Editor's note: Citation Classics Commentaries were written by the authors of some of the studies that were the most highly cited papers between 1961 and 1975. The essays were originally published between 1977 and 1993 in Current Contents, a publication of the Institute for Scientific Information (ISI), now Thomson Scientific. (ISI was founded by Eugene Garfield, also the founder of The Scientist.)
In this essay, published in 1980, Nathan Kaliss describes the experiments that opened the door to developing immunosuppressants for organ transplant and cancer immunotherapy. Kaliss described the phenomenon of "immunological enhancement" in 1952, reporting that mice simultaneously treated with a steroid and foreign tumor cells were immunized to their own tumor cells. That work laid the foundation for research on using antibodies to target tumors in animal models of cancer. His review on the subject, published in 1958, has been cited nearly 500...
I came to the Jackson Laboratory in July 1947 as a senior fellow of the American Cancer Society. My introduction to "enhancement" was a seminar that summer by George Sneil describing attempts to preimmunize mice with homologous freeze-dried tumor against subsequent tumor allografts. Paradoxically, some of the grafts, rather than experiencing accelerated rejection, grew progressively. This was intriguing since cancers were involved, and the immediate question was whether a "cancer stimulating substance" was the effector. I addressed myself to this but my research was interrupted by the Laboratory's destruction in an October 1947 forest fire.
With work resumed in the rebuilt laboratory, I found that pretreatment with freeze-dried normal tissues, specifically and necessarily from mice of strains indigenous to the test allografts, resulted in progressive graft growth. These results militated against the assumption of an "enhancing substance." My subsequent use of antiserum was suggested by literature reports of accelerated wound healing in rabbits receiving anti-rabbit spleen serum (Quart Phi Beta Pi, 42:203, 1946). My treatment of prospective hosts with either rabbit anti-mouse or mouse anti-mouse tissue serum did ensure the tumor allografts' survival.
The experiments that eventually established an immunological basis for enhancement, and related "active" and "passive" enhancement, were sparked by a report of intraperitoneal (ip) metastases appearing in mice given freeze-dried tumor and cortisone ip and a subcutaneous inoculum of live tumor (PNAS, 38:991—5, 1952). (I could not confirm these results experimentally and concluded that live cells in inadequately freeze-dried tumor were the progenitors of the ip "metastases.")
Cortisone treatment involutes lymphoid tissues and inhibits antibody production, and this was the tool I used to demonstrate that antigraft antiserum in the host, actively or passively acquired, was the requisite for tumor allograft survival (hence the term "immunological enhancement"). Indeed, subcutaneous allografts were rejected by mice pretreated simultaneously with a supernatant of freeze-dried homologous tumor and cortisone. The grafts survived in animals given supernatant alone or (and this was the decisive result) pretreated with supernatant and cortisone and in addition given antigraft alloantiserum at the time of tumor grafting. The grafts also grew progressively in mice given alloantiserum plus cortisone or antiserum alone.
Immunological enhancement, whose expression involves fundamental immunological interactions still to be elucidated, is a definitive area of concern in immunobiology and tissue transplantation. The broad outlines of its experimental conditions for cancer allografts were detailed in my 1958 review, thus accounting for its frequent citation. Clinically, enhancement should promise the survival of normal grafts, seemingly the case with human kidney grafts, but it poses a hazard in cancer immunotherapy. As the complexities of immunology are unraveled, however, the hope is to be able to manipulate reactions so as to avoid cancer enhancement and facilitate normal allograft survival.
Nathan Kaliss, The Jackson Laboratory, Bar Harbor, Maine, May 6, 1980