# Hydrogel-Based Aged Immune Organoids to Study Epigenetics and Trajectory of B Cells

> **NIH NIH R01** · GEORGIA INSTITUTE OF TECHNOLOGY · 2024 · $771,620

## Abstract

PROJECT SUMMARY
Aged individuals, who are often at higher risk of fatality in life-threatening infectious diseases, do not form high-
quality antibodies against new infections. Humoral immunity against infections depends on the germinal center
(GC) differentiation process in the B cell follicles of lymph nodes. In GCs, naïve B cells rapidly proliferate in
response to T cell-dependent antigens and somatically mutate into high-affinity antibody-secreting cells, i.e.,
plasma cells. A significant concern is that with aging, B cells exhibit a decreased expansion of B cells and GC
reaction in response to antigen. However, it is unclear whether this is solely due to immune senescence and a
defect in B cells or the follicular T helper cell (TFH), and whether the lymphoid microenvironment of B cell follicles
plays a role. B cells in young mice assume heterogeneous cell fates upon stimulation, with only a fraction
differentiating into antibody-secreting cells (ASC), however, this phenomenon remains unknown in B cells from
old mice. Notably, plasma cell differentiation in young B cells is controlled by multiple cell division-coupled
epigenetic programs, which also remains understudied in old B cells. Because aged mice cannot generate
sufficient GCs to provide insight into ASC fate and epigenomic remodeling of GC B cells, necessitating the
development of a tissue-engineered model of aged lymphoid tissues. The long-term goals of this R01 are 1) to
develop an ex vivo “aged B cell follicle” organoid technology capable of providing lymphoid microenvironment
signals in a plug-and-play manner to induce early GC programming of aged B cells from mice and human B
cells, therefore enabling the study of plasma cell fate and regulation of the epigenome of B cells; and 2) to
identify checkpoint targets that can be suppressed to boost GC response in aged B cells. PI has
demonstrated that GCs phenotype could be generated in organoids using B cells from >2-yr old mice
when differentiated under young lymphoid microenvironment conditions, however to a lesser extent than
young B cells. However, true differentiation fate of aged B cells ex vivo can only be realized in a
microenvironment representative of old lymph nodes.The R01 is highly significant and innovative because it
will 1) establish lymphoid microenvironment of aged lymph nodes and engineer a hydrogel-based “aged”
immune organoid to study vaccine and infection responses, 2) enable control over the ex vivo B cell
differentiation of aged B cells in ex vivo cultures and generate antigen-specific antibodies against infections,
3) define the cell division kinetics of B cell differentiation and identify the molecular and epigenetic trajectories of
aged B cell fate and ASC formation, and 4) identify checkpoint targets to accelerate GCs in aging.

## Key facts

- **NIH application ID:** 10996708
- **Project number:** 1R01AI181282-01A1
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Ankur Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $771,620
- **Award type:** 1
- **Project period:** 2024-07-12 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996708

## Citation

> US National Institutes of Health, RePORTER application 10996708, Hydrogel-Based Aged Immune Organoids to Study Epigenetics and Trajectory of B Cells (1R01AI181282-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10996708. Licensed CC0.

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