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 NHP models increasingly include the use of recombinant cytokines, chemokines or immunomodulatory receptors in vivo. The close evolutionary relationship between human and NHPs provide adequate cross reactivity between human recombinant factors with NHP cells, albeit differences in affinity/bioactivity have been noted. However, most, if not all NHP determinants are not identical to human factors, often leading to a more or less rapid development of neutralizing antibody responses to the xenogeneic factor in vivo, potentially leading to data that are difficult to interpret. The practical consequence of this issue is the restriction of the use of such factors to single or short-term treatment whereas most such """"""""natural"""""""" immunomodulators work optimally only when administered in low but repeated doses. Clearly, availability of well-characterized and standardized purified NHP specific recombinant factors would alleviate this serious caveat. Among NIH investigators, a """"""""CRISP"""""""" search identified >30 proposals that would directly benefit from such reagents. Letters of support from 25 investigators are supplied with this application. In this application, it is proposed to develop a resource for providing NHP cytokines/chemokines/soluble co-stimulatory factors, DNA constructs capable of expressing such factors and explore strategies for improving the pharmacokinetics and biological effects of such reagents in vivo. The applicants submit that this resource will greatly enhance the validity of studies using such factors in a variety of NHP models of human disease, including but not restricted to candidate vaccines against infectious disease. Specifically, the applicant will establish a resource for: 1) Preparation, testing and distribution of nonhuman recombinant cytokines/chemokines and soluble factors. 2) Construction and testing of optimized plasmid based constructs for the expression of NHP cytokines/chemokines and immunomodulatory factors. 3) Development and testing of """"""""primatized"""""""" NHP cytokine/chemokines and immunomodulatory factors with extended half-life and biological activity in vivo.
Showing the most recent 10 out of 16 publications
