Human immune organoids to decode B cell response in healthy donors and patients with lymphoma PMID: 39506098

mRNAエンジニアリング：分子設計、標的指向型デリバリー、トランスレーショナル研究の課題

2026-08-20

Human immune organoids to decode B cell response in healthy donors and patients with lymphoma

Nat Mater. 2025 Feb;24(2):297-311. doi: 10.1038/s41563-024-02037-1.

Zhe Zhong ¹ ² ³ , Manuel Quiñones-Pérez ¹ ³ , Zhonghao Dai ¹ ³ , Valeria M Juarez ¹ ³ , Eshant Bhatia ¹ ³ , Christopher R Carlson ¹ ³ , Shivem B Shah ⁴ , Anjali Patel ³ , Zhou Fang ¹ ³ , Thomas Hu ¹ ³ , Mayar Allam ¹ ³ , Sakeenah L Hicks ⁵ , Mansi Gupta ⁵ , Sneh Lata Gupta ⁶ , Ethan Weeks ² , Stephanie D Vagelos ⁷ , Alejandro Molina ⁸ , Adriana Mulero-Russe ¹ ⁹ , Ana Mora-Boza ¹ ² , Devyani J Joshi ⁶ , Rafick P Sekaly ⁶ , Todd Sulchek ¹ ² , Steven L Goudy ³ ¹⁰ , Jens Wrammert ⁶ , Krishnendu Roy ¹¹ , Jeremy M Boss ⁵ ⁶ , Ahmet F Coskun ¹ ³ , Christopher D Scharer ⁵ , Andrés J García ¹ ² , Jean L Koff ¹² , Ankur Singh ¹³ ¹⁴ ¹⁵

Affiliations

1. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
2. George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
3. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
4. Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
5. Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, GA, USA.
6. Emory Vaccine Center, Emory School of Medicine, Emory University, Atlanta, GA, USA.
7. School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA.
8. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA.
9. School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
10. Department of Otolaryngology, Emory School of Medicine, Emory University, Atlanta, GA, USA.
11. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
12. Winship Cancer Center, Emory School of Medicine, Emory University, Atlanta, GA, USA.
13. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA. [email protected].
14. George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. [email protected].
15. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. [email protected].

Abstract

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.