At the beginning of the 1970s, researchers thought that macrophages might help initiate the immune response, but the underlying mechanisms were obscure. Macrophages might process antigens, according to various theories, by producing immunogenic RNA (Askonas and Rhodes, 1965), acting as reservoirs that exocytosed antigen (Cruchaud and Unanue, 1971), altering antigens extracellularly (Shortman and Palmer, 1971), or, perhaps most popular, retaining whole protein antigen on their surface (Unanue et al., 1969).
Ralph Steinman remembers the puzzle surrounding the macrophage's role and how it might process antigens. He and Zanvil Cohn at the Rockefeller University in New York decided that the horseradish peroxidase (HRP) enzyme—newly adapted as part of an assay system for EM (Graham and Karnovsky, 1966)—would serve as both a model antigen and a clear and sensitive endocytic tracer. They reasoned that HRP's journey into the macrophage as an active enzyme would be easy to...
