The 2 nd International Congress of

1. The 2nd International Congress of International Prof. Dr. Alireza Yalda Academic Foundation in Medical Sciences 24-27 October 2011, Tehran, Iran The influence of psyche on the immune system , President, Institute of Interventional Allergology and Immunology, Cologne / Bonn, Germany Prof. Alireza Ranjbar, MD,PhD

2. In recent years one of the most rapidly advancing areas in medicine has been immunology and its interactions with various psychological states. • Considerable data indicate that psychological disorders may increase an organism's vulnerability to certain diseases by means of exerting an immunosuppressive effect, especially those diseases intimately associated with immunologic mechanisms, such as infection, malignancy, and autoimmune diseases. • Significant evidence suggests that the immune system is capable of profoundly affecting central nervous system (CNS).

3. Charles L. Raison, et al., Atlanta, USA, 2005 • Depression has been linked to a worse outcome in multiple medical disorders • Increasing amounts of data suggest that inflammatory responses have an important role in the pathophysiology of depression. • Depressed patients have higher levels of • - proinflammatory cytokines, • - acute phase proteins, • chemokines and • cellular adhesion molecules. Inflammation and the pathogenesis of depression

4. Charles L. Raison, et al., Atlanta, USA, 2005 Inflammation and the pathogenesis of depression • Proinflammatory cytokines interact with • - neurotransmitter metabolism, • - neuroendocrine function, • synaptic plasticity and • behavior • that characterize depression.

5. Charles L. Raison, et al., Atlanta, USA, 2005 Inflammation and the pathogenesis of depression Stress, which can precipitate depression, can also promote inflammatory responses through effects on sympathetic and parasympathetic nervous system pathways. Depression might be a behavioralby product of early adaptive advantages conferred by genes that promote inflammation. These findings suggest that targeting proinflammatory cytokines and their signaling pathways might represent a novel strategy to treat depression.

6. Psyche , CNS and Immune System Experimental and clinical trials

7. The influence of CNS on Immune System Experimental studies

8. In animal trials by directly stimulating the brain, different investigators have produced alterations in the immune response.

9. Lesions in the dorsal hypothalamus of rabbits have been shown to suppress both humoral and cellular immunity. (Korneva EA, Khai LM, Fiziol Zh SSSR, 49:42-48, 1963) • Mesencephalic stimulation and electrical stimulation of the lateral hypothalamus in rats enhance antibody responses. (Korneva EA, Khai LM, Fiziol Zh SSSR,53:42-47, 1967 ) • Bilateral anterior hypothalamic lesions in guinea pigs protect against lethal anaphylaxis (Freedman DX, Fenichel G, Arch Neurol Psychiatr, 79:164-169, 1958; Szentivanyi A, Filipp G Ann Allergy 16:143-151, 1958 ; Luparello TJ, Stein M, Park DC:, Am J Physiol. 207:911-914, 1964 )

10. The influence of Immune System on CNS Experimental studies

11. Corticotropin-releasing factor (CRF) and vasopressin (VP) mRNA levels in adult rats after Injection with IL-1ß

12. Indomethacin reduces ACTH response to iv. IL-1ß

13. ACTH secretion in rats by IL-1ß Injection with and without anti-CRF treatment

14. Time course of the neurochemical Response to IL-1ß in mice

15. Human studies Clinical trials

16. Human studies Example 1 Stress and Immune System

17. In a human study, bereavement was found to be associated with depressed lymphocyte function. In this study there was a 10-fold difference in T-cell function at 5 weeks between the 26 bereaved spouses and the controls.

18. Human studies Example 2 Depression and Cancer

19. Depressive Symptoms and Prospective Incidence of Colorectal Cancer in Women C. H. Kroenke, G. BennettAmerican Journal of Epidemiology 2005 162(9):839-848 • The authors examined depressive symptoms and prospective • incidenceof colorectal cancer and distal colorectal adenomas in • 81,612women without prior cancer from the Nurses' Health • Study • 400cases of colorectal cancer and 680 distal colorectal • adenomasaccrued between 1992 and the year 2000. • Depressive symptomswere assessed in 1992 and 1996 with the • five-question MentalHealth Index (MHI-5), a subscale of the • Short-Form 36 healthstatus survey.

20. Depressive Symptoms and Prospective Incidence of Colorectal Cancer in Women C. H. Kroenke, G. BennettAmerican Journal of Epidemiology 2005 162(9):839-848 Scores ranged from 0 to 100, and women with scoresbetween 0 and 52 were defined as having significant depressivesymptomatology. The authors also created four categories acrossthe range of Mental Health Index scores: 0–52, 53–75,76–85, and 86–100 (referent).

21. Depressive Symptoms and Prospective Incidence of Colorectal Cancer in Women C. H. Kroenke, G. BennettAmerican Journal of Epidemiology 2005 162(9):839-848 Results: Womenwith the highest levels of depressive symptoms had an elevatedrisk of incident colorectal cancer (hazard ratio = 1.43, 95%confidence interval: 0.97, 2.11) compared with women with thelowest levels of symptoms (ptrend = 0.04). Associations appearedstronger in overweight women. However, depressive symptoms wereunrelated to risk of colorectal adenomas. Associations are consistentwith a possible role in late promotion of the disease.

22. Human studies Example 3 Stress and Autoimmune Disease

23. Rheumatoid arthritis and depression The role of pro-inflammatory cytokine-induced SAPK/MAPK and JAK/STAT Malemud CJ, Miller AH,Ohio 44106-5076, USA Expert Opin Ther Targets. 2008 Feb;12(2):171-83 • Adult rheumatoid arthritis (RA) patients are frequently clinically • depressed • Peripheral inflammation in RA may influence • neurotransmitter metabolism, • neuroendocrine function, • synaptic plasticity, as well as • growth factor production, • which can modify neural circuitry and contribute to depression.

24. Rheumatoid arthritis and depression The role of pro-inflammatory cytokine-induced SAPK/MAPK and JAK/STAT Malemud CJ, Miller AH,Ohio 44106-5076, USA Expert Opin Ther Targets. 2008 Feb;12(2):171-83 A convergence between pro-inflammatory cytokine-induced synovial joint inflammation in RA and the effects of pro-inflammatory cytokines on the brain may occur through activation of the stress-activated/mitogen-activated protein kinases (SAPK/MAPK) and/or Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways.

25. Rheumatoid arthritis and depression The role of pro-inflammatory cytokine-induced SAPK/MAPK and JAK/STAT Malemud CJ, Miller AH, Ohio 44106-5076, USA Expert Opin Ther Targets. 2008 Feb;12(2):171-83 Some novel anti-depression drugs that were employed in animal models of 'sickness behavior' and in human depression clinical trials suppressed clinical markers of inflammation, as well as SAPK/MAPK and/or JAK/STAT signaling in vitro. Modifying pro-inflammatory cytokine signaling pathways in the brain with antidepressants may also be useful in ameliorating peripheral inflammation in RA

26. Human studies Example 4 Depression and Infectious Disease

27. Charles L. Raisona, Sherry D. Broadwella, Andrey S. Borisova, et al., USA, 2004 Interferon (IFN)-α plus ribavirin is an effective treatment for hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Therapeutic administration of the cytokine interferon-α leads to depression in up to 50% of patients. Depression has been linked to a worse outcome in multiple medical disorders including viral illnesses. The authors examined whether increased symptoms of depression during IFN-α/ribavirin therapy were associated with a reduced treatment response as assessed by clearance of HCV. Depressive symptoms and viral clearance in patients receiving interferon-α and ribavirin for hepatitis C

28. Charles L. Raisona, Sherry D. Broadwella, Andrey S. Borisova, et al., USA, 2004 Depressive symptoms and viral clearance in patients receiving interferon-α and ribavirin for hepatitis C Methods: Depressive symptoms were evaluated in 102 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of pegylated IFN-α-2b plus ribavirin therapy using the Zung self-rating depression scale (SDS). Viral clearance was determined at 24 weeks by polymerase chain reaction (PCR).

29. Charles L. Raisona, Sherry D. Broadwella, Andrey S. Borisova, et al., USA, 2004 • Results: • 34% of subjects (10 out of 29) with a 20-point or greater • increase in SDS Index score were HCV PCR negative at 24 • weeks, • 59% (24 out of 41) of patients with a 10–19 point increase in • SDS Index and • 69% (22 out of 32) of patients with a less than 10 point increase • (χ2=7.6, df=2, p<0.05). Depressive symptoms and viral clearance in patients receiving interferon-α and ribavirin for hepatitis C

30. Charles L. Raisona, Sherry D. Broadwella, Andrey S. Borisova, et al., USA, 2004 • Results: • In addition, a 20-point or greater increase in SDS Index score • during IFN-α/ribavirin therapy significantly predicted failure to • clear virus when considered alone [crude odds ratio (OR), 3.2; • 95% confidence interval (CI), 1.3–8.0; p<0.01] or when • controlling for other factors that affected IFN-α treatment • response (adjusted OR, 3.6; 95% CI, 1.3–9.5; p=0.01). • These findings suggest that individuals who experience • significant increases in depressive symptoms during IFN-α/ • ribavirin therapy may be less likely to clear virus, highlighting • the importance of identifying and treating depressive • symptoms in this patient population. Depressive symptoms and viral clearance in patients receiving interferon-α and ribavirin for hepatitis C

31. Human studies Example 5 Stress and Infectious Disease

32. Immune system, stress and Herpes infection

39. Summary There is a bidirectional relationship between the CNS / psychological states and the immune system. Mental factors such as stress and depression have been shown to affect immune system functioning. Stress and depression are associated with worse outcomes in immune-related disorders including cancer , autoimmune disorders and infectious diseases.

40. Summary Conversely, immune system activation such as during infectious diseases, cancer, and autoimmune disorders is associated with the development of behavioral symptoms similar to those seen in the context of chronic stress or major depression. These findings implicate a role for the immune system in the cause of behavioral disorders in a wide range of medical illnesses. Finally, a paradigm is proposed in which abnormal functioning of either the hypothalamic-pituitary-adrenal (HPA) axis or the inflammatory response system disrupts feedback regulation of both neuroendocrine and immune systems contributing to the development of neuropsychiatric and immunologic disorders.

41. Positive Psychotherapy – A novel approach in Social Psychotherapy with a Transcultural Perspective discoverd by Prof. Dr. Nossrat Peseschkian by the year 1968 in Wiesbaden, Germany

42. 2000 : 1. Peseschkian-Ranjbar-Begegnung als Referenten in einem Kongress in Hamburg

44. Success is

45. Success is

46. Success is ?

47. Success is Teamwork!

48. Thank you for your attention