Bone Marrow Transplantation:

role of nutrition

Reference:

a) Robbins Basic Pathology 7th edition. Kumar, Cotran, Robbins editors. 2003.

b) Immunology, 6th edition. Roitt, Brostoff, Male. 2001

c) Nutrition, immune functions and health; Euroconferences, Paris; June 9-10, 2005

d) Internet. Accessed November 30, 2007

e) Harper’s Illustrated Biochemistry 27th edition. Murray RK, Granner DK, Rodwell VW.

Membrane

Structure

Phospholipid bilayer

Proteins

Carbohydrates

Micronutrients

Function

Solute/nutrient concentration/balance

All types of metabolic interactions

Signaling/communications

Replication

Cell membrane

Membrane dynamics

Lipids of physiologic significance d

Saturated fatty acids – no double bonds

Unsaturated fatty acids – with double bonds MUFA: one

PUFA: 2 Eicosanoids (from 20 carbon atoms)

Prostaglandins

Thromboxanes

Leukotrienes/Lipoxins

Cholesterol – precursor of Bile salts, adrenocortical hormones, sex hormones, D

vitamins, cardiac glycosides

Membrane component

Eicosanoids a

Unsaturated fatty acids

Lipids d

Physical and physiologic properties reflect chain length

and degree of unsaturation

Membrane lipids which must be fluid at all environmental

temperatures are more unsaturated than storage lipids

Phopholipids

Phosphatidylcholine (all membranes)

Phophatidylinositol (second messenger)

Cardiolipin (mitochondria)

Plasmalogen (brain and muscle)

Sphingomyelin (nervous system)

Study on fish oils use in BMT

16 consecutive patients for BMT

EPA 1.5 g/day; 3 wks

before and 180 days

after BMT (7)

Standard diet (9)

All survived

• GVHD (2)

• GVHD III or IV (3)

• Thrombotic microangiopathy (4)

• CMV disease (4)

• Died (5)

Takatsuka H, Takemoto Y, Iwata N, et. Oral eicosapentaenoic acid for complications of bone

marrow transplantation. Bone Marrow Transplantation (2001) 28, 769–774.

• ↓ LTB4

• ↓ TXA2

• ↓ PGI2

(P<0.01)

• TNFα

• IFNγ

• IL10

(P<0.05)

Eicosanoids a

-3 PUFA c

Arachidonic acid in

membrane phospholipids

Free arachidonic acid

Phospholipase A2

2-series

PG & TX

Anti

Inflammatory

effectsInflammatory

effects

Anti

Inflammatory

effects

D-series

resolvins, etc

DHA

4-series LT

COX-2COX-2

5-LOX

Inflammatory

effects

EPA

3-series

PG & TX

Less

Inflammatory

effects than

2-series

E-series

resolvins

Anti

Inflammatory

effects

5-series LT

Less

Inflammatory

effects than

4-series

COX-25-LOX

NF B

Inflammatory

effects

(e.g. cytokines)

Calder Philip, Polyunsaturated fatty acids,

inflammation, and immunity : Nutrition, immune

functions and health; Euroconferences, Paris;

June 9-10, 2005

Cells-cell interaction and eicosanoids a

Inflammation a

Inflammation a

Inflammation outcomes a

Monocytes a

Inflammation and organ failure in the ICU

SIRSTNF , IL-1 ,

IL-6, IL-12,

IFN , IL-3

IL-10, IL-4, IL-1ra,

Monocyte HLA-DR

suppression

CARS

days

Insult

(trauma, sepsis)

Inflam

mato

ry b

ala

nce

Tissue inflammation, Early

organ failure and death

weeks

Immunosuppression

2nd Infections Delayed MOF

and death

Griffiths, R. “Specialized nutrition support in the critically ill: For whom and

when? Clinical Nutrition: Early Intervention; Nestle Nutrition Workshop Series

Cell Injury a

Cell changes a

Free radical generation a

Cellular injury types a

Apoptosis a

Inflammatory mediators a

Cytokines a

Kinin/clotting/complement system a

Complement system a

The microcirculatory environment

nucleus

• oxygen

• macronutrients

• micronutrients

• substrates

• hormones

• cytokines

• energy production

• substrate utilization

• substrate synthesis

• protein / complex

subs synthesis

• CO2

• breakdown products

• micronutrients

• substrates

• hormones

• cytokines

Capillary arterial side Capillary venous side

LOCAL EFFECTS

SYSTEMIC EFFECTS

Endothelium interaction

• Interaction with clotting mechanism

• interaction with inflammation process

Normal environment a

Inflammation b

Inflammation a

Neutrophil actions a

Activated leucocyte a

Leucocyte mechanisms a

Current

update

B Cell

Naive Th cell Th0

Th1

Th2

CTL NK Cell B cell

Interleukins d

Name Source Function

IL-1 macrophagessmall amounts induce acute phase reaction, large amounts induce

fever.

IL-2 TH1-cells

stimulates growth and differentiation of T cell response. Can be used

in immunotherapy to treat cancer or suppressed for transplant

patients.

IL-3 T cells stimulates bone marrow stem cells

IL-4

TH2-cells, just activated naïve

CD4+ cell, memory CD4+

cells

involved in proliferation of B cells and the development of T cells and

mast cells. Important role in allergic response (IgE)

IL-5 TH2-cellsrole in differentiation of B cells, eosinophil production, and IgA

production

IL-6 macrophages, TH2-cells induces acute phase reaction

IL-7stromal cells of the red marrow

and thymusinvolved in B, T, and NK cell survival, development, and homeostasis

IL-8macrophages, epithelial cells,

endothelial cellsNeutrophil chemotaxis

IL-9T-cells, specifically by CD4+

helper cellsstimulates mast cells

IL-10 monocytes, TH2-cells, mast cells inhibits Th1 cytokine production

IL-11 bone marrow stroma acute phase protein production

Interleukins d

Name Source Function

IL-12 macrophages NK cell stimulation, Th1 cells induction. May suppress food allergies

IL-13 TH2-cellsStimulates growth and differentiation of B-Cells (IgE), inhibits TH1-cells and

the production of macrophage inflammatory cytokines

IL-14T cells and certain malignant

B cellscontrols the growth and proliferation of B cells

IL-15

mononuclear phagocytes

(and some other cells)

following infection by

virus(es).

Induces production of Natural Killer Cells

IL-16

a variety of cells (including

lymphocytes and some

epithelial cells)

Chemoattracts immune cells expressing the cell surface molecules CD4

IL-17 - Induces production of inflammatory cytokines

IL-18 macrophages Induces production of Interferon-gamma (IFNγ)

IL-20 - regulates proliferation and differentiation of keratinocytes

IL-21 - Induces proliferation in natural killer cells (NK) and cytotoxic T cells

IL-22 -

Activates STAT1 and STAT3 and increases production of acute phase

proteins such as serum amyloid A, Alpha 1-antichymotrypsin and

haptoglobin in hepatoma cell lines

IL-23 - Increases angiogenesis but reduces CD8 T-cell infiltration

Interleukins d

Name Source Action

IL-24 -Plays important roles in tumor suppression, wound healing and

psoriasis by influencing cell survival.

IL-25 -Induces the production IL-4, IL-5 and IL-13, which stimulate eosinophil

expansion

IL-26 -Enhances secretion of IL-10 and IL-8 and cell surface expression of

CD54 on epithelial cells

IL-27 - Regulates the activity of B lymphocyte and T lymphocytes

IL-28 - Plays a role in immune defense against viruses

IL-29 - Plays a role in host defenses against microbes

IL-30 - Forms one chain of IL-27

IL-31 - May play a role in inflammation of the skin

IL-32 -Induces monocytes and macrophages to secrete TNF-α, IL-8 and

CXCL2

IL-33 - Induces helper T cells to produce type 2 cytokines

Inflammation Outcomes a

Histopath a

Nitric Oxide a

Nitric oxide b

L-arginine

L-arginine

Nitric oxide

AS

L-citrullineNADP+

NOS

O2

BH4

Ca2+

NADPH+ + H

GTP

ASS

ASL

Plasma membrane

Wu and Meininger, 2002, Annu Rev Nutr. 22: 61-68

Flynn et al, 2005, Nutrients and Signalling 225-252

Inducible NOS: activity b

ceramide

LDL & linoleic acidmacrophages

glutamine

Fe, cobalt, nickel

Vitamin A & D3

ginseng

islets, liver, colonHigh fat diet

argininecopper

Arteries, aorta,

vascular smooth

muscle cellsPhytanic acid

polyphenols Brain, heart,

Retinal cells kidney

Fructose

Fe

Wu G, Nutritional regulations of NO

synthesis and its implications for

health; : Nutrition, immune functions

and health; Euroconferences, Paris;

June 9-10, 2005

Inducible NOS: activity b

3 & 6 PUFA

polyphenols

fructose

macrophages

glutamine

Cd, Cr, Cu, Lead

carotenoids

High ethanolLung, GIT

Taurine

Lysineendothelial cells,

vascular smooth

muscle cellsVit A, D3, & E

neuronal

cells

kidney

Fructose

glucosamine

Melatonin & Vit D3

Niacin & B6

High glucose

High salt dietIron

Wu G, Nutritional regulations of NO

synthesis and its implications for

health; : Nutrition, immune functions

and health; Euroconferences, Paris;

June 9-10, 2005

Histopath a

Inflammation and organ failure in the ICU

SIRSTNF , IL-1 ,

IL-6, IL-12,

IFN , IL-3

IL-10, IL-4, IL-1ra,

Monocyte HLA-DR

suppression

CARS

days

Insult

(trauma, sepsis)

Inflam

mato

ry b

ala

nce

Tissue inflammation, Early

organ failure and death

weeks

Immunosuppression

2nd Infections Delayed MOF

and death

Griffiths, R. “Specialized nutrition support in the critically ill: For whom and

when? Clinical Nutrition: Early Intervention; Nestle Nutrition Workshop Series

glutamine

Immunonutrients

Glutamine

Glutamine

supplementation

during the pre-

operative phase

alone: effect on

immune indices and

clinical outcome in

malnourished

abdominal surgery

patients in the first

week post-operative

period. Asprer J et al.

(under review,

Nutrition

International journal)

glutamine

* p < 0.05, ANOVA

Repeated measures

Glutaminecd3 - Pan T lymphocytes

0

200

400

600

800

1000

1200

1400

1600

1800

2000

5d preop 1d preop 7d postop

valu

es

cd3c

cd3g

cd4 - T helper

0

100

200

300

400

500

600

700

800

5d preop 1d preop 7d postop

valu

es

cd4c

cd4g

cd22 - B cells

0

50

100

150

200

250

5d preop 1d preop 7d postop

valu

es

cd22c

cd22g

cd56 - NK cells

0

50

100

150

200

250

300

350

5d preop 1d preop 7d postop

valu

es

cd56c

cd56g

Host-microbial interaction c

Lecuit M, Sonnenburg J. Host-microbial relationship in the intestine: sensing commensal and pathogenic bacteria:

Nutrition, immune functions and health; Euroconferences, Paris; June 9-10, 2005

Gut – inductive and effector sites c

Per Brandtzaeg, Mucosal adaptive immunity: impact of exogenous stimuli and feeding; Nutrition, immune

functions and health; Euroconferences, Paris; June 9-10, 2005

macrophages

Cytotoxic T cells

Cytotoxic T cells

Ligands

(glycoproteins)

macrophages

Nutraceuticals: to give or not to

Dose Content in preps

Glutamine 0.4 – 0.5 g/kg 12 – 15 g/L

Arginine ? 4 – 16 g/L

Omega-3-fatty

acids (EPA)

2 – 6 g/day 1 – 2 g/L

Antioxidants

Carotenoids

Vitamin C,E

>100% daily

requirement

Single or

combinations

Maximum effect when given at the proper dose