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Optimization of B Cell Responses in Human Immune System Mice Through Organoid Based Screening
Haiqiao Sun1, He Li1, Xu Zhu1
1National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 26, 2026
Summary
Researchers developed a spleen organoid system to enhance B cell responses in human immune system (HIS) mice. This strategy successfully generated high-affinity antibodies against SARS-CoV-2, paving the way for therapeutic antibody development.
Area of Science:
- Immunology
- Cell Biology
- Drug Discovery
Background:
- B cells in human immune system (HIS) mice show limited responses to antigens.
- This deficiency is attributed to the lack of T cell-provided second signals after B cell receptor (BCR) stimulation.
Purpose of the Study:
- To develop an organoid screening system to identify signals that enhance B cell responses in HIS mice.
- To establish a method for generating therapeutic antibodies against SARS-CoV-2.
Main Methods:
- Utilized a spleen organoid system with HIS mouse splenocytes for signal screening.
- Identified key cytokines (IL-4, IL-10, IL-21, CD40L) and factors (TNF-α, CpG) that promote B cell proliferation, differentiation, and class-switching.
- Translated findings in vivo using CpG-adjuvanted vaccination and sequential cytokine delivery.
Main Results:
- A combination of IL-4, IL-10, IL-21, and CD40L significantly enhanced B cell proliferation and differentiation.
- TNF-α and CpG synergistically promoted IgG class-switch, with temporal signal separation improving responses.
- In vivo application led to antigen-specific B cell expansion, differentiation, and IgG class-switch in HIS mice.
- RBD-specific B cells yielded recombinant antibodies with high binding affinity and neutralizing activity against SARS-CoV-2 pseudovirus.
Conclusions:
- The spleen organoid platform is effective for screening B cell response modulators in HIS mice.
- A generalizable strategy was established to obtain fully human antibodies for therapeutic development.
