Allergenic Pollen in Europe and in the Mediterranean Area
Sergio Bonini and Ginevra Menghi
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- Personal studies cited
- Mechanisms of Immunotherapy
- Mechanisms
- SIT for venom hypersensitivity
- SIT for allergic rhinitis
Sergio Bonini and Ginevra MenghiSan Raffaele H, INMM-CNR, Rome, Italy The genetic susceptibility to mount a specific IgE antibody response to environmental allergens is one of the major pathophysiological features of allergic subjects, which is eventually able to initiate a cascade of pathogenetic mechanisms and to trigger symptoms upon natural or experimental allergen exposure. Several genetic and environmental factors may influence the sensitisation process. Among these special attention has recently been devoted to the protective role of an early microbial exposure1-3. However, there are substantial differences in the quality and intensity of the final outcome of an IgE-allergen interaction, not only depending on the degree of sensitisation, but also on the type, load and route of allergen reaction, as well as on the reactivity of target tissues and organs participating in it. Accordingly, in some subjects the presence of IgE antibodies to allergens is not associated with clinical manifestations, in other causes mild reversible symptoms, in others induces persistent allergic inflammation and tissue remodelling, in others, finally, is only an epiphenomenon without causal relationships to disease4-5. With reference to this last evenience, we should like to note that a polyclonal IgE activation is a frequently associate hallmark of allergic patients, but distinct from the specific IgE response to a given allergen. In fact, different genetic and environmental factors influence the typical Th2 cytokine profile of allergic subjects which results in: polyclonal IgE activation; eosinophil overproduction, activation and tissue recruitment; mast cell and basophil overexpression and priming6. Interestingly enough, the Th2 profile may be documented in allergic subjects even in the absence of specific IgE antibodies, as it occurs in some forms of non allergic asthma, in non-allergic rhinitis with eosinophilia, in nasal polyps, in vernal keratoconjunctivitis, in atopic eczema, etc7. Due the redundancy of factors influencing the allergic response (including endocrine8 and neural factors9-11 which we recently called attention on), the clinical value of any nosography, diagnostic or therapeutic approach only focussing on specific IgE is limited. Further diagnostic markers should be available in clinical practice to better dissect the heterogeneous allergic phenotype12 and to implement a more selective treatment based on the pathophysiological abnormalities preferentially involved in individual cases13. Personal studies citedMatricardi PM, Rosmini F, Riondino S, Fortini M, Ferrigno L, Rapicetta M, Bonini S. Exposure to foodborne and orofecal microbes versus airborne viruses, in relation to atopy and allergic asthma: epidemiological study. Br Med J. 2000; 320: 412-17. Matricardi PM, Bonini S. High microbial turnover rate preventing atopy: a solution to inconsistencies impinging on the Hygiene hypothesis? Clin Exp Allergy 2000; 30: 1506-1510. 3. Matricardi PM, Rosmini F, Panetta V, Ferrigno L, Bonini S. Hay fever and asthma in relation to markers of infection in the United States. J Allergy Clin Immunol 2002; 110: 381-38716 4. Bonini Se, Bonini St, Vecchione A, Naim DM, Allansmith MR, Balsano F. Inflammatory changes in conjunctival scrapings after allergen provocation in humans. J Allergy Clin Immunol. 1988; 82: 462. 16 Bonini St, Bonini Se, Bucci MG, Berruto A, Adriani E, Balsano F, Allansmith MR. Allergen dose response and late symptoms in a human model of ocular allergy. J Allergy Clin Immunol. 1990; 86 (6): 869-876. Ruffilli A, Bonini Se. Susceptibility genes for allergy and asthma. Allergy. 1997; 52: 256-73. Bonini St, Bonini Se, Lambiase A, Marchi S, Pasqualetti P, Zuccaro O, Rama P, Magrini L, Juhas T, Bucci MG. Vernal keratoconjunctivitis revisited: a case series of 195 patients with long-term followup. Ophthalmology 2000; 107: 1157-63. Bonini St, Lambiase A, Schiavone M, Centofanti M, Bonini Se. Estrogen and progesteron receptors in vernal keratoconjunctivitis. Ophthalmology. 1995; 102: 1374-79. Bonini Se, Lambiase A, Bonini St, Angelucci F, Magrini L, Manni L, Aloe L. Circulating nerve growth factor levels are increased in humans with allergic diseases and asthma. Proc Natl Acad Sci. USA 93, 1996; 10955-60. Bonini S. Do neurotrophins play a role in allergic diseases and asthma? Clin Exp Allergy 2003; 33: 543-545. Micera Micera A, Vigneti E, Pickholtz D, Reich R, Pappo O, Bonini S, Maquart FX, Aloe L, Levi-Schaffer F. Nerve growth factor displays stimulatory effects on human skin and lung fibroblasts, demonstrating a direct role for this factor in tissue repair. Proc Natl Acad Sci USA 2001; 98(11): 6162-7. Bonini S, Matricardi PM, Torre A, Rasi G. The heterogeneity of allergic phenotypes. Genetic and environmental interactions Ann Allergy Asthma Immunol 2001; 87 (Suppl 3): 48-51. Bonini Se, Rasi G. Who benefits from immunotherapy? Allergy. 1997; 52: 693-94. *****
School of Medicine, University of Southampton e-mail A.J.Frew@soton.ac.uk Introduction Specific allergen immunotherapy (SIT) involves the administration of allergen extracts to modify or abolish symptoms associated with atopic allergy. The process is specific, in that the treatment is targeted at those allergens recognised by the patient and physician as responsible for symptoms. A decision to use SIT therefore demands a careful assessment of the patient’s condition and the role of allergic triggers. This form of therapy was first attempted at the end of the 19th century and then reported in the second decade of the 20th century by Noon and Freeman at St Mary's Hospital, London [1]. Immunotherapy then became popular in North America and in Europe but some differences in practice have gradually developed either side of the Atlantic. Typically, patients are started on a very low dose of allergen, given by subcutaneous injection. The dose is then increased in a series of weekly injections until a plateau or maintenance dose is achieved. The maintenance dose is then given at 4-6 weekly intervals for 3 to 5 years. Alternative induction regimes may give several doses on each day, or may give the whole series of incremental injections in a single day (rush protocols). The main drawback to rush and semi-rush protocols is the risk of adverse reactions, which are much commoner than in conventional protocols. On the other hand, full protection can be attained in a few days as compared to the three months required in the conventional regime. MechanismsSeveral mechanisms have been proposed to explain the beneficial effects of immunotherapy. Early studies showed that SIT induces allergen-specific IgG antibodies. This led to suggestions that SIT might work by inducing antibodies which would intercept the allergen and “block” the allergic response. In patients treated for venom anaphylaxis, the development of allergen-specific IgG antibody correlates with clinical efficacy but for other allergens, the magnitude of the IgG response is not closely related to the degree of efficacy. Moreover, the rise in IgG follows rather than precedes the onset of clinical benefit. Allergen-specific IgE levels rise temporarily during the initial phase of SIT, but fall back to pre-treatment levels during maintenance therapy [2]. The immediate skin test response can be reduced after SIT but this effect is relatively small compared to the degree of clinical benefit. In contrast, the late-phase skin test response is virtually abolished after successful SIT. Similar patterns are observed for late-phase nasal and airway responses [3]. With the recognition of the role of T-cells as orchestrators of the allergic response, investigators have turned to study the effects of SIT on cellular responses to allergen. Both in the skin and in the nose, successful SIT is accompanied by a reduction in T-cell and eosinophil recruitment in response to allergen challenge. In parallel, there is a shift in the balance of Th1 and Th2 cytokine expression in the allergen-challenged site. Th2 cytokine expression is not affected but there is an increased proportion of T-cells expressing the Th1 cytokines IL-2, IFN- and IL-12 [4-6]. These findings suggest that SIT has a modulatory effect on allergen-specific T-cells, which would explain why the clinical and late-phase responses are attenuated without such a large effect on allergen-specific antibody levels. SIT for venom hypersensitivityAnaphylaxis to hymenoptera venom is relatively rare, but can be fatal. Venom-specific IgE antibodies can be found in 30-40% of adults for a few months following a sting, but these usually disappear in a few months. Some individuals react more vigorously with high concentrations of venom-specific antibodies, which may persist for many years without further exposure to stings. This group of patients are at risk of anaphylaxis to subsequent stings and a small number die from anaphylaxis each year. The introduction of pure venom SIT preparations has led to a substantial improvement in the effectiveness of SIT for venom allergy. Desensitisation with venom extracts accelerates the rate at which the risk decreases and has been shown to provide protection against field and laboratory stings. After completing venom SIT, there is a residual risk of about systemic reactions of 10%, but these are typically mild. Consideration should also be given to providing injectable adrenaline and other anti-allergic medication for use in the event of a sting during therapy. SIT for allergic rhinitisSIT has been widely used to treat allergic rhinitis. As with other uses of SIT, it is important to select patients appropriately. The allergic basis of the rhinitis should be carefully assessed both on history and on skin tests or blood tests, and other causes should be excluded. Tests of nasal sensitivity are not used in routine clinical practice but may be useful for assessing effectiveness in clinical trials. The effectiveness of SIT in seasonal allergic rhinitis has been confirmed in many trials, using grass, ragweed and birch pollen. Moreover, SIT has been shown to be clinically effective even in patients with severe seasonal rhinitis that is resistant to conventional drug therapy [8]. Limited data is available regarding the long term efficacy of rhinitis, but a recent study demonstrate that the effects last for at least six years after discontinuing therapy [9]. The benefits of SIT for perennial rhinitis are less than for seasonal rhinitis. In part this reflects the difficulty in determining the extent to which allergy is responsible for perennial symptoms. Allergy to house dust mite is common and dose not always cause symptoms. Conversely, there are other causes of perennial rhinitis including vasomotor instability, infection, aspirin sensitivity etc. Nevertheless, clinical trials have shown a definite benefit in appropriately selected subjects. Clearer evidence has been obtained in rhinitis due to pet allergy. Several studies have shown a marked improvement in tolerance of cat exposure after SIT, confirmed both on challenge tests and simulated natural exposure [7]. As with any therapy, the risks and cost-effectiveness of SIT need to be assessed on a case by case basis. Current drug therapy for rhinitis can be very effective, but a significant proportion of rhinitis patients experience nose bleeds from intranasal steroids and drowsiness from their antihistamines. Others find pharmacotherapy inconvenient or ineffective. Moreover, we are now more aware of the adverse effects of rhinitis on quality of life. SIT offers a useful option for these patients as well as a logical approach to dealing with the underlying problem. Directory: attachments attachments -> A unified Modeling Approach to Climate System Prediction James Hurrell* 1, Gerald A. Meehl 1, David Bader 2 Download 2.68 Mb. Share with your friends:
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