Core B, the Antibody / Ig Fusion Core, provides an important means by which the PPG will achieve its goals of understanding the immune response in tolerance, autoimmunity and infection. Core B will coordinate the use of mAb and Ig fusion proteins to enable the study of the roles of the PD-1 and other coinhibitory pathways in regulating immune responses during acute and chronic infection, chronic graft versus host disease (cGVHD), and autoimmunity. To achieve these goals Core B has the following aims:
Aim 1 : To maintain and produce existing and newly generated mAbs and Ig fusion proteins for PPG investigators. An extensive set of mAbs and fusion proteins against coinhibitory molecules has been generated in previous cycles of this PPG and these will continue to be produced as well as characterized for additional activities and uses.
Aim 2 : To generate novel monoclonal antibodies and Ig fusion proteins to study the function and expression of coinhibitory receptors and ligands. CD112R and CD101 are newly identified co-inhibitory molecules that impact T cell exhaustion and the PD-1 pathway. Core B will generate novel antibodies that will facilitate analysis of the function and expression of coinhibitory molecules particularly CD112R, CD101 and PD-1/PD-L pathway members as well as other coinhibitory pathways. These include novel mouse anti-mouse antibodies made in knockout mice that see novel epitopes and facilitate long-term treatment of mice without anti-antibody responses. These novel mouse anti-mouse mAbs will also be made as recombinant mAbs with mutated Fc to eliminate effects due to cell depletion or FcR signaling. This best models PD-1 mAbs used in clinical trials. Tyrosine phosphorylation of the PD-1 cytoplasmic domain mediates PD-1 biological activity. Core B will make phospho PD-1 ITIM mAbs and together with our phospho PD-1 ITSM mAb, use these to monitor PD-1 signaling and understand the roles of the PD-1 ITSM and ITIM motifs in regulating different T cell subsets in different disease states. The production of these critical reagents by a core not only will be time and cost efficient, but also provide standardized reagents that will facilitate comparison of data by investigators in this PPG. Core B will work closely with all PPG investigators, providing mAbs and Ig fusion proteins and identifying new needs. These reagents will allow PPG investigators to develop a comprehensive understanding of the roles of positive and negative second signals in modulating T cell activation, tolerance and exhaustion.
Core B will make antibodies and Ig fusion proteins for use by Program investigators in experimental models of infection, autoimmunity, cancer and transplantation. These antibodies and Ig fusion proteins will be useful tools for identifying mechanisms that regulate immune responses, and guiding translation to new therapies for human diseases. .
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