Nickel Allergy: Lack of Correlation Between Systemic TH1 Immune Response and Skin Patch Testing

Dear Editor, We read with interest the article in the November 2004 issue concerning nickel allergy in a case where an atrial septal defect was being closed.¹ To test whether a patient reporting nickel allergy was sensitive to a device, they applied the device to the skin, eliciting a contact allergic response. Nickel allergy has also been implicated in adverse responses to other steel implants. We have had a number of cases where percutaneous coronary intervention was required in patients reporting nickel allergy, raising concern about possible reaction to the stents. Nickel allergy has been postulated as having a role in in-stent restenosis, a response to the nickel present in virtually all stents, though this is disputed.^2,3 The identification of patients with nickel allergy using skin patch testing has limitations.³ There is marked variability of response, even in the same patient at different times. Furthermore, there appears to be a discrepancy between skin allergy and systemic response. Typically, skin contact dermatitis, a type 2 allergic response, is mediated by the TH1 pathway involving interleukin 2 (IL-2) stimulation of lymphocytes, resulting in cell activation, migration and proliferation. The nickel molecule may be presented to T cells as a hapten by dendritic cells within the dermis.⁴ The mechanism of response to internal implants is less well understood, but has also been thought to involve a TH1 response. We therefore examined the effect of in vitro exposure to nickel on the lymphocyte TH1 response. Initially, blood was obtained from 5 patients with positive skin patch tests for nickel allergy. Mononuclear cells were isolated and incubated with varying concentrations of nickel to identify the optimum concentration and duration of incubation that resulted in cell proliferation by percentage in the synthesis phase of the cell cycle (% S phase) at 120 hours. Next, blood was taken from 10 patients, of which 5 were patch test-positive and 5 were negative, and mononuclear cells were again isolated and incubated with the optimal conditions as determined previously. These were then tested in a blinded fashion for markers of TH1 immune response, IL-2, CD69 (a marker of early T-cell activation) and DNA synthesis. In the first 5 patients with markedly positive skin patch tests, the optimum concentration used to induce increased cell proliferation was 25 µg/ml nickel sulphate solution per (1 x 10)6 cells. In part 2, incubation with nickel did not produce any significant increase in CD69 or IL-2 at 24 or 72 hours in nickel allergic patients. An increase in the percentage of cells in the synthesis phase was noted in only 1:5 allergic patients using a nickel concentration previously determined to be optimal. Furthermore, nickel caused increased activation in 1:4 control, patch test-negative subjects. The response of mononuclear cells to nickel sulphate appears to be variable, and not correlated with the skin patch test response. The presence of a positive skin patch test may not reliably predict a systemic response to a nickel implant, while a negative test does not exclude a systemic response. Other investigators have also found that nickel allergy may be independent of dendritic cells and the TH1 pathway.⁵ Thus, testing for a TH1 response does not provide a reliable means of predicting whether nickel allergic patients will react to implantable nickel-containing devices such as stents. More work is needed to determine the mechanism of nickel sensitization with nickel-containing implants and whether a documented skin allergy is necessarily a contraindication to their use. Acknowledgements. We are grateful to Dr. Paul Keown (Immunology) for advice and to Dr. Charles Morton (Dermatology) for help in the recruitment of patients.

1. Singh HR, Turner DR, Forbes TJ. Nickel allergy and the Amplatzer septal occluder. J Invasive Cardiol 2004;16:681–682. 2. Koster R, Vieluf D, Kiehn M, et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet 2000;356:1895–1897. 3. Hillen U, Haude M, Erbel R, Goos M. Evaluation of metal allergies in patients with coronary stents. Contact Dermatitis 2002;47:353–356. 4. Aiba S, Tagami H. Dendritic cells play a crucial role in innate immunity to simple chemicals. J Investig Dermatol Symp Proc 1999;4:158–163. 5. Nasorri F, Sebastiani S, Mariani V, et al. Activation of nickel-specific CD4+ T lymphocytes in the absence of professional antigen-presenting cells. J Invest Dermatol 2002;118:172–179.