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

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

doi:10.1038/s41563-024-02037-1

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

Nat Mater. 2024 Nov 6. doi: 10.1038/s41563-024-02037-1. Online ahead of print.

Authors

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 Shah⁴, Anjali Patel³, Zhou Fang^{1

3}, Thomas Hu^{1

3}, Mayar Allam^{1

3}, Sakeenah L Hicks⁵, Mansi Gupta⁵, Sneh Lata Gupta⁶, Ethan Weeks², Stephanie D Vagelos⁷, Alejandro Molina⁸, Adriana Mulero-Russe^{1

9}, Ana Mora-Boza^{1

2}, Devyani J Joshi⁶, Rafick P Sekaly⁶, Todd Sulchek^{1

2}, Steven L Goudy^{3

10}, Jens Wrammert⁶, Krishnendu Roy¹¹, Jeremy M Boss^{5

6}, Ahmet F Coskun^{1

3}, Christopher D Scharer⁵, Andrés J García^{1

2}, Jean L Koff¹², 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].

PMID: 39506098
DOI: 10.1038/s41563-024-02037-1

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.