Allergy to nickel: Systemic effects and oral immunotherapy

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

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Allergy to nickel: Systemic effects and oral immunotherapy

  1. 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 andImmunotoxicology 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-ACDResolution 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 1
  2. 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 challengeModified 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 LArgy 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 2
  3. 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 foodsApricot  Nickel linked to proteins can be stable, notHerrings all biologically available.BroccoliCarots  Nickel present in the lipid portion isLettuce completely biologically available. Di Gioacchino Di GioacchinoSystemic 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 3
  4. 4. Changes in circulating lymphocyte Nickel metabolism after Ni-challengeUrine and serum Ni levels in controls and in ACD and SNAS women, before and 4 and 24 hours after Nichallenge. 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 challengeT 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-challengeM. 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 afteroral 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 4
  5. 5. IL-5 and Nickel Allergy IL-5 and Nickel Allergy IL5 in control and sensitized patients before and after oral nickel exposureIL5 % changes 24 h after oral nickel challenge in control subjects and in patientswith 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 treatmentMinelli et al IJIP 2010 Di Gioacchino Minelli et al IJIP 2010 Di Gioacchino 5
  6. 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 treatmentMinelli 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 Results4 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 6
  7. 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 Di Gioacchino 7

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