The objectives are to optimize and to begin the pharmaceutical development of two novel therapeutics for the treatment of allograft rejection or autoimmune or inflammatory diseases. Specifically, we will: (1) optimize as to length and amino acid composition a homodirner of a heptadecapeptide (CKS-17) which already has demonstrable activity in in vivo animal studies; (2) purity to homogeneity a lOkDa protein fragment (rPl5E-10) which includes the CKS-17 sequence and which is 1OOOX as potent as the CKS-17 homodimer in in vitro assays of immune function; and (3) confirm activity of "optimized" peptides and purified rPl5E-10 in both in vitro and in vivo assays of cell-mediated immune function and inflammation. Such assays will include mononuclear cell proliferation to mitogens and antigens, neutrophil and monocyte chemotactic responses, tolerance to allogeneic skin grafts, accumulation of neutrophils ormonocytes at in vivo inflammatory foci, and carrageenan-induced paw edema. Both these novel compounds have the potential for acting at an early stage in the development of immune or inflammatory reactions and thus may modify disease as opposed to ameliorate symptoms. Both compounds offer potential advances for commercial development, particularly for the long-term treatment of chronic diseases such as arthritis.Awardee's statement of the potential commercial applications of the research:The research offers the potential for commercial applications in the development of one or more novel, potent analogues of P I 5E which have utility in the treatment of inflammatory or autoimmune diseases or in the treatment of graft rejection. The potential that such analogues work through mechanisms different from currently used drugs suggest that they might address currently unmet medical needs.National Institute of Allergy and Infectious Diseases (NIAID)
