Project Summary Chlamydia trachomatis (Ct) is the most common bacterial sexually transmitted infection worldwide, and public health measures including test-and-treat strategies have been ineffective at curbing incidence and prevalence. As a consequence, Ct pelvic inflammatory disease and sequelae of ectopic pregnancies and infertility continue to be important medical issues. Currently there is no therapy that prevents PID-associated infertility. The central hypotheses of the grant based on Chlamydia muridarum (Cm) mouse model data is that selective TNFR2 blockade will prevent chlamydia PID associated immunopathology and infertility. Enabling this investigation are a humanized inhibitory anti-human TNFR2 monoclonal antibody developed by the Johnson lab and a new humanized TNFα/TNFR1/TNFR2 (hTNF) mouse model developed by Biocytogen. Aim #1: To establish a hTNF mouse breeding colony and compare Cm bacterial shedding and immunopathology scores in hTNF mice with wild type C57BL/6 mice bred in the same facility. Aim #2: Use gene synthesis technology to rapidly generate subclass variants of the successfully humanized rat anti-human TNFR2 26C09 monoclonal antibody to investigate their inhibitory activity in human PBMC activation assays and determine efficacy of mouse equivalents for preventing immunopathology in the Cm-hTNF mouse model.