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Szentvanyi A. The beta-adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 1968;42:203-232

Benner MH, Enta T, Lockey Jr S, Makino S, Reed CE. The immunosuppressive effect of epinephrine and the adjuvant effect of beta-adrenergic blockade. J Allergy 1968;41:110-111 (Abstract – never published in paper form)

Smith JW, Steiner AL, Newberry Jr. WM, Parker CW. Cyclic nucleotide inhibition of lymphocyte transformation. Clin. Res. 1969;17:549 (Abstract – later published in J Clin Invest. 1971;50:432-441)

May CD. Effects of compounds which inhibit lymphocyte stimulation on the utilization of glucose by leukocytes. J Allergy 1970;46:21-28

Hadden JW, Hadden EM, Middleton E Jr. Lymphocyte blast transformation. I. Demonstration of adrenergic receptors in human peripheral lymphocytes. Cell Immunol. 1970;1:583-595

For this 7^th Pillar Article Series, the editor found it extremely difficult to just mention one single author or a single author group that started “adrenergic modulation of leukocytes”. Therefore, the presentation differs from the usual report.

Andras Szentvanyi is credited for his insight into beta-adrenergic mechanisms in asthma where he clearly mentioned the beta-adrenergic effect on cell proliferation (1). This publication was seen as a theoretical starter although the author already had long-standing experiences on adrenergic effects in asthma. In this publication, Szentvanyi wisely summarized the effect on mitosis of adrenergically-induced intracellular glucose changes, which was studied early in non-immune cells such as fibroblasts (2). Two important abstracts given on research conferences showed inhibitory effects of adrenaline and cyclic adenosine monophosphate (cAMP) on leukocyte proliferation (3, 4). Glucose utilization was again an important aspect for lymphocyte proliferation, and cAMP was inhibitory in experiments with phytohemagglutinin-stimulated cells (5).

With this information present, it was John W. Hadden (23. Oct. 1939 – 1. April 2013) and colleagues in 1970 who showed very clear effects of adrenergic compounds on phytohemagglutinin-stimulated leukocyte proliferation (6). He observed inhibitory effects through β-adrenergic pathways (think of the cAMP effects from above because that is the canonic signaling pathway) and mainly stimulatory effects through α‑adrenergic pathways (inhibition of cAMP). The studies were carried out with tritiated thymidine incorporation into peripheral blood leukocyte cells of healthy donors.

The groups around Charles W. Parker (St. Louis, USA), Charles E. Reed (Wisconsin, USA) and Charles D. May (New York, USA) lost more and more contact to adrenergic immunomodulation. They were strong allergologists, and this field moved on to more immunological and therapeutic aspects of allergy. In contrast, John W. Hadden remained faithful to neuroimmunomodulation for one more decade before he moved to drugs and biologicals for immunotherapy. In 1993, he formed a biotech company that focused on immunotherapy of cancer and infection. He and Andras Szentvanyi edited the first and second volume of Immunopharmacology Reviews in 1990 and 1996, respectively.

The journal Neuroimmunomodulation published more than 80 papers related to the link between catecholamines and immunomodulation, some of which are given in the reference list (7-11).

References

1. Szentvanyi A. The beta-adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 1968;42:203-232
2. Lettré H, Albrecht M. Zur Wirkung von β-Phenyläthylaminen auf in vitro gezüchtete Zellen. Hoppe-Seylers Zeitschrift f. physiol. Chemie (now: Biological Chemistry) 1941;271:200-207
3. Benner MH, Enta T, Lockey Jr S, Makino S, Reed CE. The immunosuppressive effect of epinephrine and the adjuvant effect of beta-adrenergic blockade. J Allergy 1968;41:1110-111 (Abstract)
4. Smith JW, Steiner AL, Newberry Jr. WM, Parker CW. Cyclic nucleotide inhibition of lymphocyte transformation. Clin. Res. 1969;17:549 (Abstract)
5. May CD. Effects of compounds which inhibit lymphocyte stimulation on the utilization of glucose by leukocytes. J Allergy 1970;46:21-28
6. Hadden JW, Hadden EM, Middleton E Jr. Lymphocyte blast transformation. I. Demonstration of adrenergic receptors in human peripheral lymphocytes. Cell Immunol. 1970;1:583-595
7. Genaro AM, Cremaschi GA, Gorelik G, Sterin-Borda L, Borda ES. Downregulation of beta adrenergic receptor expression on B cells by activation of early signals in alloantigen-induced immune response. 2000;8:114-21
8. Page GG, Ben-Eliyahu S. Natural killer cell activity and resistance to tumor metastasis in prepubescent rats: deficient baselines, but invulnerability to stress and beta-adrenergic stimulation. 2000;7:160-168
9. Oberbeck R, Schmitz D, Wilsenack K, Schüler M, Pehle B, Schedlowski M, Exton MS. Adrenergic modulation of survival and cellular immune functions during polymicrobial sepsis. 2004;11:214-223
10. Kitamura H, Shiva D, Woods JA, Yano H. Beta-adrenergic receptor blockade attenuates the exercise-induced suppression of TNF-alpha in response to lipopolysaccharide in rats. 2007;14:91-96
11. Straub RH, Dufner B, Rauch L. Proinflammatory α-Adrenergic Neuronal Regulation of Splenic IFN-γ, IL-6, and TGF-β of Mice from Day 15 onwards in Arthritis. Neuroimmunomodulation. 2020;27:58-68