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To the editor: This year marks the 50th anniversary of thediscovery of ‘inhibitory factor’, which is nowrecognized as interferon1. During the pasthalf-century, a vast body of evidence hasaccumulated that demonstrates the crucialinvolvement of the interferon family invarious phases of host defense, includingantiviral and anticancer immune responses. I salute the two groups that initially identifiedthe inhibitory factor, or interfering reagent,which one of them named interferon. Theirachievements were independent and usedvery different experimental systems with acommon context of viral interference.
Back in 1954, Japanese virologists Yasu-ichi Nagano and Yasuhiko Kojima of the Institute for Infectious Disease (now the Institute of Medical Science) at theUniversity of Tokyo published a report2 inFrench that described an inhibitory factorderived from tissue suspensions of vacciniavirus–infected rabbit skin or testis. At thattime Nagano and Kojima were studyingvaccination with vaccinia virus inactivatedby ultraviolet irradiation. They noticed thata few hours after intradermal inoculation ofrabbits with the inactivated virus, the rabbitskin showed resistance to a challenge at thesame site with live vaccinia virus. They
hypothesized that the quick inhibition ofvirus multiplication must be due to thepresence of some “facteur inhibiteur”2
(inhibitory factor). That 1954 paperdemonstrated that the activity could be separated from the virus particlessedimented by ultracentrifugation and wasfound in the supernatant. The authors,however, were not able to reconcile theantivirus activity shown in the rabbit skin experiments with the fact thatintraperitoneal injection of mice with the supernatant elicited the production of virus-neutralizing antibodies. Thisambiguity was later ascribed to the presenceof small amounts of virus remaining in thesupernatant after centrifugation. Indeed, by1958 Nagano and Kojima had accumulatedevidence, with thrice-centrifugedsupernatant, that the inhibitory factor wasdistinct from both virus particles andimmune serum against virus3. The featuresof the inhibitory factor coincided with whatis now classified as type I interferon.
Another landmark paper4, by Scottishvirologist Alick Isaacs and Swiss researcherJean Lindenmann, working at the NationalInstitute for Medical Research of the MedicalResearch Council, was published in 1957 andnamed ‘interferon’ as the interfering reagent
in the study of viral interference of influenzavirus. Isaacs and Lindenmann found thatheat-inactivated influenza virus, when added to chick chorioallantoic membranefragments, could induce the formation of an‘interfering’ reagent that inhibited growth of live influenza virus when added to freshmembranes. This interfering reagent is nowalso classified as type I interferon.
Those initial investigations into the natureof host responses to viruses have grown into an enormous literature on interferons.It is a credit to the insight of the originalinvestigators that a term coined 50 years ago is still in use today and that the field ofinquiry they started remains a burgeoningand active area of research.
Yoshihiko Watanabe
Department of Molecular Microbiology,Graduate School of Pharmaceutical Sciences,Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.e-mail: [email protected]
1. Nathan, C. & Sporn, M. J. Cell Biol. 113, 981–986(1991).
2. Nagano, Y. & Kojima, Y. C. R. Seances Soc. Biol. Fil.148, 1700–1702 (1954).
3. Nagano, Y. & Kojima, Y. C. R. Seances Soc. Biol. Fil.152, 1627–1629 (1958).
4. Isaacs, A. & Lindenmann, J. Proc. Roy. Soc. Lond. BBiol. Sci. 147, 258–267 (1957).
Fifty years of interference
NATURE IMMUNOLOGY VOLUME 5 NUMBER 12 DECEMBER 2004 1193
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