PHOTOTHERAPY IN THE TREATMENT OF ALLERGIC RHINITIS

Allergic rhinitis (AR) is one of the most common allergic diseases, affecting 20% of the adult population and up to 40% of children (Salib et al., 2003). It is associated with decreased learning, performance and productivity at work and school, as well as a reduced quality of life. The detrimental effects of AR on quality of life (QOL) include fatigue, irritability, memory deficits, excessive daytime somnolence, and depression. The annual economic impact of AR is calculated to be between $ 6.3 billion and $ 7.9 billion without counting its detrimental effects on QOL (Fineman, 2002). Current therapeutic options such as allergen avoidance, medication and immunotherapy are far from ideal. It is important to develop an effective modality to relieve the symptom except for targeting the complexity of underlying inflammatory mechanism of AR. Phototherapy is the application of light to a pathological area to promote tissue regeneration, reduce inflammation and relieve pain. Several types of phototherapeutic devices are currently used for medical treatment using selected wavelengths and controlled dosage of irradiation. Significant suppression on the clinical symptoms of AR by the phototherapy treatment of ultraviolet (UV) and visible light was reported (Csoma, et al., 2004, 2006; Koreck, et al., 2005, 2007). Narrow-band red light phototherapy was found to markedly alleviate the clinical symptoms of AR (Neuman & Finkelstein, 1997). In addition to UV and visible light therapy, far infrared ray (FIR) therapy is also reported to have beneficial effects to patients with AR (Hu & Li, 2007). Photochemical effect is elicited using UV and visible light irradiation, whereas thermal effect is induced with FIR irradiation. Although different mechanisms are involved when light sources with different ranges of wavelengths are employed, phototherapy represents a noninvasive, alternative intervention for the treatment of AR. This chapter is organized as follows. First, pathophysiology and traditional management of AR are briefly reviewed. Second, photobiology and phototherapy related to AR are summarized. Finally, the clinical outcomes of FIR therapy as well as red light acupoint stimulation on patients with AR are described.


CONTENTS
List of publications related to the subject of the thesis 4 List of abbreviations 5 1. Introduction 6 2. Aims 9 3. Methods 9 3.1. Investigation of the effect of different wavelengths on the immediate type hypersensitivity reaction in the skin 9 3.1. 1

I. Introduction
Allergic rhinitis is one of the most common health problems in many countries, because it is a high-cost, high-prevalence disease, affecting about 15-30% of the population.
The number of the patients with allergic rhinitis is still increasing, especially in the welldeveloped, industrialized countries [1]. Although it is not associated with severe morbidity and mortality, allergic rhinitis has a major effect on the quality of life. Its increasing prevalence, its impact on the individual quality of life and social costs [2,3] and its role as a risk factor for asthma [4], underline the need for improved treatment options for this disorder. year. It has the same clinical symptoms such as seasonal allergic rhinitis, but the main symptom is the nasal blocking, and its frequent complication is sinusitis.
The etiology of allergy is multifactorial, it is genetically determined, but environmental factors also play an important role in the development of the typical symptoms. The inflammation of the nasal mucosa is frequently induces the inflammatory condition of the paranasal sinuses (rhinosinusitis).
The inflammation is a type I, or immediate hypersensitivity reaction of the nasal mucosa that arises in consequence of an allergen-immunoglobulin E (IgE) interaction in sensitized individuals [5]. The development of the disease is characterized by an initial sensitization phase to a specific allergen, when no clinical symptoms are present. At later time-points the encounter of the same allergen by sensitized individuals is followed by the elicitation of an allergen specific immune response and the activation of effector mechanisms.
Previous studies have established that a shift towards T-helper 2 (Th2) cells plays a role in the initiation and maintenance of the disease [6,7], Eosinophils, mast cells and basophils are considered the effector cells of hay fever [8,9]. Following an allergen challenge these cells release inflammatory mediators such as histamine, tryptase, leukotrienes, prostaglandins, cytokines and eosinophil cationic protein (ECP), which are responsible for most of the pathological processes occurring in the nasal mucosa [5,[9][10][11].
Elimination of the inhalative allergens -which are responsible for developing of hay phosphodiesterase inhibitors and intranasal heparin, and there have been developments in appropriate allergen-specific immunotherapy [12]. However, the complete suppression of the clinical symptoms may not be achieved in most of the cases with the currently available drugs. The use of these drugs is controversial in special subsets of patients such as pregnant and breast-feeding women [13], and pharmacotherapy has a numerous side-effects, too. All of these characteristics of allergic rhinitis highlight the need for effective new treatment options.
Phototherapy has a profound immunosuppressive effect [14][15][16][17][18], and the different phototherapeutic methods utilizing both ultraviolet (UV) and visible (VIS) light has been widely used for the therapy of various inflammatory skin diseases, including atopic dermatitis and psoriasis [19][20][21]. Initially, broadband UV light sources in the 290-320 nm UVB spectrum range (BB-UVB) were used for the treatment of allergic and non-allergic skin diseases.
During the last few years, these light sources have been replaced with the more efficient narrow-band UVB light sources operating at 311 nm + 2 nm wavelength (NB-UVB) [12]. A new, highly effective laser-based phototherapy has been introduced recently for the treatment of different skin diseases based on the use of the 308 nm xenon chloride excimer laser The "super narrow-band" 308 nm xenon chloride (XeCl) excimer laser has been found to be more effective than NB-UVB in inducing T cell apoptosis in vitro and is also clinically more effective for the treatment of an inflammatory skin disease, psoriasis [22][23][24].
These results now have been confirmed by other groups and the 308 nm excimer laser is currently widely used for the treatment of allergic and non-allergic skin diseases [25,26] In addition ultraviolet A (UVA; 315-400 nm), psoralen plus UVA (PUVA), combined UVA-UVB and high-dose UVA1 (340-400 nm) therapies are also essential in the dermatological practice. The major mechanisms of immunosuppression induced by the various forms of phototherapy in the skin involve apoptosis induction in infiltrating T cells, reduction in the number and function of Langerhans cells, and the induction of immunomodulatory cytokines such as IL-10 [16-18, 22, 27-34] Although the different atopic diseases, e.g. atopic dermatitis and allergic rhinitis, share many common pathogenetic factors, and there are a large number of phototherapeutic modalities for the treatment of atopic dermatitis, the use of UV-based therapies for the treatment of allergic rhinitis has never been reported. Therefore we were interested in whether phototherapy might also be effective for the treatment of allergic rhinitis.
Skin prick test (SPT) is the most frequently used in vivo test for the diagnosis of immediate type allergic reaction identifying an allergen responsible for the development of an allergic disease such as hay fever. To perform SPT a drop of the suspected allergen solution is applied to a skin test area of the forearm. The upper layer of the skin is then pricked using a lancet to promote the penetration of the allergen through the epidermis. After 20 minutes the allergen is removed and the skin reaction is checked. If wheal (urtica) and/or skin reddening (flare reaction) is detected it suggests that the investigated allergen induced an IgE mediated allergic reaction. The size of the urtica/flare reaction reflects the severity of the allergic response. SPT is also used to assess the clinical efficacy of different drug treatments for allergic diseases, such as hay fever or asthma, since there is a good correlation between the suppression of the reaction in SPT and inhibition of the clinical symptoms [35,36]. Based on these facts, it seemed reasonable to use SPT in order to test the efficacy of the different forms of phototherapy for the treatment of allergic rhinitis. We assumed that if phototherapy suppresses SPT reactions it may also be effective in inhibiting clinical symptoms of allergic rhinitis.

Aims
2.1. In the first series of our study we tested the capacity of different wavelengths to inhibit the wheal formation in the SPT reaction.
2.2. According to these results in the second series of our study we sought to investigate the effect of these different light sources in the treatment of allergic rhinitis and thus to identify the clinically most effective wavelengths, which combine the advantages of high efficacy and few side effects. with the same antigen on both the irradiated and non-irradiated skin areas.

Skin prick test
The SPT is a method that is widely used to investigate the immediate hypersensitivity reaction to a specific allergen in the skin [35]. SPTs were performed with recombinant allergens (Soluprick-Epipharm Allergie-Service GmbH). Ragweed, muggle, cat and dog hair antigens were used for the investigations. Twenty-micro litre aliquots of the test solutions were placed on the patients' forearms, with a distance of more than 3 cm between individual application points. Sterile 0.9% sodium chloride solution and histamine hydrochloride were used for control purposes. Reactions were recorded 20 min after testing and the wheal size was measured by digital planimetry. After determination of the individual sensitivity of each patient, for each individual one allergen was chosen that induced an "optimal" wheal of approximately 10 mm in diameter. SPT reactions were then examined with this antigen on the irradiated and non-irradiated control skin areas 24, 48 and 72 hours after irradiation.

Statistical analysis
To evaluate the effect of different wavelength irradiations on the development of allergeninduced wheals, the size of the wheals that developed on the irradiated areas were compared with those on the non-irradiated control test areas. Differences in wheal size were analyzed statistically by means of repeated measures one-way ANOVA followed by Dunnett's posthoc test. If parametric ANOVA was not applicable we used Friedman repeated measures ANOVA, followed by Dunnett's post-hoc test. Differences were considered to be statistically significant at p< 0.05.

Intranasal phototherapy
3.2.1. Assessment of tolerability and efficacy of intranasal XeCl laser therapy in hay fever
All of the patients suffered from severe, ragweed-induced hay fever that did not respond well to conventional antiallergic treatment, all had a history of rhinitis of at least 2 ragweed seasons. The diagnosis of allergic rhinitis was confirmed by positive SPT results to ragweed (a wheal greater than 5 mm) and by measurement of the ragweed-specific IgE antibody level.
Patients with significant nasal structural abnormalities, bronchial asthma The patients were enrolled after the beginning of the ragweed season, when the pollen counts were above 50/m 3 in Szeged area. Seventy-two patients with allergic rhinitis were recruited to participate in the study. After the screening visit 23 patients were excluded because they did not meet the inclusion criteria. Forty-nine patients were randomly assigned to receive either mUV/VIS irradiation in the active treated group (25 patients investigator examined the patients weekly and performed nasal lavages. At these weekly visits patients also scored their symptoms. TNS, a sum of scores for sneezing, rhinorrhoea, nasal itching and nasal obstruction, which is considered the most common and best established parameter for the clinical assessment of allergic rhinitis, was also calculated. Nasal obstruction was also evaluated by using acoustic rhinometry. At the end of the protocol, the overall efficacy of the therapy was assessed on a scale from 1 to 4 (with 1 corresponding to significant, 2 moderate, 3 slight and 4 no global improvement of symptoms). was less than that obtained 24 hours after treatment, but on the 2 x MED laser irradiation, the wheal size was approximately 40% less than the size of the wheal on the non-irradiated control areas (Fig.2.). The XeCl laser irradiation had no effect on histamine-induced wheal formation (data not shown).
Hours Fig. 2.: Effect of the 308 nm XeCl UVB irradiation on the SPT reaction.
UVB irradiation suppresses the allergen induced wheal size. Values represent wheal size 24 and 48 hours after irradiation with different doses of UVB expressed as a percentage of the untreated control. Error bars represent the standard error of mean. Significant decreases were observed 24 hours after irradiation at lxMED and 2xMED. Differences in wheal size were analyzed statistically by means of repeated measures one-way ANOVA followed by Dunnett's post-hoc test (n=7). Differences were considered to be statistically significant at p< 0.05.

Effects of the UVA irradiation on the SPT reaction
There was a tendency for decreasing of the wheal size in case of UVA irradiation. The strongest, statistically significant inhibition developed 72 h after the UVA treatment, it was 20,36% at 0.5 J/cm 2 , 23,3% at 1 J/cm 2 and 21,8% at 2 J/cm 2 (p<0.05) (Fig.3.). No correlation was found between the inhibition of allergen-induced wheal formation and the UVA dose.

Effects of the VIS irradiation on the SPT reaction
There was a tendency for decreasing of the wheal size in case of VIS irradiation, but VIS irradiation didn't influence significantly the wheal formation (Fig.7.). No correlation was found between the inhibition of allergen-induced wheal formation and the VIS dose.

Effects of the low-dose XeCl laser treatment on the clinical symptoms of allergic rhinitis
Of the 10 enrolled patients, 7 completed the 2-week treatment period. Three patients dropped out before completing the study, because of the significant worsening of their symptoms (lack of effect). Following treatment, there was no significant improvement in the sneezing, rhinorrhoea, nasal itching, nasal blockage or TNS (Fig.9.). The patients tolerated the treatment well, and no severe side effects were observed. Mild dryness of the nasal mucosa occurred in 2 patients; this did not need any intervention, and it disappeared within few days after the last treatment.

Effects of the medium-dose XeCl laser treatment on the clinical symptoms of allergic rhinitis
All eight patients enrolled in the medium-dose XeCl laser group completed the study. After the 2-week treatment period, significant improvements were observed in the sneezing, rhinorrhoea and nasal blockage scores, and also in the TNS (Fig. 10.). The improved clinical symptoms were usually first noted 4-5 days after the start of therapy, and thereafter the improvement was continuous. At the end of the XeCl laser treatment, the symptom scores were reduced by more than 50%. The XeCl laser treatment also reduced the severity of nasal itching, but the decrease was statistically not significant. No severe side effects occurred, but mild dryness of the nasal cavity was observed in 6 of the 8 patients; this was relieved by application of a vitamin A-containing oil. The clinical scores of sneezing, rhinorrhoea, nasal blockage and the TNS decreased significantly(p=0.018, p=0.035, p=0.013, respectively; Wilcoxon's Sum of Ranks Test, n=8) during the 2-week treatment period.

Effects of the PUVA treatment on the clinical symptoms of allergic rhinitis
Thirteen of the seventeen enrolled patients completed the study. Three subjects dropped out because of noncompliance and one because of a lack of efficacy. All the patients who completed the study responded well to the PUVA treatment. After the 3-week treatment period, significant improvements were observed in all of the nasal symptoms (sneezing, rhinorrhoea, nasal itching and nasal blocking) and also in the TNS (Fig. 11.). Fig. 12. shows the improvement of the TNS during the PUVA treatment in two patients with the change of the pollen number within the 3-week treatment period. The diagrams represent that the TNS were decreasing continuously due to the treatment, whereas the pollen number was still high.
Mild dryness of the nasal mucosa was the only side-effect observed in three patients, this was easily overcome with vitamin A oil.  The diagram also shows the change of the pollen number within the three-week treatment period. The diagrams represent that the total nasal scores were decreasing continuously due to the treatment, whereas the pollen number was still high.

Effects of the mUV/VIS and 1-VIS treatment on the clinical symptoms of allergic rhinitis
Forty-nine patients received intranasal irradiation either with mUV/VIS light (n=25, f:m=18:7, mean age: 37.8 years) or 1-VIS (n=24, f:m=15:9, mean age:39.3 years). The two groups did not differ in age, disease duration or clinical scores at the beginning of treatment protocol. TNS significantly decreased after mUV/VIS (p = 0.004) and slightly increased after 1-VIS treatment (p > 0.05) (Fig.l3.a.). In the mUV/VIS group the individual scores decreased compared to baseline for sneezing (p = 0.016), rhinorrhea (p = 0.007) and nasal itching (p = 0.014). The scores for nasal obstruction improved slightly during phototherapy but changes did not reach statistical significance (p > 0.05) (Fig.l3.b.). In the control group, none of the scores improved significantly at the end of treatment. In fact, a significant increase was observed in the score for nasal obstruction (p = 0.017) (Fig.l3.b.). No improvement of nasal obstruction was recorded using acustic rhinometry (data not shown). TNS significantly decreased after mUV/VIS (p = 0.004) and slightly increased after 1-VIS treatment (p > 0.05) (Fig. 13.a.). In the mUV/VIS group the individual scores decreased compared to baseline for sneezing (p = 0.016), rhinorrhoea (p = 0.007) and nasal itching (p = 0.014). The scores for nasal obstruction improved slightly during phototherapy but changes did not reach statistical significance (p > 0.05) (Fig.I3.b.). In the control group, none of the scores improved significantly at the end of treatment. In fact, a significant increase was observed in the score for nasal obstruction (p = 0.017) (Fig.l3.b.). In the overall efficacy assessment at the end of the treatment, mUV/VIS proved to be significantly more efficient than 1-VIS (p = 0.004) The therapy was well tolerated, the only side effect was dryness of the nasal mucosa, which occurred in all patients from the mUV/VIS group, and in 6 patients from the control group.
All patients, except one from the mUV/VIS group, scored the dryness as mild. In these patients dryness was controlled with emollients. In one patient who scored the dryness as severe the treatment was stopped.
The drop out rates in the active treatment versus the control group did not differ. In the mUV/VIS group we had 5 drop-outs (one because of lack of efficacy, one because of dryness of the mucosa, one for lack of compliance and 2 because of a modified holiday schedule). In the control group we had 4 drop-outs (2 in consequence of lack of efficacy, one for lack of compliance and one because of an upper respiratory infection). In the control group a significantly higher consumption of rescue medication was recorded compared to the mUV/VIS group (93 tablets in the control group versus 57 tablets in the mUV/VIS group).

Mechanism of the UV light induced immunnosuppression
UV irradiation has been successfully used for the treatment of hyperproliferative and inflammatory skin diseases for many years. Initially, BB-UV light sources in the UVB range 290-320 nm were used for such treatment, but during the last few years these light sources have been replaced with the more efficient NB-UVB light sources operating at 310-313 nm [15]. We recently introduced new, highly effective XeCl excimer laser-based UVB phototherapy for the treatment of different skin diseases [19,[37][38][39]. The XeCl laser was found to be more effective than conventional UVB light sources in the phototherapy of skin disorders [22,37]. These results have been confirmed by other groups and the 308 nm excimer laser is currently widely used for the treatment of skin diseases [25,26]. UVA  [27,30,31,33,34,[41][42][43]. It has been demonstrated previously that UV radiation induces keratinocyte and T-cell apoptosis [22,32] and UV radiation is known to modulate the expression of adhesion molecules on Langerhans cells and keratinocytes [14,33,41,44,45]. UV irradiation suppresses histamine release from mast cells [46] and decreases the number of infiltrating eosinophils in the skin.

Pathomechanism of allergic rhinitis
All of these inflammatory cells and processes are important in the pathogenesis of allergic rhinitis, which is an allergen-induced, IgE-mediated inflammatory disease of the nasal mucosa. During sensitization in the nasal mucosa allergen is taken and presented by antigen

Mechanism of the UV light induced suppression of the immediate type hypersensitivity reaction in the skin
UV therapy has long been used in the treatment of different inflammatory skin diseases, and as there are many common pathogenetic factors in these skin disorders and allergic rhinitis, we have now addressed the question of whether phototherapy might also be effective for the treatment of hay fever.
The SPT is a method that is widely used to investigate the immediate hypersensitivity reaction to a specific allergen in the skin, and it has been shown that there is a good correlation between the SPT reaction and the nasal symptoms in patients with allergic rhinitis. So in the first series of our study we investigated the effects of the different kind of irradiations on the immediate-type hypersensitivity reaction in the skin in order to identify the wavelengths, which are able to suppress most effectively the clinical symptoms of allergic rhinitis.
There was a tendency for decreasing of the wheal size in case of VIS irradiation, but VIS irradiation didn't influence significantly the wheal formation. By the effect of the UVA irradiation a tendency for decreasing of urtica formation was also observed, the suppression was statistically significant only 72 hours after the treatment. The UVB irradiation with the 308 nm XeCl excimer laser and the PUVA treatment suppressed the allergen-induced wheal development in a dose-dependent manner, the inhibition was statistically significant at erythematous doses. The fact that the XeCl laser and PUVA treatment had no effect on histamine-induced wheal formation suggests that the XeCl laser and PUVA treatment inhibit

Possible mechanisms of rhinophototherapy
According to the SPT results in the second series of our study we investigated the effects of different light sources in the treatment of allergic rhinitis. At first we used the biologically most effective UVB light source, the 308 nm XeCl excimer laser to assess the efficacy of phototherapy in hay fever, and we found that intranasal UVB phototherapy with medium-dose 308 nm XeCl excimer laser significantly suppressed the nasal symptoms of patients with severe hay fever, whereas in low dosages had no effect on the symptoms. For the treatment of skin diseases with NB-UVB irradiation, the therapy is started usually with a UVB dose of 0.8 x MED dose, which is gradually increased, depending on the patient's tolerance, and irradiation is performed 3-4 times weekly [15]. Since the XeCl excimer laser is more effective than NB-UVB, and since there were no data on the tolerability of the nasal mucosa to the XeCl excimer laser, we started the treatment of the nasal cavity with a lower UVB dosage than that we usually apply in the therapy of skin diseases. It emerged that the intranasal XeCl excimer laser illumination had no effect on the clinical symptoms of patients with hay fever when the treatment was started at the low dosage of 0.25 x MED twice weekly, but a significant improvement was seen when the treatment was started with 0.4 x MED and was continued with increasing dosages four times weekly. Mild dryness of the nasal mucosa was the only side effect observed, but it disappeared completely within a few days after the last XeCl laser treatment.
Then we investigated the efficacy of intranasal PUVA treatment in hay fever and we showed that PUVA treatment of the nasal cavity also significantly reduced the nasal symptoms of patients with allergic rhinitis. The treatment of the nasal mucosa was started with a low dose of UVA and the dosage was then gradually increased. We applied four treatments weekly.
Mild dryness of the nasal mucosa was the only side-effect observed during the treatment, and this was easily countered with vitamin A oil.
Based on these previous results then we applied a combination of low dose UVB, low dose  [14], increases the production of immunosuppressive cytokines in macrophages [33,42,43,55] , induces apoptosis in the T cells [22], in activated mast cells [55] and eosinophils, inhibits histamine release from the mast cells in vitro [46,56], Our group also investigated the effect of the mUV/VIS and 1-VIS light on eosinophils and inflammatory mediators in the nasal lavage, on T-cell, eosinophil and RBL-2H3 cell apoptosis and on the mediator release from RBL-2H3 cells. Koreck et al [57] found that in the mUV/VIS group the percentage of eosinophils and the ECP level in the nasal lavage decreased significantly during therapy, whereas, both the eosinophil cell count and the ECP level increased slightly in the control group. The nasal fluid IL-5 levels decreased after treatment in the mUV/VIS group and increased in the control group; as concerns the changes from the mean baseline values the difference between the two groups was statistically significant. A slight decrease of IL-4 levels was observed in nasal lavages from patients treated with mUV/VIS light and a slight increased in the samples from the control group, but changes did not reach statistical significance. mUV/VIS irradiation induced a dose-dependent increase in both, apoptotic T cells and eosinophils. No pro-apoptotic effect of 1-VIS irradiation was observed in either T cells or eosinophils. Moreover, a dose dependent increase of both CD3 + CD45RO + and CD3 + CD45RA + was observed after mUV/VIS irradiation. RBL-2H3 cells were resistant to mUV/VIS induced apoptosis.
We found that following mUV/VIS irradiation the P-hexosaminidase release was inhibited.
Even low doses of mUV/VIS (15 -60 mJ/cm 2 ) induced a significant decrease of Phexosaminidase release and higher doses (240 mJ/cm 2 ) had a complete blocking effect. In contrast, no inhibitory effect of 1-VIS irradiation was observed.
Allergic inflammation is associated with a shift in the cytokine balance towards a Th2 predominance [7]. Several data indicate that Th2 cytokines (IL-5 and IL-4) are present in increased amounts in the nasal mucosa of allergic rhinitis patients [6,7]. IL-5 is a cytokine, which promotes the maturation, activation and prolonged survival of eosinophils, the main effector cells in hay fever [58]. The suppression of prolonged eosinophil survival induced by IL-5 is a potential therapeutic strategy for the resolution of allergic rhinitis. In our study irradiation of the nasal mucosa resulted in a significant decrease in local IL-5. T lymphocytes are major sources of IL-5 [59]. Thus, apoptosis of these cells following phototherapy might be Not only T cells and eosinophils, but also mast cells and basophils have important roles in the effector phase of the allergic reaction [9]. They are the principal source of different mediators and especially of histamine. The role of histamine in allergic rhinitis has been well studied and is mirrored by the wide use of antihistamines in the treatment of allergic rhinitis [65]. In our study, we demonstrated that mUV/VIS irradiation is able to inhibit mediator release from RBL-2H3 cells. It has been shown that ^-hexosaminidase release following allergen challenge of RBL-2H3 cells passively sensitized to murine IgE correlates with histamine release and SPT [66]. Several other therapeutic agents used for the therapy of allergic rhinitis and asthma have been already tested in this in vitro model of histamine release, and have been shown to be potent in inhibiting IgE-mediated histamine release [67,68]. Our findings are in concordance with previous studies in which the inhibitory effect of UVA and UVB light on histamine release was assessed [53]. The use of mUV/VIS, which is characterized by low dose UVA and low dose UVB is followed by a very strong inhibitory effect, and in fact a complete blocking effect could be achieved at certain doses.
The data reported here demonstrate that phototherapy was able to inhibit the effector phase of the allergic reaction at multiple checkpoints. In contrast with antihistamines, which influence predominantly histamine-mediated features of the allergic process, phototherapy has a different, more complex action spectrum. This suggests that intranasal phototherapy might be an alternative for patients not controlled by antihistamines. Our data support this indication considering that all enrolled patients were non-responders to conventional therapies, including the latest generation of antihistamines.

Possible side effects
It is well known that repeated high-dose ultraviolet light irradiation has carcinogenic potential.
The ultraviolet light-induced carcinogen effect is linked to the cumulative doses of the ultraviolet light (usually requiring many years). For PUVA treatment there is a higher risk for cancer development among patients that have received more than 260 PUVA treatments with a cumulative dose of between 100 -500 J/cm 2 [69]. If long wave-UVA (340 -400 mJ/cm 2 ) is used alone -without previous photosensitization -for the treatment of skin disorders, usually much higher UV dosages are used. For example, for the treatment of atopic dermatitis wavelengths between 340-400 nm are used with an effective dose between 50-100 J/cm per t treatment. This results in a cumulative dose of 750 j/cm over a three-week treatment period [70]. Since the irradiation dosages for the phototherapy or photo-chemotherapy of the nasal mucosa uses much lower cumulative dose than the threshold for increased cancer risks, the probability of carcinogenesis in the present therapeutically schemes is extremely low.
Similarly as for topical corticosteroids used for the treatment of the disease, UV light by its immunosuppressive effect might facilitate the appearance of viral and bacterial infections on the treated areas. However, the likelihood for this is lower than that of the presently used local immunosuppressants since ultraviolet light has a direct anti-microbial effect. We did not observe any infections during this study.
Phototherapy of the nasal cavity was tolerated well, in fact the only side effect observedsimilarly as for locally applied corticostreroids-was mild dryness of the mucosa which occurred at 50% of patients during the duration of the treatment. This symptom was easily overcome with vitamin A oil, except one patient from the mUV/VIS group, who scored the dryness of the nasal mucosa as severe and the treatment was stopped.

Summary
Hay fever is a very common allergic disorder, its prevalence is about 8,1% among the children, 21% among the adolescents and 11% among the adults in Hungary [71]. The treatment of allergic rhinitis is a complex problem, including the elimination of the inhalative allergens from the patient's environment, the specific pharmacotherapy and immunotherapy.
However in a lot of cases patients don't respond well to the conventional antiallergic treatment or the drug therapy is contraindicated, and the combined pharmacotherapy has a numerous side-effects, so every new therapeutic tool is therefore of great importance.
Since UV irradiation has been shown to exert both local and systemic immunosuppression and is effectively used in the treatment of several immune mediated skin diseases, we were interested in whether phototherapy might also be effective for the treatment of allergic rhinitis. Since there is a good correlation between the suppression of the reaction in SPT and inhibition of the clinical symptoms, firstly we investigated the effect of different wavelengths UV irradiations to inhibit the wheal formation in the SPT reaction. We found that irradiation with the 308 nm XeCl excimer laser, PUVA, the combined UVA-UVB, Geroxalen plus UVA-UVB treatment and irradiation with mUV/VIS light significantly inhibited the allergen induced immediate type hypersensitivity reaction in the skin, while UVA and VIS irradiation didn't influence significantly the SPT reaction. Based on these results we tested the effect of these different light sources in the treatment of allergic rhinitis, and we found that phototherapy of the nasal cavity with medium dose 308 nm XeCl excimer laser, 8-MOP plus UVA, or mUV/VIS light resulted in a significant improvement of the clinical symptoms of allegic rhinitis. Phototherapy was tolerated well; the only side effect was the slight dryness of the nasal mucosa. In conclusion, our findings indicate that phototherapy represents an efficient therapeutic modality for the treatment of patients suffering from allergic rhinitis.