune reconstitution.
The aims of this grant are focussed on application of the basic knowledge of LCF-CD4 interactions to develop directed therapies in diseases dependent upon CD4+ T cell numbers and their migration and proliferation.
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