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Most of the C5a functional effects occur through C5aR, and the pharmaceutical industry has focused on this receptor for the development of new anti\u2010inflammatory therapies. We used a novel approach to generate and test therapeutics that target C5aR. We created human C5aR knock\u2010in mice, and used neutrophils from these to immunize wild\u2010type mice. This yielded high\u2010affinity blocking mAbs to human C5aR. We tested these anti\u2010human C5aR mAbs in mouse models of inflammation, using the human C5aR knock\u2010in mice. These antibodies completely prevented disease onset and were also able to reverse established disease in the K\/B \u00d7 N arthritis model. The physiological role of the other C5a receptor, C5L2 is still unclear, and our studies with blocking mAbs to human C5L2 have failed to demonstrate a clear functional role in signaling to C5a. 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