Zhe Zhong, Manuel Quiñones-Pérez, Zhonghao Dai, Valeria M. Juarez, Eshant Bhatia, Christopher R. Carlson, Shivem B. Shah, Anjali Patel, Zhou Fang, Thomas Hu, Mayar Allam, Sakeenah L. Hicks, Mansi Gupta, Sneh Lata Gupta, Ethan Weeks, Stephanie D. Vagelos, Alejandro Molina, Adriana Mulero-Russe, Ana Mora-Boza, Devyani J. Joshi, Rafick P. Sekaly, Todd Sulchek, Steven L. Goudy, Jens Wrammert, Krishnendu Roy, Jeremy M. Boss, Ahmet F. Coskun, Christopher D. Scharer, Andrés J. García, Jean L. Koff, Ankur Singh
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引用次数: 0
摘要
当幼稚 B 细胞在淋巴组织的生殖中心(GC)内分化成浆细胞时,就会产生抗体。接受有效免疫疗法的 B 细胞淋巴瘤患者会表现出抗体生成减少,导致感染率升高和疫苗疗效降低,即使在 B 细胞恢复后也是如此。目前的体外模型无法维持长期的 GC 反应,也无法有效测试 B 细胞反应。在此,我们开发了模拟淋巴组织微环境的合成水凝胶,使来自扁桃体和外周血单核细胞衍生 B 细胞的人类 GC 得以产生。由外周血单核细胞衍生的免疫器官组织比扁桃体衍生的免疫器官组织能更长时间地维持GC B细胞和浆细胞,并表现出独特的B细胞编程,包括GC区、体细胞超突变、免疫球蛋白类别转换和B细胞克隆。对转录和表观遗传过程的化学抑制可促进浆细胞的形成。将极化的 CXCL12 蛋白整合到淋巴器官芯片中可调节健康供体 B 细胞的 GC 反应,但对淋巴瘤患者的 B 细胞则无效。我们的系统可以快速、可控地模拟免疫反应和 B 细胞紊乱。
Human immune organoids to decode B cell response in healthy donors and patients with lymphoma
Antibodies are produced when naive B cells differentiate into plasma cells within germinal centres (GCs) of lymphoid tissues. Patients with B cell lymphoma on effective immunotherapies exhibit diminished antibody production, leading to higher infection rates and reduced vaccine efficacy, even after B cell recovery. Current ex vivo models fail to sustain long-term GC reactions and effectively test B cell responses. Here we developed synthetic hydrogels mimicking the lymphoid tissue microenvironment, enabling human GCs from tonsils and peripheral blood mononuclear cell-derived B cells. Immune organoids derived from peripheral blood mononuclear cells maintain GC B cells and plasma cells longer than tonsil-derived ones and exhibit unique B cell programming, including GC compartments, somatic hypermutation, immunoglobulin class switching and B cell clones. Chemical inhibition of transcriptional and epigenetic processes enhances plasma cell formation. While integrating polarized CXCL12 protein in a lymphoid organ-on-chip modulates GC responses in healthy donor B cells, it fails with B cells derived from patients with lymphoma. Our system allows rapid, controlled modelling of immune responses and B cell disorders.
期刊介绍:
Nature Materials is a monthly multi-disciplinary journal aimed at bringing together cutting-edge research across the entire spectrum of materials science and engineering. It covers all applied and fundamental aspects of the synthesis/processing, structure/composition, properties, and performance of materials. The journal recognizes that materials research has an increasing impact on classical disciplines such as physics, chemistry, and biology.
Additionally, Nature Materials provides a forum for the development of a common identity among materials scientists and encourages interdisciplinary collaboration. It takes an integrated and balanced approach to all areas of materials research, fostering the exchange of ideas between scientists involved in different disciplines.
Nature Materials is an invaluable resource for scientists in academia and industry who are active in discovering and developing materials and materials-related concepts. It offers engaging and informative papers of exceptional significance and quality, with the aim of influencing the development of society in the future.