Viewpoint On:

Ader R. Letter: Behaviorially conditioned immunosuppression. Psychosom Med. 1974;36:183-184

Ader R, Cohen N. Behaviorally conditioned immunosuppression. Psychosom Med. 1975;37:333-340

Robert “Bob” Ader was born in 1932 in the Bronx, New York City. He graduated from the Horace Mann School, a remarkable place of famous alumni (1). In 1953, he finished a bachelor’s degree in psychology from Tulane University in New Orleans. He earned the Ph.D. in psychology from Cornell University in 1957. After moving to Rochester, state of New York, Robert Ader spent his entire career at the University of Rochester. He was director of the Division of Behavioral and Psychosocial Medicine in the University of Rochester’s department of psychology and director of the Center for Psychoneuroimmunology Research. He died in December 2011 in the age of 79.

His partner Nicolas Cohen was born in 1938. He received his bachelor in biology from Princeton University in 1959 and his Ph.D. from the University of Rochester, N.Y., in 1966. Between 1965 and 1967, as a postdoctoral scholar, he trained in microbiology and immunology at the University of California in Los Angeles. He joined the University of Rochester, N.Y., Department of Microbiology and Immunology in 1967. He took a sabbatical at the Basel Institute for Immunology, Basel, Switzerland in 1975-76. He was Director of the Division of Immunology (1979-2004). He retired in 2004.

The Idea of Ader and Cohen

While Metalnikov and Chorine in the late 1920s demonstrated conditioned immunoactivation (2), Ader and Cohen focused on immunosuppression. The first important paper of the two authors appeared in 1975 (3). In this paper, they described that an illness-induced taste aversion was conditioned in rats by pairing saccharin with cyclophosphamide, an immunosuppressive agent. To induce a clearly defined immunological readout, they injected sheep red blood cells into the animals that induced hemagglutinating antibodies measured 6 days after antigen administration. High titers were observed in placebo-treated rats, in non-conditioned animals and in conditioned animals that were not subsequently exposed to saccharin. No agglutinating antibody was detected in conditioned animals treated with cyclophosphamide at the time of antigen administration (positive control to show immunosuppression through the agent). Conditioned animals exposed to saccharin at the time of or following the injection of antigen were significantly immunosuppressed (the important conditioned group). For the first time, these data showed strong inhibition of the immune system through Pavlovian conditioning. It complemented the work of Metalnikov and Chorine form the late 1920s (the anti-Metalnikov effect). This work was replicated one year later (4). Important studies of Ader and Cohen followed (5, 6).

In a review paper, Ader wrote (7) “This study (3) demonstrated that, like other physiological processes, the immune system was subject to classical (Pavlovian) conditioning, providing dramatic evidence of an inextricable relationship between the brain and the immune system.”

In one form or the other, immune conditioning stood the test of time (8), and some of the experiments have also been published in Neuroimmunomodulation (9-15).

References

1. https://en.wikipedia.org/wiki/List_of_Horace_Mann_School_alumni
2. Metalnikov S, Chorine V. Role des reflexes conditionnels dans l’immunite. Ann Inst Pasteur (Paris) 1926;40:893–900 [we reported on Metalnikov / Chorine in a special Pillar Article]
3. Ader R, Cohen N. Behaviorally conditioned immunosuppression. Psychosom Med. 1975;37:333-340
4. Rogers MP, Reich P, Strom TB, Carpenter CB. Behaviorally conditioned immunosuppression: replication of a recent study. Psychosom Med. 1976;38:447-451
5. Bovbjerg D, Ader R, Cohen N. Behaviorally conditioned suppression of a graft-versus-host response. Proc Natl Acad Sci U S A. 1982;79:583-585
6. Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science. 1982;215:1534-1536
7. Ader R. Historical perspectives on psychoneuroimmunology. In: Friedman TW, Klein AL, Friedman AL (Eds.) Psychoneuroimmunology, stress and infection. CRC Press, Boca Raton, 1995, pp. 1-21.
8. Hadamitzky M, Lückemann L, Pacheco-López G, Schedlowski M.: Pavlovian Conditioning of Immunological and Neuroendocrine Functions. Physiol Rev. 2020;100:357-405
9. Bauer D, Busch M, Pacheco-López G, Kasper M, Wildschütz L, Walscheid K, Bähler H, Schröder M, Thanos S, Schedlowski M, Heiligenhaus A.: Behavioral conditioning of immune responses with cyclosporine a in a murine model of experimental autoimmune uveitis. Neuroimmunomodulation. 2017;24:87-99
10. Vidal J, Chamizo VD.: The conditioned stimulus elicits taste aversion but not sickness behavior in conditioned mice. Neuroimmunomodulation. 2010;17:325-32
11. Pacheco-López G, Niemi MB, Kou W, Baum S, Hoffman M, Altenburger P, del Rey A, Besedovsky HO, Schedlowski M.: Central blockade of IL-1 does not impair taste-LPS associative learning. Neuroimmunomodulation. 2007;14:150-156
12. Haour F.: Mechanisms of the placebo effect and of conditioning. Neuroimmunomodulation. 2005;12:195-200
13. Mei L, Li L, Li Y, Deng Y, Sun C, Ding G, Fan S.: Conditioned immunosuppressive effect of cyclophosphamide on delayed-type hypersensitivity response and a preliminary analysis of its mechanism. Neuroimmunomodulation. 2000;8:45-50
14. Exton MS, von Hörsten S, Strubel T, Donath S, Schedlowski M, Westermann J.: Conditioned alterations of specific blood leukocyte subsets are reconditionable. Neuroimmunomodulation. 2000;7:106-14
15. Rogers CF, Ghanta VK, Demissie S, Hiramoto N, Hiramoto RN.: Lidocaine interrupts the conditioned natural killer cell response by interfering with the conditioned stimulus. Neuroimmunomodulation. 1994;1:278-83

(Featured image declaration: by Alan O’Rourke from flickr.com)