Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances its immunogenicity and reduces its allergenicity
Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances its immunogenicity and reduces its allergenicity
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DOI：
10.1067/mai.2000.107927
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发表时间：
2000-07-01
影响因子：
14.2
通讯作者：
Raz, E
中科院分区：
文献类型：
--
作者：
Tighe, H;Takabayashi, K;Raz, E
背景：过敏原免疫治疗是不方便的，并与过敏反应的风险。通过过敏原的化学修饰来提高免疫治疗安全性的努力没有成功，因为它大大降低了它们的抗原性。最近，免疫刺激DNA序列目的：我们试图确定ISS与主要的短豚草变应原Amb a 1的缀合是否导致小鼠中增强的免疫原性潜力和人类受试者中降低的变应原性。将22-mer ISS寡脱氧核苷酸（ISS-ODN）与Amb a 1偶联并用于小鼠、兔和猴的免疫。在小鼠中，Amb a I-ISS缀合物诱导T（H）1应答（IFN-γ分泌），而Amb a 1诱导T（H）2应答（IL-5分泌）。用Amb a I-非ISS缀合物未观察到T（H）1应答。Amb a 1与ISS ODN共注射诱导T（H）1应答的效果要差得多。在针对T（H）2应答致敏的小鼠中，注射Amb a I-ISS偶联物诱导从头T（H）1应答，并抑制Amb a 1激发后的IgE抗体形成。Amb a 1-ISS偶联物在兔和食蟹猴中诱导高滴度抗Amb a 1 IgG抗体，而单独的Amb a 1或Amb a 1与ISS-ODN共注射均未诱导可检测的应答。Amb a 1-ISS偶联物的致敏性比Amb a 1单独偶联物低30倍，而ISS-ODN与Amb a 1的混合偶联物不能降低组胺的释放。结论：Amb a 1-ISS偶联物具有增强的T（H）1偏向性免疫原性和降低的致敏性。它可能提供一种比现有方法更有效和更安全的过敏原免疫治疗方法。
Background: Allergen immunotherapy is inconvenient and associated with the risk of anaphylaxis. Efforts to improve the safety of immunotherapy by means of chemical modification of allergens have not been successful because it greatly reduced their antigenicity. Recently, immunostimulatory DNA sequences (ISS or CpG motifs) have been shown to act as strong T(H)1 response-inducing adjuvants.Objective: We sought to determine whether conjugation of ISS to the major short ragweed allergen Amb a 1 results in enhanced immunotherapeutic potential in mice and decreased allergenicity in human subjects.Methods: A 22-mer ISS oligodeoxynucleotide (ISS-ODN) was coupled to Amb a 1 and used for immunization of mice, rabbits, and monkeys.Results: In mice the Amb a I-ISS conjugate induced a T(H)1 response (IFN-gamma secretion), whereas Amb a 1 induced a T(H)2 response (IL-5 secretion). The T(H)1 response was not observed with an Amb a I-non-ISS conjugate. Coinjection of Amb a 1 with ISS-ODN was much less effective in inducing a T(H)1 response. In mice primed for a T(H)2 response, injection with Amb a I-ISS conjugate induced a de novo T(H)1 response and suppressed IgE antibody formation after challenge with Amb a 1. Amb a 1-ISS conjugate induced high-titer anti-Amb al IgG antibodies in rabbits and cynomolgus monkeys, whereas Amb a 1 alone or Amb a 1 coinjected with ISS-ODN did not induce a detectable response. Amb a I-ISS conjugate was less allergenic than Amb a 1 alone, as shown by a 30-fold lower histamine release from human basophils of patients with ragweed allergy, whereas mixing ISS-ODN with Amb a 1 did not reduce histamine release.Conclusion: Amb a 1-ISS conjugate has an enhanced T(H)1-biased immunogenicity and reduced allergenicity. It may offer a more effective and safer approach for allergen immunotherapy than currently available methods.