Prof. Mario Di Gioacchino - Conferencia dictada en el XVII Congreso Latinoamericano de Alergia, Asma e Inmunología, Cartagena, 2012

1. Clinical pictures of Nickel allergy
Allergy to nickel: systemic effects
and oral immunotherapy
Type IV Hypersensitivity
Cell-mediated delayed reaction
Mario Di Gioacchino
Occurs 24-72 hours after exposure to Nickel
Professor of Occupational Medicine and Allergy
Head of the “Immunotoxicology and Allergy” Unit
“Università G. d’Annunzio” Foundation, Chieti, Italy
Chair of ICOH-SC on “Allergy and Immunotoxicology”
Vice president of the Italian Society of Nanotoxicology
SC on Allergy and
Immunotoxicology
Di Gioacchino
Antigen presentation Allergic contact dermatitis
 Initiation
– CD8+ and CD4+ lymphocyte proliferation
 Amplification
– CD8+ induced cytotoxicity
– Inflammatory cytokine (IFN, TNF, IL17,) secretion
– MHC-1 e MHC-2, ICAM-1 expression on epidermal cells.
 Damage
– Eczematous lesions due to cytotoxic activity of T CD8+ cells
Role of APC-independent T cell presentation (full-competent including infiltration of mononuclear cells in both dermis and
activation of the T cells or mechanism involved in the maintenance of epidermis, with intercellular edema between keratinocytes.
peripheral T cell tolerance)
Di Gioacchino
Di Gioacchino Di Gioacchino
Nickel Systemic Contact Dermatitis
Allergic contact dermatitis Oral challenge with Ni in Ni-ACD
Resolution
 Resolution of ACD probably
involves T cells secreting high
levels of IL-10 (T-IL-10 ), which
impairs the functions of dendritic
cells, but can also directly
modulate T cells.
 T-IL-10 cells are selectively
attracted by the chemokine I-309,
produced by activated T cells, and
by keratinocytes
Modified from Cavani et al. 2001 Modified from Jansen Contact Dermatitis and Di Gioacchino IJIP
Di Gioacchino Di Gioacchino
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2. Systemic Nickel Allergy Syndrome
(SNAS)
Oral challenge with Ni in Ni-ACD “Allergy Vaccine” International Meeting in Cyprus 2004
Proceedings in “International Journal of Immunopathology and Pharmacology” Clinical picture of SNAS
 Nickel allergic contact dermatitis
 Systemic symptoms after ingestion of nickel rich foods:
– Meteorism, diarrhea, vomiting, abdominal pain, GER, etc.
– Widespread of cutaneous symptoms
– Flare-up of previous lesions and Ni positive patch tests
 Disappearance/reduction of symptoms after low Ni diet
 Reappearance of symptoms after Ni oral challenge
Modified from Jansen Contact Dermatitis and Di Gioacchino IJIP
Di Gioacchino Di Gioacchino
Dietary exposure estimates of Nickel from
Concentration of Nickel and other elements in
the UK Total Diet selected snack and convenience foods
 Cereals 0.17 mg/kg  Instant tea 7.8-12
 Poultry 0.04
 Fish 0.08  Instant coffee 0.62-1.3
 Eggs 0.03
 Roasted cashews 4.1-4.7
 Green vegetables 0.11
 Other vegetables 0.09  Custard 0.02-0.03
 Potatoes 0.10
 Milk 0.02  Lentils 1.6-2.3
 Dairy products 0.02
 Nuts 2.5  Mixed nuts 0.99-5.29
Ysart G, Miller P, Crews H, Robb P, Baxter
 Fresh fruits 0.03 M, De L'Argy C, et al. Food Additives and
Contaminants, Volume 16, Issue 9 January
 Dried peas 0.39-0.76 Archive MAFF. MAFF UK
 Oil and fats 0.03 1999, pages 391 - 403
[Last updated on 1998 Mar].
 Haricot beans 0.65-2.3
Di Gioacchino Di Gioacchino
Smart GA, Sherlock JC. Food Additives
Contaminants 1987;4:61-7
A study of nickel content in Korean foods
 A green tea bag 235.57 (mg/Kg)
 A black tea bag 62.79 plant food
 Chocolate 27.87
 Crisps 12.70
cereals
 Wheat flour 12.15 pulses
 Onions 0.02
 Garlic 0.016
vegetables:
 Milk 0.004 - green leavers
 Eggs 0.002
 Salt 0.0 Han HJ, Lee BH, Park CW, Lee CH, Kang YS.
- roots
Korean J Dermatol 2005;43:593-8. - tubers
Di Gioacchino
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3. Foods with high Ni content Foods with high Ni content
 Oats  Almonds  Crisps  Brussels Sprouts
 Cocoa  Hazelnuts
 Asparagus  Canned foods
 Chocolate  Pears
 Beer  Onions
 Beans  Soy
 Rhubarb  Wheat flour
 Lentils  Spinach
 Cabbage
 Mais  Tomato  Mushrooms
 Margarine
 Tea  Oysters  Lettuce
 Wine
Flyholm MA, Nielson GD, Andersen A. Zeitschrift für
 Raisin
Lebensmitteluntersuchung und -Forschung. 1984. p. 427-31
Di Gioacchino Di Gioacchino
Foods with moderate Ni content Nickel content in foods
Apricot  Nickel linked to proteins can be stable, not
Herrings
all biologically available.
Broccoli
Carots  Nickel present in the lipid portion is
Lettuce completely biologically available.
Di Gioacchino Di Gioacchino
Systemic Nickel Allergy Syndrome SNAS: pathogenetic aspects
 There are demonstrations that the Oral Ni Challenge (5 mg) 3 pts groups: A. ACD +; SNAS -
pathogenesis of SNAS involves B. ACD +; SNAS +
immunological factors unusual for a IV C. Healthy controls
type immunoreactions.
1) Study of nickel metabolism
2) Evaluation of blood lymphocyte subpopulations
 First hypothesis: food ingested nickel
3) Lymphocyte subpopulations in the intestinal mucosa
may act as hapten and induce an IgE
4) Evaluation of “in vivo” and “in vitro” cytokine release
medicated reaction: no scientific evidence
Di Gioacchino Di Gioacchino
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4. Changes in circulating lymphocyte
Nickel metabolism after Ni-challenge
Urine and serum Ni levels in controls and in ACD and SNAS women, before and 4 and 24 hours after Ni
challenge.
T cells in control and sensitized patients before and 4 and 24 h after oral nickel challenge
CD4+ cell changes
40
30
20
10
% of changes
0
-10
-20
-30
-40
-50
basal test 2 test 3
controls group A group B
M. Di Gioacchino et al: Arbeitstagung Mengen und Spurenelemente. 1995
Di Gioacchino M. Di Gioacchino, et al Contact Dermatitis 2000 Di Gioacchino
Changes in circulating lymphocyte Changes in circulating lymphocyte
after Ni-challenge after Ni-challenge
T cells in control and sensitized patients before and 4 and 24 h after oral nickel challenge
T cells in control and sensitized patients before and 4 and 24 h after oral nickel challenge
CD8+ cell changes
CD4+CD45RO+ cell changes
30 40
30
20
20
10 10
% of changes
% of changes
0
0
-10
-10
-20
-20 -30
-40
-30
-50
-40 -60
basal test 2 test 3 basal test 2 test 3
controls group A group B controls group A group B
M. Di Gioacchino, et al. Contact Dermatitis 2000 Di Gioacchino M. Di Gioacchino, et al Contact Dermatitis 2000 Di Gioacchino
CD4 in intestinal epithelium after Ni-challenge CD8 in intestinal epithelium after Ni-challenge
M. Di Gioacchino, et al Lymphocyte subset changes in blood and gastrointestinal mucosa after M. Di Gioacchino, et al Lymphocyte subset changes in blood and gastrointestinal mucosa after
oral nickel challenge, in nickel sensitized women. Contact Dermatitis 43; 2000 Di Gioacchino oral nickel challenge, in nickel sensitized women. Contact Dermatitis 43; 2000 Di Gioacchino
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5. IL-5 and Nickel Allergy IL-5 and Nickel Allergy
IL5 in control and sensitized patients before and after oral nickel exposure
IL5 % changes 24 h after oral nickel challenge in control subjects and in patients
with Ni-DAC and Systemic Nickel Allergy Syndrome.
*
60%
40%
20% IL-2
IL-5
0%
-20%
-40%
controls DAC SNAS
* (p<0.01)
Modified from CS Jensen, et al Contact Dermatitis 2004
M. Di Gioacchino et al: Life Sciences 64:1485-1491; 1999 Di Gioacchino CS Jensen, et al Contact Dermatitis 2004 Di Gioacchino
Is it possible to modulate cytokines
In vitro Ni induced cytokine release release in SNAS patients?
p=0,001
 Oral nickel treatment in SNAS patients (open
study) comparing:
p=ns
– Low Ni diet + oral nickel (group 1)
p=0,01
– Low Ni diet alone (group 2)
p=ns
 End points:
p=0,01 – cytokine release from ex-vivo Ni-stimulated cells
comparison pre v/s post treatment
– clinical outcome (VAS, rescue medications)
Di Gioacchino M, et al Di Gioacchino Minelli et al IJIP 2010 Di Gioacchino
Changes (%) in Th1,Th2, Treg cytokine release
Treatment schedule pre- post treatment (diet alone)
 After an increasing phase, 1.5 µg Ni/week was
orally administered for a year.
 Low Nickel diet – Brama-Ni (author M. Braga)
(www.lofarma.it/static/upl/Al/Allergianichel_COP_bassa.pdf)
 Gradual reintroduction of Ni containing foods
from the seventh month of treatment
Minelli et al IJIP 2010 Di Gioacchino Minelli et al IJIP 2010 Di Gioacchino
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6. Changes (%) in Th1,Th2, Treg cytokine release
pre- post Ni treatment Clinical outcome
 VAS significantly better in group 1 respect to
group 2 at the end of treatment;
p=0,05
p=0,07
p=0,05
p=0,006
p=0,05
p=0,05
p=0,005
p=0,002  The number of patients necessitating rescue
p=0,004
p=0,004 medications significantly lower in group 1
respect to group 2.
The open study does not allow to definitely
establish the efficacy of a treatment
Minelli et al IJIP 2010 Di Gioacchino Minelli et al IJIP 2010 Di Gioacchino
Double blind placebo controlled study on the Outline of the study
efficacy and tolerability of the desensitizing
therapy with nickel in patients suffering from This was a 60 week, prospective, randomized, double
blind, placebo controlled phase III trial, with four
Systemic Nickel Allergy Syndrome (SNAS) parallel groups.
Inclusion criteria were:
Participating researchers: 1) Presence of Ni-ACD (confirmed by patch test);
M. Di Gioacchino (coordinator - Chieti), O. De Pità 2) History of gastrointestinal and/or cutaneous
(Roma), V. Di Rienzo (Latina), M. Minelli (Lecce), V. symptoms of SNAS;
Patella (Salerno), L. Ricciardi (Messina), D. Schiavino
3) At least 70% clinical improvement after 1 month low
(Roma), S. Voltolini (Genova).
nickel diet;
4) Positivity of the Ni oral challenge.
Di Gioacchino
Outline of the study Results
4 Groups Results of the study demonstrated the effectiveness
– Group 1: Maintenance dose 1.5 µg/week of the treatment.
– Group 2: Maintenance dose 0.3 µg/week
– Group 3: Maintenance dose 30 ng/week
– Group 4: Placebo The work are under review in a scientific journal, the
data will be made public as soon as the manuscript
 End point: disappearance/reduction of symptoms will be published.
evaluated as difference in post/pre
– VAS
– Gastrointestinal and cutaneous symptoms
– Oral challenge with Nickel
– Drug consumption
Di Gioacchino Di Gioacchino
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7. Conclusions
 SNAS has a definite clinical pattern and is characterized by
Thankyou for your attention
specific immunologic features respect to Ni-ACD
 Oral administration of Ni induces immunological changes
(essentially reduction of Ni-induced inflammatory cytokine
and increase in Ni induced regulatory cytokines) and clinical
improvement.
m.digioacchino@unich.it
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