1 Introduction

1.1 Prevalence of Nickel Allergy

Nowadays, nickel is the most important worldwide contact sensitizer, and in recent decades, a constant increase in nickel dermatitis, corroborated by positive patch tests, has been observed in parts of the world especially among female patients. There are some risk factors that favor the onset of contact allergy: first of all, the inherent sensitization potential of the hapten, but also the frequency and duration of exposure, the presence of occlusion, any skin penetration-enhancing factors, altered skin barrier function, and environmental nickel pollution [1, 2].

Nickel sensitization can induce three forms of diseases: allergic contact dermatitis (ACD), mediated by a type IV immune reaction; respiratory allergy (RA), mediated by a type I immune reaction; and systemic nickel allergy syndrome (SNAS), whose pathogenesis, still not completely understood, involves both Th1 (typical of ACD) and Th2 (typical of RA) cytokine patterns.

RA to nickel, typically manifesting as asthma and rhinitis, is a relatively rare IgE-mediated disease; it essentially affects nickel-exposed workers (welders in particular) who become sensitized in the workplace. In contrast, ACD is a frequent disease, affecting nearly 15–20% of the general population [3]. A comprehensive review of all the epidemiological surveys conducted from 1966 to 2007 in Europe and the USA revealed a prevalence of nickel allergy ranging from 2.5% (Germany, 1966) to 17.6% (Norway, 2007) [1], with a higher prevalence among women than men (mean 17.1% versus 3%, respectively). A subset of patients affected by ACD also suffer from gastrointestinal and cutaneous symptoms after ingestion of foods containing a high quantity of the metal. Few studies in the literature report the incidence of SNAS, which is thought to affect approximately 20% of ACD patients [4, 5].

1.2 Systemic Symptoms in Nickel Allergy

In the 1970s, some authors noted that a considerable number of nickel-sensitive patients had dermatitis at sites other than those that were in direct contact with nickel-plated items. Christensen [6] was the first author to suspect that ingested nickel could be responsible for these reactions. The most common clinical manifestations were eczematous lesions at the elbow and knee flexures, eyelids, neck, and inner thighs; recurrent vesicular dermatitis of the palms, sides of the fingers, and/or soles of the feet; symmetrical nummular eczema, and anogenital eczema. It was also noticed that the hand eczema that so often followed the sensitization to nickel, usually starting some years after the first signs of metal sensitivity, most commonly appeared as volar, vesicular, symmetric pompholyx and showed activity independent of metal handling.

These data were confirmed studying patients with nickel-containing dental [7] and orthopedic [8] prostheses suffering from generalized eczema and urticaria.

In the following decades, there were many reports of nickel ACD patients suffering from cutaneous symptoms after ingestion of nickel-rich foods, especially vegetables. The histopathology of the flare-up of eczema appeared similar to the findings of ACD. This clinical picture was initially attributed to an abnormal absorption/secretion of nickel. However, studies demonstrated that there were no differences in nickel absorption and elimination between healthy subjects and nickel ACD patients both reacting and not reacting to the nickel oral challenge [9, 10].

The condition was termed “systemic nickel contact dermatitis” [11, 12] or “hematogenous contact eczema” [13], and a dose-dependent relationship between nickel and the appearance of cutaneous symptoms was also observed. Subsequently, there were observations that the same patients reported also gastrointestinal disturbance (meteorism, abdominal pain, diarrhea, and constipation), and the term systemic nickel allergy syndrome was introduced as it better describes both the involvement of organs other than the skin and the implied immunologic mechanism that also involves Th2 in addition to Th1 cytokines (the latter of which are typical of ACD) [14].

Few works have addressed the clinical nosology of this syndrome, being limited to symptomatology described in case reports [15,16,17], in some therapeutic trials [18, 19] and as a result of oral nickel challenges [20]. Oral nickel challenges were performed at doses varying from 0.3 to 10 mg, and a definite dose-response reaction pattern to oral nickel exposure was observed among nickel-sensitive subjects. A systematic study was conducted in 2013 to define the clinical characteristics of these patients [4]. The study involved 361 nickel ACD patients, 144 of which had a positive history of systemic symptoms linked to the ingestion of nickel-rich foods. In particular, the patients reported variably associated ACD flare-up, flare-up of previous positive patch tests, widespread eczema (including involvement of regions without direct contact with the metal), urticaria, angioedema, meteorism, gastric acidity, abdominal colic, diarrhea, vomiting and reflux, cough, dyspnea, headache, chronic fatigue, and dizziness. SNAS was diagnosed in only 98 (27%) of patients by elimination diet (http://www.lofarma.it/it/allergie/index.html) and placebo-controlled nickel oral challenge (capsules made by Lofarma, Milan, Italy). Cough, dyspnea, headache, chronic fatigue, and dizziness, reported in the history by 30 patients as always associated with gastrointestinal symptoms, were never observed after the nickel oral challenge and therefore should not be considered as part of SNAS. Similar data have also been observed after very high dose (10 mg) nickel challenge [9, 10, 21]. Therefore, only cutaneous and gastrointestinal symptoms clinically characterize SNAS (Table 43.1).

Table 43.1 Cutaneous and gastrointestinal symptoms in SNAS patients
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In SNAS patients, systemic symptoms followed a clinically evident nickel ACD of about 5 ± 3 years, irrespective of the severity of eczematous lesions or the degree of positivity of nickel patch tests. Skin and gut manifestations appeared almost always in combination, except for ten patients showing only cutaneous symptoms (ACD flare-up and widespread eczema) and eight patients with only gastrointestinal disturbance (meteorism and dyspepsia, combined with colic, gastric acidity, vomiting, diarrhea, or reflux). The most frequent manifestation of SNAS was the flare-up of previous ACD eczematous lesions reported by almost all patients, followed by a flare-up at the site of a previously positive nickel patch test. Such symptoms were variably associated with eczema in regions not in contact with the metal, or with urticaria and angioedema.

The majority of patients (73%) reported that systemic symptoms followed the ingestion of a single nickel-rich food, while other patients required a higher nickel intake to elicit symptoms. Similarly, almost all SNAS patients reacted to an oral challenge with the lowest nickel dose. Many authors criticize the usefulness of this test, as the dose of 1.25 mg is higher than that of a single nickel-rich food. In any case, the authors who studied the dose-response relationship of oral exposure to nickel in sensitive subjects found a very high sensitivity and specificity for the oral nickel challenge [11]. Challenged patients reacted to oral nickel exposure at doses ranging from 0.3 to 4 mg with increasing symptoms, while none of the healthy controls reacted.

SNAS is associated with lactose intolerance in a very high percentage of patients (63–74% from various studies) [4, 22]. It can be hypothesized that in SNAS patients the nickel-induced pro-inflammatory status could temporarily impair the brush border enzymatic functions, resulting in hypolactasia.

The incidence of other IgE-mediated diseases was similar to that of the general population, as 2 patients had atopic dermatitis, 29 had respiratory allergy to pollens and/or mites (8 asthma and 21 rhinitis), and 4 had allergy to latex and were also sensitive to latex cross-reactive fruits.

1.3 Pathogenesis of SNAS

Recent studies have clarified many aspects of the pathogenesis of SNAS. They especially have clarified that it is a nosological entity distinct from other forms of allergy to nickel. In particular, no IgE antibodies were found in SNAS patients, and there was evidence that involvement of the immune system was more complex than the type IV immune reaction seen in ACD.

Studies have focused on (1) nickel metabolism and (2) nickel immune response both before and after nickel challenge, comparing results obtained in SNAS patients, ACD patients, and normal subjects.

1.3.1 Nickel Metabolism

It has been estimated that the average human daily intake of nickel is approximately 200 μg and that a nickel dietary requirement of about 50 μg per day is important in human nutrition [23]. Most ingested nickel remains unabsorbed within the gastrointestinal tract and excreted with feces, and only about 1 to 10% is absorbed. Serum concentrations vary from 1.6 to 7 μg/L and urinary nickel concentration from 2 to 5 μg/L. The nickel concentration in sweat is high, ranging from 7 to 270 μg/L; thus, sweating may provide an important route for the excretion of nickel from the body. Furthermore, sweat, which may contain up to 20 times as much nickel as plasma, may influence the amount of nickel that reaches the skin [24].

It has been shown that urine is the most reliable parameter to follow after oral intake of nickel, even though both serum and urinary levels of nickel reflect the nickel intake [25]. Nickel blood concentrations vary greatly in different reports of oral challenge with the metal. It is known that many factors, including diet, stress, age, and seasonal variation, may influence serum nickel levels. In rats intravenously injected with nickel chloride, 90% was eliminated in the urine within 4 days postinjection, and only 3% was excreted by fecal discharge [26]. Nickel urinary excretion is rapid, not dose-dependent, and its elimination appears to follow first-order kinetics [27]. Estimates of the half-life of urinary removal of nickel range from 20 to 60 h [28, 29].

Atopy seems to be a factor influencing nickel absorption and excretion; in fact, blood levels and nickel excretion were determined in patients with nickel allergy and different types of eczema with and without atopy before and after a single oral dose of nickel sulfate. Urinary excretion of nickel was found to be age dependent (decreasing with increasing age), and the level of nickel in urine was significantly (p < 0.005) higher in the atopy groups compared to the controls [30].

Only one study compared SNAS patients to ACD and non-allergic subjects. In this case, similar serum nickel concentrations in allergic patients and controls, both before and after metal ingestion, were observed among the three groups. Urine and serum nickel were in the range of the reference values (0.2 to 2.0 μg/L of serum or urine) at baseline. A similar peak of urine and serum concentrations was determined 4 h after the Ni challenge (5 mg), with a similar decrease after 24 h [21].

In conclusion, no alteration of nickel metabolism is present in SNAS patients.

1.3.2 Nickel Immune Response

It has been demonstrated that both Th1 and Th2 immune responses are involved in eliciting ACD. Analyses of cytokine production by Ni-specific T cells have demonstrated a mixed Th1- and Th2-type cytokine profile in both T-cell clones and peripheral blood mononuclear cells (PBMC) [31,32,33,34]. Analyses of Ni-specific T-cell clones generated from PBMC and the skin of allergic patients have also suggested that both CD4+ and CD8+ T cells are involved in the immune response to Ni [35, 36]. However, comparing among ACD patients those reacting to the oral administration of nickel (SNAS patients) versus nonreactors, a more specific immune involvement has been determined. The oral administration of nickel induced a decrease of blood CD8+CD45RO+ cells in both ACD and SNAS patients (this was significantly greater in SNAS patients, p < 0.001), whereas CD4+CD45RO+ lymphocytes significantly decreased only in SNAS patients [37,38,39]. These results suggest a migration of memory T cells from the blood to the peripheral tissues. In particular, there is evidence that CD4+CD45RO+ cells increased in the intestinal mucosa, particularly in the epithelium, in SNAS patients after nickel challenge. CD8+ cells, in contrast, decreased after nickel challenge in the gastric epithelium due to cell apoptosis [37].

NiSO4-stimulated peripheral blood mononuclear cells (PBMC) from nickel-allergic patients have been shown to produce increased levels of Th1 and Th17 cytokines and a variable increase in Th2 cytokines [32, 40,41,42]. In biopsies of positive patch test reactions taken from different skin sites in nickel-allergic patients, a statistically significant increased expression of mRNA for IFN-γ, IL-2, IL-4, and IL-10 was found [43, 44]. These findings partially contrasted with the results of previous studies with a similar design showing that a Th1 cytokine profile developed in such individuals [45,46,47].

When nickel ACD patients were divided between responders to oral nickel (induction of widespread eczema and gastrointestinal symptoms after oral nickel challenge) and non-responders, an increase in Th2 cytokines was exclusively seen in responders. In particular, IL-5 was the cytokine with the most relevant increase [10, 37, 38]. Cytokine production was also measured in therapeutic trials in SNAS, demonstrating that in such patients an overproduction of Th2 cytokines (IL-5 mainly but also IL-13 and IL-4) is characteristic of the disease and its modulation follows desensitization treatment, which also induces an increase in IL-10 [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48].

In conclusion, available data indicate that, in SNAS patients, nickel challenge induces a mobilization of CD4+CD45RO+ cells from the blood to the gastrointestinal mucosa. Also, in addition to the Th1 and Th17 cytokines typical of nickel ACD, in SNAS patients there is an increased production of Th2 cytokines that is reversible after nickel desensitization.

2 Diagnosis

The diagnosis of SNAS requires a history of nickel ACD, the appearance of the above-described cutaneous and/or gastrointestinal disturbances following the ingestion of nickel-rich foods, and the disappearance or substantial improvement of such symptoms after a low nickel diet. Essential for the diagnosis is to confirm that symptoms reappear after a double-blind placebo-controlled oral nickel challenge. Nickel ACD should be diagnosed by the history and the results of a nickel patch test performed according to the International Contact Dermatitis Research Group criteria [49].

Symptomatic patients should be administered a low nickel diet. The nickel daily dietary intake has been estimated between 200 and 600 μg. A low nickel diet contains a maximum of 50 μg of the metal. A list of the nickel content in foods is provided in Table 43.2. The diet should be followed for at least 1 month, and patients who respond to this should undergo a nickel oral challenge.

Table 43.2 Nickel content in foods
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The provocation test consists of administering a capsule containing talc as placebo or nickel sulfate at increasing doses from 0.6 mg. The oral challenge is performed in the morning, in individuals who have been fasting for 12 h. If the test is still negative, the nickel dose will be increased to 1.25, 2.50, 3.75, and 5.00 mg at 1 day intervals from the last dose. The skin status and systemic symptoms are evaluated and recorded 24 h after the challenge. Positive reactions include eczematous eruptions of previously unaffected skin, flare-up at previous sites of contact dermatitis, including flaring at sites of previous positive patch test reactions to nickel, and urticaria, angioedema, and/or gastrointestinal symptoms. Figure 43.1 shows two skin reactions after oral nickel challenge.

Fig. 43.1
figure 1

(a) and (b) Examples of skin reactions after oral nickel challenge

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The diagnosis of SNAS is confirmed in the case of a positive challenge. In such cases, the low nickel diet can be used as treatment. However, the low nickel diet consists of a list of forbidden foods without a healthy balanced dietary plan. This regimen is difficult to follow not only because of its impact on the patient’s quality of life, but also because nutritional characteristics of many nickel-containing foods (fiber, carbohydrates, essential elements and vitamins, etc.) are important for human health. For this reason, a nutritionally balanced diet with low nickel content [4] has been developed, also providing a list of allowed foods and a number of appropriate recipes (available at http://www.lofarma.it/it/allergie/index.html) to increase patients’ compliance. Despite this, maintaining the diet for a long time strongly impacts the patient’s quality of life. Therefore, desensitization treatment should be considered.

3 Induction of Immunological Tolerance to Nickel

Continuous exposure to nickel may lead to oral tolerance mechanisms that modulate nickel sensitivity [50]. Many experimental studies have been made in animal models to study the induction of immunological tolerance to some antigens and haptens by repeated oral administration. The tolerance was mediated by T regulatory cells and suppressor lymphocytes [51, 52].

Tolerance to metals was also studied, in particular nickel and chromium. Animals treated via the oral route with nickel and chromium powder failed to react to subsequent immunization, whereas control animals not pretreated became clearly hypersensitive [53]. The results of these studies were confirmed in mice. After oral administration of nickel sulfate (NiSO4) in drinking water for 10 weeks, treated mice were tolerant toward the subsequent sensitization step with NiSO4, in comparison to the controls. CD4negCD8+ T cells were implicated in the mechanism of tolerance [54]. Moreover, some experiments demonstrated a long-term desensitization mediated by antigen-presenting cells (APCs), CD4-8+ T cells, and T regulatory cells. In fact, when splenic T cells or lymph node cells of orally tolerized mice donors were transferred to naïve recipients, even after a treatment-free interval of 20 weeks, they specifically prevented sensitization of the recipient mice. The lymph node cells of such donors were anergic, because in vivo sensitization with NiCl2 and in vitro restimulation with the hapten did not induce IL-2 production that was seen in lymph node cells of mice not tolerant before sensitization [55]. Results were confirmed by subsequent studies showing that the oral administration of nickel (both as NiSO4 and NiCl2) to mice already sensitized to the metal was also able to induce a long-term persistent desensitization mediated by antigen-presenting cells (APCs), CD4-8+ T cells, and T regulatory cells. In fact, nickel oral administration induced T suppressor cells and tolerogenic APCs that were able to maintain tolerance when activated by the antigen in the presence of a danger signal [56]. These animal experimental studies were the basis for the use of a desensitizing treatment in humans.

The efficacy and safety of hyposensitization to nickel in humans were initially evaluated in patients affected solely by contact allergy. The first attempt was made by Sjoval and Coll [57] in 1987 who, having observed that patients with nickel ACD reported an improvement of their hand eczema and metal sensitivity after a positive oral provocation test with nickel salts, administered orally capsules containing 5 mg of NiSO4 to nickel-sensitized patients for 6 weeks; this treatment led to reduction of the degree of contact allergy, measured as an increase in the lowest dose of NiSO4 able to induce positive patch test reactions before and after treatment. No effects were observed with a dose of 0.5 mg. Other studies showed contrasting results. Morris [58] reported clinical improvement in 85% of patients without tolerance to nickel during challenge tests who completed a sublingual hyposensitization treatment. Bagot et al. [59] did not obtain positive results in a double-blind placebo-controlled study involving patients who ingested 5 mg capsules of nickel sulfate per week for 7 weeks. On the other hand, the weekly subcutaneous administration of increasing doses (10−6–10–3 mol/L) of a nickel sulfate-containing solution failed to show improvement in nickel ACD [60].

The first attempt to utilize the oral administration of nickel in patients with SNAS was made in 1995 [61]. The authors treated patients with ACD that showed systemic symptoms with ingestion of nickel-rich foods with increasing doses of oral nickel sulfate associated with an elimination diet. The oral administration of very low doses of nickel sulfate tablets (0.1 ng daily for the first year and then every other day for the second and third years) to 51 patients led to the disappearance of symptoms in 29 of the 30 patients who completed the treatment course [61]. These preliminary results were confirmed in 2006 [5] in a large clinical trial involving 214 patients affected by SNAS. A group of 136 patients were treated for 12 months with a very low dose of nickel (up to 0.2 ng per day) while following a nickel-free diet. The control group (78 patients) only followed a nickel-free diet for the same period. After 1 year, patients gradually resumed nickel-containing foods: the majority of the nickel-treated patients (94 out of 136, 69%) showed a clear clinical improvement in their condition, 47% even achieving complete remission with no sign of disease following reintroduction of nickel-containing food; in contrast, only a minority of the patients of the control group (17.9%) could reintroduce dietary nickel without showing symptoms. Patch tests and oral provocation tests were performed in both groups before and after desensitization. Control patients did not show any modification in reactivity to nickel either via patch testing or oral challenge. In treated patients, reactivity to nickel patch tests showed no variation in 68 cases (72.3%), decreased in 17 (18%), increased in 1 (1.1%), and turned negative in 8 patients (8.6%). The oral challenge test showed an increase in tolerance to nickel in the majority of cases: 29 (30.9%) did not react, 47 (50%) reacted to a higher dose, and 17 (18%) to the same dose, while 1 patient (1.1%) showed a decrease in threshold dose.

Oral nickel hyposensitization, with high doses of metal, has been proposed also for ACD patients; however, the clinical trials set up so far involved a limited number of ACD patients, and the treatment was administered for only a short period of time. The most recent clinical trial [62] studied 28 nickel ACD patients who received a daily dose of 50 μg of NiSO4 in cellulose capsules for 3 months. In the 26 patients that completed the study, oral hyposensitization ameliorated clinical manifestations despite continued nickel exposure; moreover, the threshold of skin responsiveness to nickel increased, and the T lymphocyte responsiveness to the metal in vitro decreased. During the 1-year follow-up period, 50% of the patients experienced relapses of clinical manifestations at the sites of topical exposure to nickel, likely as a consequence of the short period of treatment.

The nickel doses used for hyposensitization treatment in the various studies were quite different, ranging from 1 ng to 5 mg, and not justified by investigative studies, until 2010 when it was established that SNAS patients tolerated 1.5 μg nickel/week without side effects, whereas ACD patients could receive much higher doses, up to 50 mg [18, 62].

At present, nickel hyposensitization in SNAS is administered at the cumulative dose of 1.5 μg/week and has proven to be effective in reducing symptoms and the need for medications. The treatment induces significant modulation of the immune system. The clinical benefits are maintained at least for 1 year, the longest period of follow-up that has been evaluated in controlled trials so far [18, 63].

The use of such treatment was validated by a phase III study conducted in 2014 [63] as a multicenter prospective double-blind placebo-controlled trial, in which 141 patients were randomly assigned to three treatments (1.5 μ g, 0.3 μ g, and 30 ng Ni/week) or placebo. The study involved patients who (1) had a positive nickel patch test, (2) reported symptoms suggestive of SNAS, (3) improved at least 70% from baseline after 1 month on a low nickel diet (severity of symptoms rated on a visual analog scale (VAS)), and (4) tested positive to a nickel oral challenge. The study lasted 1 year, and after 5 months, patients were allowed to progressively reintroduce nickel-rich foods, starting with those with a maximum of 100 mcg of nickel content.

The treatment was effective. During the reintroduction of nickel-rich foods, symptoms improved significantly in patients given the highest nickel dose compared to placebo, with a VAS score similar to that of patients on the low nickel diet. The effect of nickel oral hyposensitizing treatment (NiOHT) seemed dose-dependent, as 1.5 μg Ni/week gave the best results (Group 1), 30 ng Ni/week and placebo the worst (Group 3 and Group 4), and 0.3 μg Ni/week was intermediate (Group 2). Gastrointestinal symptoms significantly improved in parallel with VAS scores compared to placebo (Fig. 43.2), and were more sensitive to NiOHT than cutaneous manifestations, which decreased in frequency, but at the limit of statistical significance (p 0.05) compared to Group 3 and placebo. This is not altogether surprising, as skin contact with nickel, which can never be completely avoided, might have induced symptoms linked to ACD, confounding the results. The effectiveness of NiOHT with 1.5 μg Ni/week is corroborated by the observation that, during the reintroduction of nickel-rich foods, only three patients (10.3%) took rescue medications, compared to significantly more in other groups (Group 1 vs. each group, p 0.05). The subjective data, symptoms, and VAS ratings, which show post-NiOHT tolerance to nickel, are supported by objective tests such as nickel oral challenge and patch testing. As a matter of fact, at the end of treatment, significantly more patients in Group 1 than in Group 3 and the placebo group needed a higher nickel dose at the oral challenge to elicit symptoms than before treatment. Similar differences were found with patch testing at the end of the study: there were significantly more patch test negatives in Group 1 than in Group 3 and the placebo group (Fig. 43.3).

Fig. 43.2
figure 2

Changes in gastrointestinal symptoms during reintroduction of nickel-rich foods. Patients of Group 1 were treated with 1.5 μg of nickel, Group 2 with 0.3 μg of nickel, and Group 3 with 30 ng of nickel. Group 4 received placebo

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Fig. 43.3
figure 3

Positive and negative patch tests in the four groups at the end of the study, showing a significant increase in negative patch tests in Group 1. Patients of Group 1 were treated with 1.5 μg of nickel, Group 2 with 0.3 μg of nickel, and Group 3 with 30 ng of nickel. Group 4 received placebo

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The efficacy of desensitization seems to be linked to an increase of IL-10 [48], a regulatory cytokine involved in the action of vaccines for inhalant and hymenoptera venom allergy [64]. These changes in regulatory cytokines led to the hypothesis that nickel tolerance after NiOHT might be a consequence of the differentiation and proliferation of nickel-specific T regulatory lymphocytes, which can maintain immune tolerance to nickel in healthy subjects [65]. This also can explain the effectiveness of the low nickel doses administered: high doses of antigen favor an anergy-driven pathway to tolerance, while low doses of antigen promote a suppressive pathway via regulatory T cells producing IL-10 and TGF-β [66, 67].

4 Conclusion

SNAS can be defined as the appearance of cutaneous (in regions without direct nickel contact) and gastrointestinal symptoms after the ingestion of nickel-rich foods and is found in approximately 20% of nickel ACD patients. The diagnosis can be made in patients with ACD to nickel whose gut and skin symptoms disappear or improve after a low nickel diet. The gold standard for the diagnosis is the double-blind placebo-controlled oral challenge with nickel. The pathogenesis of the disease involves both Th1 and Th2 patterns of cytokines.

Nickel hyposensitization is effective in patients suffering from SNAS. The majority of such patients can safely consume nickel-containing foods after 1 year of treatment. Clinical experience with this regimen in ACD patients, although positive and encouraging, is scarce in terms of the number of patients treated and length of the hyposensitization course and is followed by a relapse of cutaneous symptoms after a relatively short period of time. In any case, nickel hyposensitization is able to modulate immune responses to nickel, restoring a state of tolerance that seems to be mediated by T regulatory lymphocytes. This is a promising area, and further research is required.