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A18 – How learning shapes immunity

Martin Hadamitzky, Manfred Schedlowski

Based on our established taste-immune paradigm in rats employing the immunosuppressive drug cyclosporine A (CsA), we will investigate extinction and reconsolidation of behavioral conditioned immune responses of immunomodulating compounds with distinct cell signaling pathways (rapamycin, methotrexate), Moreover, we will employ DREADDs to analyze the role of brain structures steering these learning processes, and will analyze the potential clinical relevance of learned immunomodulation employing a tumor model as well as a model of chronic inflammatory autoimmune disease.

Guiding questions of A18:

  • Are learned immune responses restricted to calcineurin inhibitors such as CsA or does conditioning with other immunomodulating drugs and distinct cell signaling pathways such as RAPA or MTX operate under similar mechanisms?
  • Which brain areas mediate learning and extinction processes of conditioned immunopharmacological effects?
  • Can extinction of the learned immunopharmacological effects of RAPA and MTX be inhibited by administering sub- or low-therapeutic drug doses during retrieval as reminder cues concomitantly with the CS?
  • Are behaviorally conditioned anti-proliferative (RAPA) and anti-metabolic effects (MTX) of clinical relevance by interfering with disease progression in animal models of tumor growth and inflammatory autoimmune diseases?
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Martin Hadamitzky

Projektleiter A18

Universität Duisburg-Essen

Manfred Schedlowski

Projektleiter A18

Universität Duisburg-Essen

Laura Heiß-Lueckemann

Postdoc A18

Universität Duisburg-Essen

Marie Jakobs

Doktorandin A18

Universität Duisburg-Essen

Julia Bihorac

Doktorandin A18

Universität Duisburg-Essen

10 project-relevant publications

Bihorac J, Salem Y, Lückemann L, Schedlowski M, Doenlen R, Engler H, Mark MD, Dombrowski K, Spoida K, Hadamitzky M (2024) Investigations on the Ability of the Insular Cortex to Process Peripheral Immunosuppression. J Neuroimmune Pharmacol 19:40. https://doi.org/10.1007/s11481-024-10143-9 

Hadamitzky M, Bosche K, Wirth T, Buck B, Beetz O, Christians U, Schniedewind B, Luckemann L, Güntürkün O, Engler H, Schedlowski M (2016) Memory-updating abrogates extinction of learned immunosuppression. Brain Behav Immun 52:40-48. https://doi.org/10.1016/j.bbi.2015.09.009

Hadamitzky M, Lückemann L, Pacheco-López G, Schedlowski M (2020) Pavlovian Conditioning of Immunological and Neuroendocrine Functions. Physiol Rev. 100:357-405. https://doi.org/10.1152/physrev.00033.2018 

Hadamitzky M, Schedlowski M (2022) Harnessing associative learning paradigms to optimize drug treatment. Trends Pharmacol Sci. 43:464-472. https://doi.org/10.1016/j.tips.2022.03.002 

Hetze S, Barthel L, Lückemann L, Günther HS, Wülfing C, Salem Y, Jakobs M, Hörbelt T, Bendix I, Sure U, Petschulat J, Schedlowski M, Hadamitzky M (2022). Taste-immune associative learning amplifies immunopharmacological effects and attenuates disease progression in a rat glioblastoma model. Brain Behav Immun. 106:270-279. https://doi.org/10.1016/j.bbi.2022.09.006 

Jakobs M, Hörbelt-Grünheidt T, Hadamitzky M, Julia Bihorac, Salem Y, Leisengang S, Christians U, Schniedewind B, Schedlowksi M, Hadamitzky M, Lückemann L (2024b). The effects of fingolimod (FTY720) on leukocyte subset circulation cannot be behaviorally conditioned in rats. J Neuroimmune Pharm. 19:18. https://doi.org/10.1007/s11481-024-10122-0 

Lückemann L, Hetze S, Hörbelt T, Schedlowski M, Hadamitzky M (2021) Incomplete reminder cues trigger memory reconsolidation and sustain learned immune responses. Brain Behav Immun. 95:115-121. https://doi.org/10.1016/j.bbi.2021.03.001 

Lückemann L, Stangl H, Straub RH, Schedlowski M, Hadamitzky M (2020) Learned immunosuppressive placebo response attenuates disease progression in a rodent model of rheumatoid arthritis. Arthritis Rheumatol. 72:588-597. https://doi.org/10.1002/art.41101 

Lückemann L, Unteroberdörster M, Martínez-Gómez EM, Schedlowski M, Hadamitzky M (2019) Behavioral Conditioning of Anti-Proliferative and Immunosuppressive Properties of the mTOR Inhibitor Rapamycin. Brain Behav Immun. 79:326-331. https://doi.org/10.1016/j.bbi.2019.04.013

Schwarting RKW, Wöhr M, Engler H, Sungur A, Schedlowski M (2024) Behaviorally conditioned effects of psychoactive drugs in experimental animals: What we have learned from nearly a century of research and what remains to be learned. Neurosci Biobehav Rev 162:105721. https://doi.org/10.1016/j.neubiorev.2024.105721