What’s Missing for Effective Stem Cell Therapies Practical Clinical Approach

1. What’s Missing for Effective Stem Cell Therapies Practical Clinical Approach

2. Dr JanethyBalakrishnanBokström • M.B.B.S (India) • M.Sc. Health Care Mgmt. (Wales) • ABAAM, Board Certified Physician in Anti Aging Medicine (USA) • CBNS, CNS Certified Nutrition Specialist (USA) • AARAM, Master Trainer and Fellowship in Aesthetic Medicine (USA)

3. Other cellular injections • Previously, enthusiastically injecting ovine embryonic cells and placenta extracts intradermally into patients face. • Positive results • Outcome due to cytokines, growth factors or stem cells?? …..vague in transparency of active ingredients • Lack of uniformity in results…… or benefits could have also been caused by the stimulation of the needles?

4. Autologous IV Stem Cell Transplant for total Rejuvenation

5. Back to why Stem cell plasticity theory was hot but now some of us think its clinical application is questionable. Can transdifferentiation be clinically applied? As we could not really figure out clinically, the practical aspect of science on how CD34+ cells can rejuvenate the face and body without a ‘bridge’ for proper homing.

6. Function of Progenitor Cells • The majority of progenitor cells lie dormant or possess little activity in the tissue in which they reside. • They exhibit slow growth and their main role is to replace cells lost by normal attrition. In case of tissue injury, damaged or dead cells, progenitor cells can be activated.

7. Back to Basics • Growth factors or cytokines are two substances which trigger the progenitors to mobilize towards the damaged tissue. At the same time, they start to differentiate into the target cells.

8. Messenger molecules called cytokines • The immune system also can deploy signaling molecules, which are soluble factors that send messages to the immune cells. • These Cytokines direct immune cells to the site of damage (in response to inflammatory) and activate the cells, bringing them in full force to the infected area. • Cytokines act in autocrine or paracrine fashion (hormone-like).

9. Key intercellular regulators and mobilizers • Lymphokines are cytokines and also referred to as immunomodulating agents (interleukin, interferon) which are produced by T cells. • Crucial to innate and adaptive inflammatory responses, cell growth and differentiation, cell death, angiogenesis, and developmental as well as repair processes

10. What is the missing factor? • For better utilization of transplanted stem cells it is more effecctive to prime the body with thymus peptides, hormones and enzymes. • These extracts will also help in maturation of T cells as our thymus involutes as we age. • We also need to re-balance the right cytokines

11. Relevance of T cells • These extracts and their down stream cell products (such as interleukins and interferons) control all phases of maturation, development, antigen commitment, proliferation and cytotoxic activity of the various T cells. • Thymic hormones also stimulate non-specific phagocytic and cytotoxic cells to respond against foreign or “nonself” antigens.

12. Cells of immune system • Lymphocytes or T cells which fight invading molecules directly (cell-mediated) • B cells which form antibodies (humoral) • The immune system also includes the phagocytic cells,such as macrophages and neutrophils, which remove the debris created from destroying cells and tissue at the site of an infection.

13. Subsets of T cells • Helper T cells –CD4+ • Cytotoxic T cells-CD8+ • Memory T cells either CD4+ or CD8+ • Regulatory T cells or Suppressor T cells • Natural Killer T cells

14. Macrophage Cytokines • Interleukin-1 (IL1), macrophage-colony stimulating factor (MCSF) • Interleukin-6 (IL6), granulocyte-colony stimulating factor (GCSF) • Interferon-alpha (INFa), macrophage derived growth factor (MDGF) • Epidermal growth factor (EGF), transforming growth factor-beta (TGFb) • Tumor necrosis factor-alpha (TNFa), platelet derived growth factor (PDGF) • Basic fibroblast growth factor (FGF), heparin-binding growth factor (HBGF) • Granulocyte macrophage-colony stimulating factor (GMCSF

15. Cytokines that stimulate haematopoiesis • Stem Cell Factor; pluripotent stem cell factor • IL-7 ; immature lymphoid progenitors • IL-3; immature progenitors • GM-CSF; immature and committed progenitors, mature macrophages • G-CSF; committed progenitors • M-CSF; committed prgenitors

16. Why up-regulate T cells? With advancing age, human T cells reveal reductions in the proliferative response to activation, in diversity of the T-cell receptor antigen repertoire. Therefore, stem cell therapies can be effective only if cells that are capable of responding are still present in the repertoire.

17. Autoimmune endocrine disorders or autoimmune polyglandular syndromes • Hashimoto’s thyroiditis • Graves’ disease • Autoimmune hypothyroidism • IDDM • Addison’s disease • Autoimmune hypophysitis (pituitary gland insufficiency) • Autoimmune oophritis (ovarian insufficiency) • Testicular insufficiency • Premature ovarian failure These disorders usually damage endocrine glands thereby causing hormone deficiencies

18. Causes of age related degenerative diseases • The immune system of aged humans undergoes alterations that may account for an increased susceptibility to autoimmune diseases(MS, RA, uveitis, MG etc) malignancies, HIV(-CD4) and certain infections. • It has been published that these diseases are managed either by modulation, suppression or stimulation of immune system.

19. Objective of Immunomodulation Down regulating the pro-inflammatory Th1 cytokines, IL-2 (Interleukin-2), Interferon-Gamma (IFN-γ) and Tumour Necrosis Factor-Alpha (TNF-ά)...cell-mediated response while promoting the production of regulatory Th2 cytokines such as IL-10 IL-4, IL-5 and IL-13 ...mainly humoral or antibody type responses

20. References • Cellular and Molecular Immunology Updated edition-6 Abdul K Abbas, Andrew Lichtman, ShivPillai

21. The Immune-Brain Connection - When the brain is injured, then microglia near the injury site become activated and begin secreting cytokines. The intimate relationship between microglia and neurons in the brain is an extrordinary example of the profound connection between the immune system and the brain. - Astrocytes have receptors for cytokines. - Activated T lymphocytes can pass the blood brain barrier. • Cytokines implicated in neurodegenerative diseases (Parkinson’s, Alzheimer etc) and epilepsy. • Even hair growth.

22. Psychonueroendocrino-immunology • Immune system can be influenced by brain which then send impulses to the brain by means of secreting hormones and nueropeptides. • By this way, brain endocrine and immune system have been linked together in view of fighting diseases

23. References The Effects of Psychological Stress on Humans: Increased Production of Pro-Inflammatory Cytokines and Th1-like Response In Stress-Induced Anxiety Michael Maes, Cai Song, Aihua Lin, Raf De Jongh, An Van Gastel, Gunter Kenis, Eugene Bosmans, Ingrid De Meester, Ina Benoy, Hugo Neels, Paul Demedts, AleksandarJanca, Simon Scharpe, Ronald S. Smith Cytokine, Volume 10, Issue 4, April 1998, Pages 313-318.

24. Met -Enkephalin • Opioid growth factor, also known as a cytokine • Pentapeptide, nuerotransmitter • This neuropeptide exerts various modulatory signals on different cell types, which led to its application in clinical medicine (Plotnikoff et al., ClinImmunolImmunopathol, 82:93, 1997 ;

25. References • Effect of MethionineEnkephalin on Natural Killer Cell and Cytotoxic T Lymphocyte Activity in Mice Infected with Influenza a Virus 1995, Vol. 17, No. 2, Pages 323-334 , DOI 10.3109/08923979509019754 Roger A. Burger‌, Reed P. Warren‌, John H. Huffman‌ and Robert W. Sid well‌ Department of Biology, Biomedical Research Division, Logan, Utah, 84322-6895 Institute for Antiviral Research, Utah State University, Logan, Utah, 84322-6895

26. Clinical Phytotherapy • Modulation of cytokine secretion offer novel approaches in the treatment of a variety of diseases. • In light of the adverse events experienced with recombinant cytokine-targeted therapy, and the fact that cytokines only established since 1979, it has been proven useful to consider the use of phytotherapy in the modulation of cytokine expression . .

27. Immunomodulation with cytokines, hormones,anti-oxidants and nutrients

28. Tested and proven phytotherapy Immunomodulators may be defined as botanical medicines that alter the activities of the immune system via the dynamic regulation of informational molecules--cytokines, hormones, neurotransmitters, and peptides.

29. Adaptogens • Have a non specific action on immune system • Increase the body's resistance to stress, trauma, anxiety and fatigue. • It is claimed that adaptogenic herbs are distinct from other substances in their ability to balance endocrine hormones and the immune system, and they help the body to maintain optimal homeostasis

30. Polysaccharides • Biological response modifiers • Specifically, beta-glucans stimulate the innate branch of the immune system. • Research has shown beta-glucans have the ability to stimulate macrophage, NK cells, including T-Cells and B-Cells., and immune system cytokines.

31. 1-3,1-6, Beta Glucans • Beta glucans are sugars (polysaccharides) that are found in the cell walls of bacteria, fungi, yeasts, algae, lichens, and plants, such as oats and barley

32. Mucosal immune system • Mucosal surface of the Gastrointestinal tract and Respiratory tract are colonized by lymphocytes and APCs that are involved in immune response and inhaled antigens • GI, Considered largest part of the immune system

33. Maintaining a healthy gastrointestinal barrier is essential for optimal immune function • Phosphatidylcholine is one of the components of the protective mucosa that lines your intestinal tract and provides the first barrier defense

34. Phospholipids • Eg- various forms of lecithin • Peanuts, liver, wheat germ, soy beans & egg yolks Peanuts Wheat germ Soy beans

35. Prebiotics and Probiotics Live microorganisms such as • Lactobacillus species, • Bifidobacterium species and • Yeasts, Prebiotics that stimulate the growth of healthy bacteria principally oligosaccharides It may beneficially affect the host upon ingestion by improving the balance of the intestinal microflora.

36. High in fiber • Fermented by the friendly bacteria in your colon to short-chain fatty acids (SCFAs), which are used as a fuel by gastrointestinal tract cells

37. The right balance and amount of proteins • Immune system can be significantly compromised with even a 25% reduction in adequate protein intake • Amino acids called glutamine and arginine as nutrition therapy in pre-surgery patients because of their ability to stimulate the immune system. • Interestingly,, an imbalance in the ratios among amino acids and poor quality of proteins can also affect the immune response.

38. Glutathione • Good source is whey protein • Triple powered antioxidant is produced in the liver from 3 amino acids – cysteine, glutamic acid & glycine • Protects cells throughout the body, as well as organ tissues, help prevent cancer, especially of liver • Immune system booster, a detoxifier of heavy metals & drugs • Anti-inflammatory treatments for arthritis & allergies

39. Nutrients for Immunity • Polysaccharides and Lipids stimulate secretion mainly of the antibodies IgM • Especially in the absence of T helper cells….termed T or thymus independent • Essential Fatty Acids

40. Omega 3 (PUFA) • Plant form – alpha linolenic acid Walnut Flax seed Pumpkin

41. Omega 3 • Animal form – EPA, DHA is most effective Salmon Sardine Tuna Anti inflammatory cytokines

42. Omega 6 (PUFA) • Linoleic acid – corn, sunflower, sesame Corn Sunflower seeds Sesame seeds

43. Omega 6 Gamma linolenic acid – evening primrose oil, borage oil, blackcurrant seed Pro-inflammatory cytokines originate with linoleic acids which are transformed into the omega-6 family of fatty acids, (IL-1) (IL-6) (TNF-a).

44. Omega 6 • Arachidonic acid – meat, dairy produce, eggs (excellent source of protein) Meat Dairy produce Eggs

45. Vitamins on Cytokines • Vitamins may also affect cytokine production by influencing the polarization of effector CD4+ T cells. • For instance, retinoic acid enhances Treg expansion while simultaneously inhibiting Th17 cells • Conversely, vitamin D favors Th2 polarization and diverts Tregs from their regulatory function

46. Cutaneous immune system • The skin contains a specialized cutaneous immune system consisting of lymphocytes and APCs • Langerhans cells • Dendritic cells • Epidermis is a site of post-thymicor extra- thymic T cell maturation PMID: 3065297 [PubMed - indexed for MEDLINE]

47. Vitamin D –a D-Lightful story • Sunshine vitamin – prevents depression and obesity. • In vitro studies suggest that vitamin D suppresses proinflammatory cytokines and increases antiinflammatory cytokines. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Am J ClinNutr. 2006 Apr;83(4):754-9. PMID: 16600924 [PubMed - indexed for MEDLINE]

48. Significance of T cells with Vitamin D • During adaptive immune responses, DC activate T cells and endow them with specific homing properties. • Vit D3, signal T cells to express chemokines to migrate to skin specific chemokine secreted by keratinocytes • Thus, one can understand why Vitamin D deficiency symptoms or skin malignancies manifest with aging because of the immunocompromised T cells!

49. Skin immunity • T cells regulation are crucial in maintaining healthy skin when we mention diseases such as psoriasis, skin cancer and dyspigmentation. • Langerhans cells which originate from the bone marrow undergo numeric, functional, and morphologic changes after UV exposure, resulting in their depletion from the skin. • Decreases in contact hypersensitivity responses as well as delayed-type hypersensitivity occurring after UV exposure have been noted. • This immunosuppression is partially mediated by DNA damage as well as by altered cytokine expression.

50. Vitamin A (Carotenoids) Supports the cells of the skin, gastrointestinal tract and lungs - the epithelial cells Carotenes • Beta- carotene • Lycopene • Lutein (peripheral retina) Xantophylls • Zeaxanthin (central Macula) • Cryptoxanthin • Astaxanthin