NONHUMAN PRIMATE CYTOKINES, CHEMOKINES & SECONDARY SIGNAL MOLECULES

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cDNAs coding for various cytokines were cloned and sequenced from nonhuman primates. In addition to the previously characterized IL-1I, IL-1J, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12I, IL-12J, IL-15, IFNK, TNFI, TGFJ and B7-1 from macaques and mangabeys, we have extended these analyses to the cytokines IL-7, IL-16 and IL-18, the chemokines MIP-1I, MIP-1J, RANTES and SDF-1 as well as the receptors CCR-2B, CCR-5, fusin, B7.2, CTLA-4 and the hematopoietic growth factors GM-CSF, SCF and Flt3-ligand to delineate differences accounting for epitope differences and bioactivity of nonhuman primate cytokines/chemokines. There is a particular interest in cytokines that play a deterministic role in modulating the type of immune response to certain pathogens including SIV. In this regard, efforts have been devoted at expressing recombinant macaque IL-2, IL-4, IL-10, IL-12, IL-15, IL-16, IL-18 and IFNK as these factors may open very potent therapeutic pathways in wide ranging cli nical applications such as transplantation, oncology, hematology and infectious diseases. Numerous studies related to humans in these fields utilize nonhuman primate models. Yet recent data shows that injection of human recombinant cytokines most often does not allow repeated or long-term treatment due to rapid development of an immune response towards these "foreign" molecules, resulting in inactivation and clearance of these cytokines. Furthermore the immune response of primate cells to the stimulation by certain human cytokines has been found to be markedly lower than the response of equivalent cells from human origins. Recombinant macaque IL-2, IL-4 and IL-12 are currently being utilized in vivo to potentiate SIV immunizations in collaboration with 2 research teams in Europe and with Dr. Vogel's research group at the NIH. IL-12 is also currently being assessed therapeutically in SIV infected macaques with Dr. Hillyer at the Yerkes Center. Furthermore, in collaboration with Dr. Hoff man (NMRI, US Navy), we were able to show that a single injection of IL-12 was sufficient to prevent development of infection by the malarial agent Plasmodium cynomolgi in rhesus macaques. These studies bear the potential to rapidly translate into therapeutic applications for the treatment of human diseases.