This resource provides unique primate reagents and services not available commercially in support of NIH funded investigators using nonhuman primates (NHP) as pre-clinical models for vaccine efficacy and immunotherapies. State of the art investigations of immune responses related to human infectious diseases, autoimmune diseases, organ and cell allogeneic and xenogeneic transplantation models or immunization procedures that use nonhuman primate models increasingly include the use of recombinant cytokines, chemokines, growth factors or immunomodulatory ligands in vivo. While the close evolutionary relationship between human and nonhuman primates results in cross reactivity between most human recombinant factors when used with NHP cells, differences in affinity/bioactivity have been noted. More important however, most NHP molecules are not identical to human homologues, often leading to the development of neutralizing antibody responses to the xenogeneic molecule in vivo, markedly restricting the repeated and most optimal in vivo use of select immunomodulators in these models. The ready availability of standardized purified recombinant NHP reagents has largely alleviated this limitation and allowed investigators to address seminal questions using NHP during the past 11 years of funding. In addition, testing of in vivo administration of these reagents has markedly revised the clinical administration schedule, leading to more tolerable and efficacious dosing. Thus, this application requests continued support for allowing this Resource to provide NHP factors, in DNA and protein form. Specifically, the resource will perform the following: 1. Continuation and expansion of preparation, testing and distribution of NHP cytokines/chemokines and soluble receptors in protein and recombinant DNA expression vectors. 2. Characterization and in vivo testing of soluble cytokine receptors as immune modulatory enhancers. 3. Generation of modified fusion cytokines for enhanced bioavailability and synergistic bioactivity. 4. Generation of noncommercially available monoclonal antibodies to NHP cytokines in collaboration with the NIH Nonhuman Primate Immune Resource (Dr. Reimann).
Cytokines and chemokines are bioactive molecules produced in responses to physiological events, directing and shaping immune responses to immunization, infection, transplantation and disease, and many such molecules are being considered for therapeutic use or as part of natural immune adjuvants to vaccination. These molecules are however species specific and utilizing human or rodent cytokines in nonhuman primates often leads to erroneous results due to the fact that NHPs will rapidly mount immune responses against the foreign proteins. Thus, the goals of this grant are to continue and to expand the services and reagents provided by this unique resource to investigators using nonhuman primates as preclinical models for human disease and immunotherapy.
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