Studies of Hyper- IgM Syndrome

高 IgM 综合征的研究

• 批准号: 8336289
• 负责人: Ashish Jain
• 金额: $ 46.22万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8336289
• 关键词: Agonist; Antibodies; Antigens; B-Lymphocytes; Biliary; Binding; CD3 Antigens; CD40 Ligand; CD8B1 gene; Candida; Clinical Research; Clinical Trials; Clinical trial protocol document; Cryptosporidiosis; Data; Defect; Delayed Hypersensitivity; Development; Dose; Enrollment; Follicular Dendritic Cells; Goals; Half-Life; Human; IgG2; Immune; Immune response; Immunoglobulin Class Switching; Immunoglobulin M; Immunoglobulin Switch Recombination; Immunologics; In Vitro; Infusion procedures; Interferons; Interleukin-12; Investigation; Keyhole Limpet Hemocyanin; Leukocytes; Lymphatic Diseases; Mediating; Mumps; Oocysts; Pancreatic carcinoma; Patients; Pharmaceutical Preparations; Phase; Phenotype; Population; Production; Publishing; Reaction; Recombinant CD40-Ligand; Recombinants; Research Personnel; Safety; Schedule; Single-Gene Defect; Staining method; Stains; Staphylococcal Enterotoxin B; Structure of germinal center of lymph node; Syndrome; T-Lymphocyte; TNF gene; TNFRSF5 gene; TNFSF5 gene; Therapeutic; Time; Treatment Efficacy; antimicrobial; cytokine; design; experience; in vivo; novel; peripheral blood; pre-clinical; receptor; reconstitution

We recently published a clinical study to assess the therapeutic potential of recombinant human CD40 ligand in patients with XHM. We designed a one-center investigator-initiated Phase I/II clinical trial (protocol 00-I-0006) to assess safety of recombinant CD40L administration, and determine if it could restore the core immunologic defects of patients with XHM. Five patients were enrolled, and were treated on a dose escalation schedule for up to one year. We showed that administration of recombinant CD40 ligand is safe and can reconstitute deficient immune responses. Specifically, patients T cells demonstrate for the first time a capacity to synthesize IFN-γ and TNF-α when stimulated with anti- CD3, or SEB, or SEA. Studies of cytokine production by intracellular staining demonstrated that recombinant CD40L was able to prime both the CD4 and CD8 T cell populations. In addition, all patients developed positive delayed type hypersensitivity reactions to candida, and KLH, and one patient to mumps antigen. Patients on therapy also demonstrated the development of new adenopathy, improvement of primary follicle formation, expansion of both B and T cell populations in the lymphnodes, and the development of follicular dendritic cells. However, germinal center formation and immunoglobulin class switch recombination (CSR) in B cells was lacking. Further improvements in B cell terminal differentiation may require higher doses or a different class of drugs that offer greater half-life. Stimulated by these observations, we treated two XHM patients who had failed standard antimicrobial therapy for biliary cryptosporidiosis with CP-870,893, a human IgG2 antibody that is agonistic for CD40 and has shown therapeutic efficacy against pancreatic carcinoma. CP-870,893 effectively activated B cells and APCs in vitro, restoring class switch recombination in XHM B cells and inducing TNF-α and IL-12 secretion by XHM MoDCs. CP-870,893 also showed significant activity in vivo, causing decreases of leukocytes from the peripheral blood post-infusion. However, despite promising preclinical data, the patients did not experience significant immune reconstitution and the treatment was not successful in eradicating biliary cryptosporidiosis. We found that the CD40 receptor is rapidly internalized following binding with CP-870,893, providing a plausible mechanism for the limited capacity of CP-870,893 to mediate immune reconstitution in XHM. This study demonstrates that CP-870,893 suppressed oocysts shedding in XHM patients with biliary cryptosporidiosis. The continued study of CD40 agonists in XHM is warranted.

我们最近发表了一项临床研究，以评估重组人CD40配体对XHM患者的治疗潜力。我们设计了一项单中心研究人员发起的I/II期临床试验(方案00-I-0006)，以评估重组CD40L给药的安全性，并确定它是否能修复XHM患者的核心免疫缺陷。5名患者入选，并按剂量递增计划进行治疗，最长可达一年。结果表明，注射重组CD40配体是安全的，可以重建缺陷的免疫应答。具体地说，当抗CD3抗体或SEB或SEA刺激时，患者T细胞首次显示出合成干扰素和肿瘤坏死因子的能力。通过细胞内染色产生细胞因子的研究表明，重组CD40L能够同时激活CD4和CD8T细胞群。此外，所有患者对念珠菌、KLH和腮腺炎抗原均出现阳性迟发性超敏反应，1例患者出现阳性反应。接受治疗的患者还表现出新的腺病的发展，初级毛囊形成的改善，淋巴中B和T细胞群的扩张，以及滤泡树突状细胞的发展。但B细胞生发中心形成和免疫球蛋白类开关重组(CSR)缺乏。B细胞终末分化的进一步改善可能需要更高的剂量或提供更大半衰期的不同类别的药物。 在这些观察的刺激下，我们用CP-870,893治疗了两名胆道隐孢子虫病标准抗菌治疗失败的XHM患者，CP-870,893是一种对CD40具有激活性的人IgG2抗体，已显示出对胰腺癌的治疗效果。CP-870,893在体外能有效地激活B细胞和APC，恢复XHM B细胞的类开关重组，并诱导XHM MoDC分泌肿瘤坏死因子和白介素12。CP-870,893在体内也显示出显著的活性，导致输注后外周血中白细胞的减少。然而，尽管临床前数据很有希望，这些患者并没有经历显著的免疫重建，治疗在根除胆道隐孢子虫病方面也没有成功。我们发现CD40受体在与CP-870,893结合后迅速内化，这为CP-870,893介导XHM免疫重建的有限能力提供了一个可信的机制。本研究证实CP-870,893可抑制胆道XHM患者的卵囊排出 隐孢子虫病。CD40激动剂在XHM中的继续研究是必要的。