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

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Presentation on theme: "What’s Missing for Effective Stem Cell Therapies Practical Clinical Approach."— Presentation transcript:

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

2 Dr Janethy Balakrishnan Bokström  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 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. Relevance of T cells

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, Shiv Pillai

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, Aleksandar Janca, 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., Clin Immunol Immunopathol, 82:93, 1997 ;

25 References Effect of Methionine Enkephalin 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 PeanutsWheat germSoy 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 WalnutFlax seedPumpkin

41 Omega 3 Animal form – EPA, DHA is most effective SalmonSardineTuna Anti inflammatory cytokines

42 Omega 6 (PUFA) Linoleic acid – corn, sunflower, sesame CornSunflower 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) MeatDairy produceEggs

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-thymic or 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 Clin Nutr. 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

51 Vitamin C Boosts the immune system and is an antiviral by blocking the enzyme neuraminadase Research shows that it may reduce the production of cytokines TNF-a and IL-6. A study on 470 people involved giving the test group 1000 mg hourly for 6 hours and then 1000 mg 3 times daily after reporting flu symptoms. Symptoms decreased by 85%. (Pubmed PMID 10543583, 634178, 16169205, 12876306)

52 Vitamin B on immune cells Vitamin B5(pantothenic acid) promotes the production and release of antibodies from B-cells Folic Acid deficiency leads to a decrease in T-cells and can result in reduced effectiveness of the soluble factors as well. Vitamin B6 deficiency consistently impairs T-cell functioning and results in a decrease in blood lymphocyte counts. Deficiencies in vitamins B1(thiamin) and B2 (riboflavin) may impair normal antibody response, Low vitamin B12 appears to inhibit phagocytic cells and possibly T-cell function

53 A Variety of Spices is the Spice of Life

54 Red clover on Cytokines Red clover extract: activates peroxisome proliferator-activated receptor alpha and ameliorate the cytokine secretion profile of lipopolysaccharide-stimulated macrophages. It reduce the secretion of proinflammatory cytokines, interleukin-6 and TNF alpha, increased the secretion of the anti-inflammatory interleukin-10, and/or reduced the expression of nuclear factor- kappaB, inducible nitric oxide synthase, and/or cyclooxygenase 2. Tumor necrosis factor alpha production was most efficiently reduced by biochanin A and genistein. Interleukin-6 levels were most efficiently reduced by genistein and equol. Menopause. 2010 Mar;17(2):379-87. Mueller M, Hobiger S, Jungbauer A. PMID: 20142789

55 Aesthetic Perspective Curcumin and Capsaicin also inhibits the secretion of collagenase, elastase and hyaluronidase demonstrating that they can control the release of pro-inflammatory mediators such as eicosanoids.

56 Elderberry help boost immunity by increasing the body's production of cytokines Prevents and calms skin immunity Sources Barak V, Halperin T, Kalickman I. "The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines." European Cytokine Network 2001 12(2):290-6. Zakay-Rones Z, Thom E, Wollan T, Wadstein J. "Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections. " Journal of International Medical Research 2004 32(2):132-40.

57 Super food herbs for immunology * Nettle – bowel buster, cleanses the liver, keeps infections at bay, prostrate problem Aloe vera – digestion disorders, bloating, gas & flatulence Siberian ginseng – stress combater, energizing tonic, help body adapt to stress, anti-infection quality Echinacea – lymph mover, warding off common cold

58 Turn on telomerase! Astragalus membranaceus is an immunostimulant polysaccharide used for centuries in traditional Chinese medicine to increase vitality and combat weakness in wasting diseases, etc In vitro, has been shown to lower IL-6. Astragalus stimulates the immune system in various ways, in particular, by promoting the development of stem cells into active immune cells. Astragalus’ polysaccharides induce endogenous production of interferon and maximise its efficacy. Astragalus root ( 黄芪 huang qi)

59 Nutrients that promote proliferation of peripheral blood lymphocytes due to cytokine upregulation. Indian Ashwagandha root (Withania somnifera) Peruvian Cat's Claw (Uña de Gato) bark (Uncaria tomentosa) Licorice root (Glycyrrhiza glabra) Red Reishi mushroom (Ganoderma lucidum) Japanese Maitake mushroom (Grifola frondosa)

60 Cytokine upregulation Chinese Schizandra berry (Schizandra chinensis) –tonic for adrenal and Liver Golden root (Rhodiola rosea) Chinese Lovage root (Ligusticum wallichii v. sp.)

61 Cordyceps sinensis (dong chong xia cao) extract is standardised in cordyceptic acid, adenosine and polysaccharides. It is a rare medicinal fungus and a cornerstone of Chinese medicine for hundreds of years. Recent research has shown it to have immunomodulatory properties which enable it to act as either an immunosuppressor or immunostimulant.

62 Green super food-immune booster Wild blue-green algae - Miracle superfood Chlorella – Alfalfa grass – father of all foods

63 Flavon-3-ol Anthocyanins White tea, green tea, black tea, blackcurrants, blueberries, blackberries, raspberries, cherries, strawberries, broad beans, red apples, apricots, red purple cabbage & buckwheat OPCs Grape seed extract, berry extracts, red wine extract & pine bark extract (pycnogenol), dark chocolate (70-80% cocoa solid) Reservetrol

64 Minerals that support your immune system Iron deficiency results in impaired response to antibodies, and defective phagocytic cell functioning. Copper deficiency is associated with an increase in infections and may impair development of immune cells such as T-cells and the phagocytic cells. Selenium and manganese are important for supporting healing from inflammation and may be immunostimulants Zinc is a potent immunostimulant, and its deficiency can result in profound suppression of T-cell function.

65 Cytokine storm Osterholm. New England Journal of Medicine, 352 (18): 1839, Figure 3. May 5, 2005 Between cytokines and immune cells Release of more 150 known inflammatory mediators which are cytokines, free radicals and coagulation factors Symptoms are high fever, swelling and redness, extreme fatique and nausea. Immune reaction maybe even fatal

66 Avoid during cytokine storm Avoid Adaptogens that increases production of cytokines TNF-a and IL-6. Elderberry ( Med Journal2002 Nov;4:944-6 ) Micro Algae (Chlorella and Spirulina) - - (Pubmed PMID 11731916 ) Honey - (Pubmed PMID12824009) Chocolate -. (Pubmed PMID 12885154, PMID 10917928) Echinacea (Pubmed PMID 15556647, 9568541)

67 To take during the acute stage

68 References Antoine Al-Achi, Anti-inflammatory Herbs, U.S. Pharmacist, March 15, 2004. Kenneth Proefrock, Latest Updates in the Botanical Treatment of Autoimmune Diseases, Southwest Conference on Botanical Medicine 2003. K. Spellman, Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators, Alternative Medicine Review, June 2006; 11(12): 128-50. Zapata-Gonzalez, F., Rueda, F., Petriz, J., Domingo, P., Villarroya, F., Diaz-Delfin, J., de Madariaga, M. A., Domingo, J. C. (2008) Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, J. Leukoc. Biol. 84,1172-118

69 References Funahashi, H., Angst, E., Satake, M., Hasan, S., Reber, H. A., Hines, O. J., Eibl, G. (2008) QS109. The omega-3 polyunsaturated fatty acid EPA decreases the growth of pancreatic cancer cells by COX-2 dependent and independent mechanisms J. Surg. Res. 144,3116 Lim, K., Han, C., Xu, L., Isse, K., Demetris, A. J., Wu, T. (2008) Cyclooxygenase-2-derived prostaglandin E2 activates β-catenin in human cholangiocarcinoma cells: evidence for inhibition of these signaling pathways by omega 3 polyunsaturated fatty acids Cancer Res. 68,553 Sun, H., Berquin, I. M., Owens, R. T., O'Flaherty, J. T., Edwards, I. J. (2008) Peroxisome proliferator-activated receptor -mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells Cancer Res. 68,2912-2919 y acids Cancer Res. 68,553-560[[ Kim, H. H., Lee, Y., Eun, H. C., Chung, J. H. (2008) Eicosapentaenoic acid inhibits TNF--induced matrix metalloproteinase-9 expression in human keratinocytes, HaCaT cells Biochem. Biophys. Res. Commun. 368,343-349[

70 Expression of cytokines by Hormones Estrogens as well as androgens inhibit the production of IL-1β and TNFα by monocytes-macrophages. Androgens antagonize stimulatory effects of estrogens. Suggest that estradiol is more inhibitory to Thl cytokines (for example, IFNγ, IL-2) while testosterone is inhibitory to Th2 cytokines (for example, IL-4). On the other hand, cytokines control the hypothalamic-hypophyseal-adrenal gland axis as well as the sex hormones

71 Thymic hormones for HRT in regenerative medicine? Recent data point to a significant role for thymosins, lymphokines, and other soluble mediators in the senescence of the immune response that occurs with aging. Thymosin has a stimulating effect on LH, HGH, prolactin and ACTH.

72 Immunomodulators – key management of autoimmune and degenerative diseases at the causative level

73 Which protocol for now? Numerous approaches in peripheral blood stem cell mobilization and transplantation. Always trying to perfect the art of linking together the missing ‘ingredients’ and grappling to gain clinical experience on what is the best strategy and algorithm in stem cell therapy

74 Is Apheresis really necessary? Through our experience, it is a more comfortable for the patients to skip the apheresis process. There also has been data that administering high dosage of G csf prior to stem cells collection could cause ostopenia. After loads of Gcsf, amount of CD34+ collected might still not be sufficient. There is also the critical question on how the body copes with the sudden invasion of stem cells.

75 References Adverse Events in Platelet Apheresis Donors: A Multivariate Analysis in a Hospital–Based Program G.J. Despotis, L.T. Goodnough, M. Dynis, D. Baorto, E. Spitznagel Washington University School of Medicine, St. Louis, Mo., USA

76 References Ex vivo expansion of apheresis-derived peripheral blood hematopoietic progenitors Zeev Estrov 1 *, Yang O. Huh 2, Cheryl F. Ginsberg 2, David Harris 1, Quin Van 1, Nadeem Q. Mirza 3, Moshe Talpaz 1, Martin Korbling 4 1 Department of Bioimmunotherapy, U.T.M.D. Anderson Cancer Center, Houston, Texas 2 Department of Hematopathology, U.T.M.D. Anderson Cancer Center, Houston, Texas 3 Department of Surgical Oncology, U.T.M.D. Anderson Cancer Center, Houston, Texas 4 Department of Blood and Marrow Transplantation, U.T.M.D. Anderson Cancer Center, Houston, Texas email: Zeev Estrov ( * Correspondence to Zeev Estrov, Department of Bioimmunotherapy, U.T.M.D. Anderson Cancer Center, 1515 Holcombe, Box 422, Houston, TX 77030 Received: 25 July 2001; Accepted: 3 December 2001

77 References Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin Mayumi Yagi Kindred A. Ritchie, Ewa Sitnicka, Carl Storey Mayumi YagiKindred A. RitchieEwa SitnickaCarl Storey Gerald J. Roth Gerald J. Roth and Stephen BartelmezStephen Bartelmez Author Affiliations Departments of * Research, ‡ Pathology, and ** Hematology, Seattle Division, Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108; † Division of Hematology, Department of Medicine, and Departments of § Pathology and ¶ Pathobiology, University of Washington, Seattle, WA 98195; and ‖ Seattle Biomedical Research Institute, 4 Nickerson Street, Seattle, WA 98109 Communicated by Paul B. Beeson, University of Washington, Redmond, WA (received for review February 10, 1999)

78 References Megakaryocytic Progenitors Can Be Generated Ex Vivo and Safely Administered to Autologous Peripheral Blood Progenitor Cell Transplant Recipients Blood, Vol. 89 No. 8 (April 15), 1997: pp. 2679-2688 By Francesco Bertolini, Manuela Battaglia, Paolo Pedrazzoli, Gian Antonio Da Prada, Annalisa Lanza, Davide Soligo, Lorenza Caneva, Barbara Sarina, Scott Murphy, Terry Thomas, and Gioacchino Robustelli della Cuna

79 Harvesting The patients blood is harvested, approx 200ml

80 Centrifugation The blood is centrifuged in various stages

81 Counting and differentiation The blood in analyzed and the different cell types are counted. FACS

82 Separation The CD 34 cells contains Fe which makes them react to magnetic fields

83 Cultivation In this framework, cells are placed in a cell culture which contains the appropriate cytokines such as GMCSF, IL-3, SCF and flt-3L and cultivated for multiplication. 7-days in controlled temperature and humidity

84 Inverse Microscope Counting the cultivated cells

85 Reinjection After cultivation, the cells are reinjected back to the patients arm as a 2 ml cell suspension

86 Personalized and tailored This smart technique of “induction differentiation” or “programming with specific cytokines" is exciting as the signaling of stem cells is done according to the desired needs of the patients’ ailments. Immune status checked before and after.

87 Pilot study for Allogenic transplant UCB to mother Pros -Most primitive -immunologically immature -Graft versus host disease (minimal risk, compared to bone marrow and peripheral blood)

88 References Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche Bone Marrow Transplantation (2007) 39, 11–23. doi:10.1038/sj.bmt.1705538 C C Hofmeister 1, J Zhang 1, K L Knight 1, P Le 1 and P J Stiff 1 1 1 Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA Correspondence: Dr PJ Stiff, Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S First Avenue, Building 112, Room 240, Maywood, IL 60153, USA. E-mail: Received 12 October 2006; Accepted 12 October 200 6.

89 Striking the right balance Insight into cytokine balance is leading to novel therapeutic approaches particularly in autoimmune conditions, which are intimately linked to a dysregulated cytokine production. Interplay of signals Cytokine activities affect most, if not all, biological processes involved in homeostasis as well as in host defense and auto-aggression.

90 A Homeostatic system Acid/base equilibrium Fasting glucose/Insulin ratio T4/TBG ratio Catabolic/anabolic ratio… …….Cortisol/DHEAS, IL-6/DHEAS, IL-6/T, IL-6/IGF-1 Estrogen/progesterone ratio Free T and T/SHBG AA/ EPA ratio Total cholesterol/HDL ratio Free radical/antioxidants balance Minerals balance IL6/IL10 ratio Th1/Th2 balance

91 Integration of the Pillars of Anti Aging Medicine Hormonal optimization (BHRT) Biological and cellular therapy Cellular detoxification Toxic metal Detoxification - Chelation Nutritional therapuetics Biomechanics - chiropractor Exercise Stress management Prevention of inflammatory processes at the molecular and cellular level Inflammation is the key feature of autoimmune disease

92 Which strategy is the best? However, the question is not whether stem cell treatment works but how to orient further studies on clinical application to refine ……to improve the efficacy The type of cells that a stem cell will develop into is determined by the specific needs of the patients body, and through the stimulus of special substances called cytokines or growth factors This, together with an improved understanding of how T cells and the required signals interact, will allow us to better design better stem cell strategies for patients

93 Impression The emphasis is on suddenly…….. ………without preparation……………………. without the right signals………the body is called upon to deal with an enormous influx of stem cell far in excess of momentary requirements To quote a colleague of ours: “The body is fantastic in reproducing and healing itself….. sometimes, we just need to help it along the way “

94 Conclusion Primum non nocere Development of strategies to integrate the different pillars. “Immuno-elasticity”

95 Thank you

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