过敏原免疫治疗更新

王帆

Update on Allergen Immunotherapy

过敏原免疫治疗更新

作者：Ralf S. Mueller, DMV

翻译：赵博

KEYWORDS

•Allergen specific •Desensitization •Hyposensitization •Feline •Canine •Intralymphatic

关键词

•过敏原特异性•脱敏•减敏作用•猫•犬•淋巴管内

KEY POINTS

•Allergen immunotherapy is the only specific therapy for a topic dermatitis in dogs and cats.

•Selection of allergens should be based on clinical history of the animal in conjunction with positive reactions on intradermal or serum testing.

•To optimize success, the protocol should be individualized to each patient; when adapting the dose and/or frequency during the treatment, most animals show a good to excellent response.

•Adverse effects include increased pruritus and very rarely anaphylactic reactions.

•Subcutaneous, intralymphatic, and oro-mucosal administration routes have been reported; the subcutaneous route is most frequently used.

关键点

•过敏原免疫治疗是治疗犬猫异位性皮炎唯一的特异性治疗。

•过敏原的选择应根据动物的临床病史，并结合皮内试验或血清测试的呈阳性反应。

•为了优化成功，应针对每个患病动物制定个体化方案；在治疗过程中调整剂量和/或频率时，大多数动物表现出良好的反应。

•不良反应包括瘙痒增加和非常罕见的过敏反应。

•皮下、淋巴管内和口腔粘膜给药途径已有报道；皮下途径是最常用的。

INTRODUCTION

Allergen immunotherapy (AIT) is the only treatment of atopic dermatitis that is able to change the pathogenic mechanisms of the disease. By injecting relevant allergens, AIT aims at initiating an immune response that leads to activation of regulatory T cells and immunosuppressive cytokines with a subsequent improvement of clinical signs. In the past, the term allergen-specific immuno- therapy was used; but as AIT by definition contains specific allergens, AIT is as accurate and avoids stating the obvious. AIT has been used successfully in several animal species but is most commonly used in dogs. Data in cats are more limited. Initially, AIT was administered subcutaneously; but intra- lymphatic and sublingual or oral immunotherapy protocols have also been described.

介绍

过敏原免疫治疗(AIT)是治疗异位性皮炎唯一能改变发病机制的。通过注射相关过敏原，AIT旨在启动免疫反应，从而激活调节性T细胞和免疫抑制细胞因子，从而改善临床症状。过去，使用的术语是过敏原特异性免疫治疗；但由于AIT的定义包含特定的过敏原，AIT是准确的，并避免了不必要的说明。AIT已成功用于几种动物，但最常用于犬。猫的数据更有限。最初，AIT是皮下注射的；但淋巴管内和舌下或口腔免疫治疗方案也已被报道。

SELECTION OF ALLERGENS FOR ALLERGEN IMMUNOTHERAPY

For many years, intradermal testing was the gold standard for the identification of offending allergens in animals with atopic dermatitis. Today serum tests for allergen-specific immunoglobulin E (IgE) are also used, and the success rate of AIT seems to be the same when allergens are chosen based on skin testing compared with serum testing.1 Interassay and intraassay variability of serum testing has been evaluated in several studies, some of which showed a high reproducibility2; in others the reproducibility was much lower,3 emphasizing the need for independent evaluation of a testing method before it can be recommended. As healthy dogs show numerous positive reactions on both skin and serum tests,4,5 allergens should be chosen not only based on test results but also on clinical history. For example, if in a temperate climate an atopic dog shows severe pruritus all year round yet only has a strong reaction to birch pollen, this would not explain its clinical signs. Similarly, in a dog that exhibits clinical signs only in spring or summer and shows a strong positive reaction to house dust mites, it is unlikely the clinical signs are due to dust mites. Positive skin test or serum test results indicate sensitization against an allergen with subsequent IgE production, not necessarily clinically relevant hypersensitivity. Consequently, skin or serum test results are not suitable to make a diagnosis of environmental allergies in any species because of those false-positive reactions and should only be used with the aim to identify allergens suitable for AIT in animals that are diagnosed with atopic dermatitis based on history, clinical examination, and having ruled out differential diagnoses. Thus, pros and cons of AIT need to be discussed with the owners and AIT chosen as desired therapy before performing those tests. Subsequently, the results of either intradermal testing or testing for allergen-specific IgE should be interpreted in light of the clinical history of that particular patient; the allergens included in the treatment solution should be chosen based on this history.

过敏原免疫治疗中过敏原的选择

多年来，皮内试验一直是异位性皮炎动物过敏原识别的金标准。目前也使用血清过敏原特异性免疫球蛋白E (IgE)检测，通过皮肤试验和血清试验选择过敏原后，AIT的成功率似乎是一样的1。几项研究中评估了血清检测批间分析和皮内分析的变化性，其中一些具有高重复性2；其他一些则重复性要低得多3，强调在推荐一种检测方法前，要对其进行独立评估。由于健康犬在皮肤和血清测试中都表现出大量的阳性反应4，5，所以选择过敏原不仅要根据测试结果，还要根据临床病史。例如，如果在温带气候中，一只异位性皮炎患犬全年都表现出严重的瘙痒，但只对桦树花粉有强烈的反应，这不能解释它的临床症状。同样，如果一只犬只在春季或夏季表现出临床症状，并且对屋尘螨表现出强烈的阳性反应，那它的临床症状也不太可能是由尘螨引起的。皮肤试验和血清学试验的阳性结果表明对随后产生IgE过敏原的过敏，不一定是与临床相关的过敏症。因此由于这些假阳性反应，皮内试验或血清学检测结果在任何物种上都不适合作为环境过敏的诊断，只能用于已根据病史、临床检查、并排除鉴别诊断确诊了异位性皮炎并适合AIT的动物，旨在识别过敏原。因此，需要与主人讨论AIT的利弊，并在选择AIT作为理想的治疗之前，进行这些检查。随后，应根据该特定患病动物的临床病史解释皮内测试或过敏原特异性IgE检测的结果；治疗方案中包含的过敏原应根据病史选择。

MECHANISM OF ACTION

Most available information about the mechanism of action of AIT derives from studies with dogs and parallels what is seen in humans (Box 1). An increase in so-called blocking IgG antibodies was described in dogs undergoing immunotherapy6,7; but an actual binding and, thus, inactivation of offending allergens by those antibodies have not been demonstrated as of yet; it is not known whether production of those allergen-specific antibodies during AIT is correlated to a good clinical response. An increase in FoxP31 regulatory T cells and IL-10 and a decrease in allergen-specific IgE have been associated with successful immunotherapy in one study.8 In cats with experimental asthma that underwent rush immunotherapy (RIT) with CpG oligodeoxynucleotides, the percentage of eosinophils in the bronchoalveolar lavage fluid (BALF) decreased significantly with immunotherapy; but the number of regulatory T cells in the peripheral blood and the concentration of IL-10 or interferon-gamma in the BALF did not change.9

作用机制

关于AIT作用机制的大多数可用信息来自于对犬的研究，与人类的研究结果相似（框1）。在接受免疫治疗的犬上发现了所谓的阻断性IgG抗体增加6，7，但目前还没有证明这些抗体具有实际的结合作用，从而使过敏原失活；目前还不清楚这些过敏原特异性抗体的产生是否与良好的临床反应相关。在一项研究中，FoxP31调节T细胞和IL-10的增加，以及过敏原特异性IgE的减少与免疫治疗的成功有关8。用CpG寡脱氧核苷酸进行冲击免疫治疗(RIT)的实验性哮喘猫，免疫治疗后支气管肺泡灌洗液(BALF)中嗜酸性粒细胞的比例显著下降;但外周血调节性T细胞数量和BALF中IL-10或干扰素-γ浓度无明显变化9。

框1

犬和人过敏原免疫治疗的机制

ž IgG4↑

ž FoxP3+ CD4+ Treg↑

ž IL-10↑

ž IL-4↓

ž IgE↓

缩写：IgG4，免疫球蛋白G4；IL，白介素；Treg，调节T细胞。

SUBCUTANEOUS ALLERGEN IMMUNOTHERAPY

Traditionally, allergens in AIT of canine atopic dermatitis (as in other species) are injected subcutaneously during the induction period in gradually increasing volume and concentration over a few weeks to a few months depending on the protocol.10 Thereafter maintenance therapy is administered with the same amount of allergen extract every few weeks to once monthly for a period of several years. However, most dermatologists agree that the amount of allergen and the frequency of injections have to be adjusted to individual patients. If a dog shows increased pruritus directly after the injection, that then subsides again a few days later, the dose should be reduced at the next injection. If the pruritus improves after the injections but then in- creases again some time before the next allergen administration, a shorter interval be- tween injections is advisable. The final response should not be evaluated until 12 months after beginning AIT. Owners need to be made aware before choosing immunotherapy that it may take 1 year until maximal improvement has been achieved.

Patients on immunotherapy may need additional antipruritic medication during the first months of treatment. Essential fatty acids, antihistamines, lokivetmab, and shampoo therapy are unlikely to interfere with tolerance induction. However, the author prefers not to use glucocorticoids, cyclosporine, and oclacitinib as long-term therapy during the first year of AIT but rather as short treatment courses as needed.

Many studies evaluating subcutaneous AIT (SCIT) show an excellent response or a good improvement in approximately two-thirds of the dogs, independent of age, sex, breed, type of allergen, perennial or seasonal clinical signs, and high- or low-dose protocols (Table 1).1 The few studies evaluating RIT, oromucosal immunotherapy (OIT), and intralymphatic immunotherapy (ILIT) reported similar success rates.11–13 However, most studies included a small number of dogs and were case studies1; only a few studies were randomized and double blinded.12,14,15 Thus, the results need to be interpreted with caution; more studies are needed to determine factors optimizing treatment outcomes. In addition, dose-finding studies were performed only, rarely, in dogs; their results have not been conclusive.1,15,16

皮下过敏原免疫疗法

传统上，犬异位性皮炎(与其他物种一样)AIT中的过敏原通过皮下注射，根据治疗方案，在诱导期的几周到几个月的时间内逐渐增加剂量和浓度10。之后维持治疗是用相同剂量的过敏原提取物，每隔几周至每月一次，为期数年。然而大多数皮肤科医生认为，过敏原的剂量和注射的频率必须根据患病动物的具体情况进行调整。如果患犬在注射后立即出现瘙痒增加，几天后消退，那么下次注射时应该减少剂量。如果瘙痒症状在注射后有所改善，但在下一次过敏原注射前的一段时间再次加重，建议缩短注射间隔。在开始AIT的12个月后才能评估最终的反应。在选择免疫疗法之前，需要让主人意识到，可能需要1年时间才能达到最大程度的改善。

接受免疫治疗的患病动物在治疗的头几个月可能需要额外的止痒药物。必需脂肪酸、抗组胺药、异位性皮炎单抗，和香波治疗不太可能干扰诱导耐受。但作者不希望在AIT的第一年使用糖皮质激素、环孢霉素和奥拉替尼作为长期治疗，而是根据需要短期使用。

许多评估皮下AIT (SCIT)的研究显示，大约三分之二的犬治疗反应良好或极好，与年龄、性别、品种、过敏原类型、常年或季节性临床症状、高或低剂量方案无关(表1)1。少量研究评估了RIT、口腔黏膜免疫治疗(OIT)和淋巴管内免疫治疗(ILIT)有相似的成功率11-13。然而，大多数研究中包含的犬数量少，并且是个例研究1；只有少数研究是随机和双盲的12，14，15。因此，需要谨慎地解释结果；需要更多的研究来确定最佳治疗结果的因素。此外，仅在犬上进行过少量剂量研究；他们的结果还没有得出结论1，15，16。

表1 犬过敏原免疫治疗在各种研究中的成功率
研究参考	成功率（反应良好至极好）	研究中犬的数量
Keppel et al,8 2008	51	53
Mueller & Bettenay,17 1996	58	146
Nuttall et al,18 1998	22	186
Schnabl et al,16 2006	64	117
Scott et al,19 1993	60	144
Zur et al,20 2002	52	169

a大多数研究评估的反应为极好、良好、轻度/中度和较差；这项特殊的研究只将反应分为良好、部分或没有；22%反应良好，39%完全无反应。

RUSH IMMUNOTHERAPY

With subcutaneous RIT, the induction period of several weeks to months is abbrevi- ated to 1 day and injections are given hourly. Dogs are continuously monitored clinically in a hospital setting. In human medicine, RIT is performed to achieve a more rapid improvement, particularly in patients with venom hypersensitivities, but is associated with a high rate of anaphylactoid reactions. In dogs, RIT is well tolerated and has mainly been associated with increased pruritus; more severe reactions have been extremely rare.12,21 The protocol in dogs includes a recommendation of an antihista- mine administration 1 or 2 hours before the injection of the allergen extract. In a double-blinded study, the maximum improvement in clinical signs was reached after 6.8 months with RIT compared with 9.2 months with classic immunotherapy; however, in this study the difference failed to reach statistical significance.12 RIT with alum- precipitated allergens has been reported with similar safety and success rates as RIT with aqueous allergens.22 RIT has also been reported in 4 cats,23 but this number is too small to make any conclusions about safety; efficacy was not reported in this case series.

冲击免疫治疗

皮下RIT，诱导期由数周到数月缩短为1天，每小时注射一次。住院对犬进行持续的临床监测。在人医中，RIT能更快的获得改善，特别是毒液过敏的患者，但与中毒反应的高发生率有关。对犬来说，RIT耐受良好，主要是瘙痒增加；更严重的反应极其罕见12，21。对犬的治疗方案包括建议在注射过敏原提取物前1或2小时给予抗组胺药物。在一项双盲研究中，与传统的9.2个月的免疫治疗相比，RIT治疗6.8个月后可达最大临床改善；但在本研究中，差异没有达到统计学意义12。有研究显示用铝沉淀过敏原进行RIT的安全性和成功率与用水溶液过敏原进行的RIT相似22。也有4只猫RIT的报道23，但这个数量太少，无法对安全性做出任何结论；这些病例未见有效性的报道。

ORO-MUCOSAL IMMUNOTHERAPY

Oral immunotherapy has been available in some countries for several years. In humans with sublingual immunotherapy (SLIT), small amounts of allergens are administered and kept under the tongue for several minutes without swallowing; in oral immunotherapy, allergens are swallowed after oral administration. In dogs, a small amount of extract is applied between the lips and gums once to twice daily. Consequently, in animals, OIT is probably the better term. Improvement of clinical signs and a decrease in allergen-specific IgE were reported in a small number of dogs with this type of AIT.13 A larger clinical study a few years ago showed a reasonable success rate comparable with that seen with SCIT.24 In addition, dogs improved on OIT that had previously failed to improve on SCIT. Unfortunately, this study is not published. Further scientific studies are needed to evaluate optimal treatment protocols for this treatment option.

口腔黏膜免疫治疗

口服免疫疗法在一些国家已经进行好几年了。在接受舌下免疫治疗(SLIT)的人类患者中，给予少量过敏原在舌下保存数分钟而不吞咽；口服免疫治疗时，过敏原在口服后被吞食。在犬的唇部和齿龈之间涂抹少量的提取物，每天一到两次。因此，在动物中，OIT一词可能更准确。临床症状的改善和过敏原特异性IgE的减少在这种类型的AIT中有少量犬的报道13。几年前的一项更大规模的临床研究显示，与SCIT相比，OIT的成功率略高24。不幸的是，这项研究没有发表。需要进一步的科学研究来评估这种治疗的最佳方案。

INTRALYMPHATIC IMMUNOTHERAPY

In humans, ILIT is associated with a prolonged improvement after 3 monthly injections and was reported to be safer and better tolerated than SCIT.25,26 In dogs, several studies have evaluated ILIT and reported it a safe treatment alternative to SCIT or OIT.11,27,28 A smaller amount of allergen extract (typically 0.1 mL) is injected in the sub- mandibular or popliteal lymph node monthly. Based on published data, prolonged improvement is only seen in a small number of dogs; most patients will need continuous intralymphatic or subcutaneous injections, especially when aqueous aller- gens are used.27 The author has seen some dogs improve on ILIT that previously failed to improve on SCIT. Short- and midterm adverse effects seem to be very rare.11,27,28 Long-term adverse effects of ILIT are not known, and further studies about long-term safety are particularly needed with alum-precipitated extracts.

淋巴管内免疫治疗

    人ILIT每月一次在3次注射后可持续改善，且较SCIT的安全性及耐受性更好25，26。几项犬的研究评估了ILIT，并报道了它是一种可替代SCIT或OIT的安全治疗11，27，28。每月在颌下或腘淋巴结注入更少量的过敏原提取物（通常为0.1ml）。根据已发布的数据，仅在少数犬上看到了长期改善；大多数患犬需要持续淋巴管内或皮下注射，尤其是使用水溶液过敏原时27。作者看到一些以前SCIT没有改善的犬进行ILIT时有所改善。短期和中期不良反应似乎非常罕见11，27，28。目前还上不清楚ILIT的长期副反应，尤其需要对铝沉淀提取物的长期安全性进行进一步研究。

FELINE ALLERGEN IMMUNOTHERAPY

Atopic dermatitis in cats is not well defined. There is evidence for causal involvement of allergens in cats with noninflammatory alopecia, severe head and neck pruritus, lesions of the eosinophilic granuloma complex, miliary dermatitis, and feline asthma.9,29 In cats with skin disease, few studies are published evaluating AIT; almost all of them evaluated SCIT in a small number of cats.1,29–31 All of those studies showed success rates similar to what is seen in dogs with atopic dermatitis. One study reported successful RIT in 4 cats.23 No studies have been published evaluating ILIT or SLIT in cats. More information is published about the treatment of cats with asthma sensitized to various allergens in a laboratory setting.32 Successful RIT with a decrease in eosinophil numbers in bronchoalveolar lavage has been reported even when the allergen used in the extract was either not the allergen the cats were sensitized to or not the only allergen the cats were sensitized to.33 When bacterial oligodeoxynucleotides were used as an adjuvant to RIT in those cats with experimental asthma, eosinophilic airway inflammation was also significantly alleviated. 9

猫过敏原免疫治疗

猫异位性皮炎没有明确的定义。有证据表明猫非炎性脱毛、严重的头颈部瘙痒、嗜酸性肉芽肿病变、粟粒性皮炎和猫哮喘都与过敏原有关9，29。在患有皮肤病的猫中，很少有评估AIT的研究发表；几乎都是对少量猫SCIT的评估1，29-31。这些研究都显示出与异位性皮炎患犬相似的成功率。有一项研究报道了4只猫RIT的成功23。目前还没有猫ILIT或SLIT的研究发表。更多已发表的信息是关于实验室设定下多种过敏原过敏性哮喘患猫的治疗32。即使使用的提取物不是过敏猫的过敏原或不是唯一的过敏原，也有报道RIT可成功减少支气管肺泡灌洗中嗜酸性粒细胞的数量33。用细菌寡脱氧核苷酸作为实验性哮喘猫RIT的佐剂时，嗜酸性气道炎症也明显减轻9。

ADVERSE EFFECTS OF IMMUNOTHERAPY

Increased pruritus after allergen administration is the most common adverse effect seen with subcutaneous immunotherapy.1 In many cases, this can be alleviated by decreasing the volume of allergen extract injected. Other animals may benefit from the administration of an antihistamine 2 hours before allergen injection. In some cases, this may be due to adjuvants; in a double-blinded study 3 of 27 dogs treated with alum-precipitate allergens and 2 of 24 dogs treated with an alum-containing placebo showed generalized pruritus.14 Localized injection reactions may rarely be seen.1 In a small number of patients (<1%), systemic reactions may occur and include anxiety, depression, diarrhea, hyperactivity, sleepiness, urticaria/angioedema, vomiting, weakness, and very rarely collapse and anaphylaxis.1 For milder adverse effects, glucocorticoids or antihistamines may be administered; however, in patients with anaphylaxis, intravenous epinephrine is the treatment of choice.

免疫治疗的副反应

    皮下免疫治疗最常见的副反应是给予过敏原后的瘙痒增加1。许多病例中，可以通过减少过敏原提取物的注射量缓解。其他动物可通过过敏原注射2小时前给予抗组胺药改善。一些病例中，这可能是由于佐剂；一项双盲试验中27只使用铝沉淀过敏原治疗犬中的3只，24只使用含铝安慰剂犬中的2只出现了全身性瘙痒14。局部注射反应罕见1。少数病患（1%）可能出现全身反应，包括焦虑、抑郁、腹泻、多动、嗜睡、风疹/血管性水肿、呕吐、虚弱，很少出现衰竭和过敏性反应1。轻度副反应可使用糖皮质激素或抗组胺药物；而对于过敏反应病患的治疗选择是静脉注射肾上腺素。

SUMMARY

AIT is a good treatment option for environmental allergy in dogs and cats. It is the only specific therapy and the only treatment reported to change the pathomechanisms of the disease. Subcutaneous immunotherapy combines a satisfactory success rate with a good safety profile. Anaphylactic reactions are rarely seen in animals. In addition to the subcutaneous administration of allergens, more recent routes of administration, such as intralymphatic and OIT, have been described. Pilot studies with different adjuvants, such as bacterial oligodeoxynucleotides,9,34,35 pullulan,36 or mannan,37 have been published; their use may further increase safety and efficacy. The first trials have reported the use of recombinant allergens.38 However, as most of the published studies are case series with often rather small numbers of animals included, more and larger randomized studies of immunotherapy are needed in a clinical setting to provide guidance on the optimal selection of allergens, adjuvants, dosing, success rate, and adverse effects of the various protocols of immunotherapy in dogs and cats.

概要

    对环境过敏原过敏的犬猫来说AIT是一种很好的治疗选择。这是唯一的特异性治疗，唯一被报道能改变疾病病理机制的治疗。皮下免疫治疗成功率高，安全性好。动物上罕见过敏反应。除皮下给予过敏原外，已有更新的给药途径，如淋巴管内和OIT。已发表的不同佐剂的前沿研究中，如细菌寡脱氧核苷酸9，34，35、支链淀粉36或甘露聚糖，它们的使用可能进一步提高安全性和有效性。已有第一批重组过敏原使用的报道38。但大多数已发表的研究都是包含很少量动物的病例回顾。临床中需要更多和大量随机的免疫治疗研究，为犬猫各种免疫治疗方案中过敏原的选择，佐剂，剂量，成功率，副反应提供指导。

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