Transcript immune system

What’s Missing for
Effective Stem Cell
Therapies
Practical Clinical Approach
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)
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?
Autologous IV Stem Cell Transplant for
total Rejuvenation
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.
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.
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.
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).
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
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
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.
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.
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
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 factorbeta (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
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;
• M-CSF;
committed progenitors
committed prgenitors
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.
Autoimmune endocrine disorders or
autoimmune polyglandular syndromes
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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
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.
Objective of Immunomodulation
Down regulating the pro-inflammatory Th1
cytokines, IL-2 (Interleukin-2), InterferonGamma (IFN-γ) and Tumour Necrosis FactorAlpha (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
References
• Cellular and Molecular Immunology
Updated edition-6
Abdul K Abbas, Andrew Lichtman, Shiv Pillai
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.
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
References
The Effects of Psychological Stress on Humans:
Increased Production of Pro-Inflammatory
Cytokines and Th1-like Response In StressInduced 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.
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 ;
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
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 .
.
Immunomodulation with
cytokines, hormones,
anti-oxidants and nutrients
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.
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
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.
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
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
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
Phospholipids
• Eg- various forms of lecithin
• Peanuts, liver, wheat germ, soy beans & egg
yolks
Peanuts
Wheat germ
Soy beans
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.
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
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.
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
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
Omega 3 (PUFA)
• Plant form – alpha linolenic acid
Walnut
Flax seed
Pumpkin
Omega 3
• Animal form – EPA, DHA is most effective
Salmon
Sardine
Anti inflammatory cytokines
Tuna
Omega 6 (PUFA)
• Linoleic acid – corn, sunflower, sesame
Corn
Sunflower
seeds
Sesame seeds
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).
Omega 6
• Arachidonic acid – meat, dairy produce, eggs
(excellent source of protein)
Meat
Dairy produce
Eggs
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
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 extrathymic T cell maturation
PMID: 3065297 [PubMed - indexed for
MEDLINE]
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]
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!
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.
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
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)
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
A Variety of Spices is
the Spice of Life
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 factorkappaB, 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
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.
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.
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
Turn on telomerase!
Astragalus root (黄芪 huang qi)
• 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.
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)
Cytokine upregulation
• Chinese Schizandra berry (Schizandra
chinensis) –tonic for adrenal and
Liver
• Golden root (Rhodiola rosea)
• Chinese Lovage root (Ligusticum wallichii v.
sp.)
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.
Green super food-immune booster
Wild blue-green algae - Miracle superfood
Chlorella –
Alfalfa grass – father of all foods
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
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.
Cytokine storm
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
Osterholm. New England Journal of Medicine,
352 (18): 1839, Figure 3. May 5, 2005
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)
To take during the acute stage
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
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[
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
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.
Immunomodulators –
key management of autoimmune
and degenerative diseases at
the causative level
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
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.
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
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
2Department of Hematopathology, U.T.M.D. Anderson Cancer Center, Houston, Texas
3Department of Surgical Oncology, U.T.M.D. Anderson Cancer Center, Houston, Texas
4Department of Blood and Marrow Transplantation, U.T.M.D. Anderson Cancer Center, Houston,
Texas
•
email: Zeev Estrov ([email protected])
*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
References
Sustained ex vivo expansion of hematopoietic stem
cells mediated by thrombopoietin
• Mayumi Yagi Kindred A. Ritchie, Ewa Sitnicka, Carl Storey
Gerald J. Roth and Stephen 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)
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
Harvesting
The patients
blood is
harvested,
approx 200ml
Centrifugation
The blood is
centrifuged in
various stages
Counting and differentiation
The blood in analyzed and the different cell types are counted.
FACS
Separation
The CD 34 cells contains Fe which
makes them react to magnetic fields
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
Inverse Microscope
Counting the cultivated cells
Reinjection
• After cultivation, the cells are reinjected back
to the patients arm as a 2 ml cell suspension
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.
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)
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 Hofmeister1, J Zhang1, K L Knight1, P Le1 and P J Stiff1
1Cardinal
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:
[email protected]
Received 12 October 2006; Accepted 12 October 2006.
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.
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
Integration of the Pillars of Anti Aging
Medicine
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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
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
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 “
Conclusion
• Primum non nocere
• Development of strategies to
integrate the different pillars.
“Immuno-elasticity”
Thank you