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

in Nature materials by 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

TLDR

  • The study creates a new way to study how B cells work and how they respond to different treatments. The study uses synthetic hydrogels to create a model of the lymphoid tissue microenvironment, which is where B cells live and work. The study finds that immune organoids derived from peripheral blood mononuclear cells work better than those derived from tonsils. The study also finds that there are unique ways that B cells work in peripheral blood mononuclear cell-derived immune organoids. The study also finds that current models for studying B cells are not good enough and that a new model is needed. The study's findings have important implications for treating B cell lymphoma and other B cell disorders.

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.

Overview

  • The study aims to develop synthetic hydrogels that mimic the lymphoid tissue microenvironment to study B cell responses and their programming. The study uses tonsil-derived and peripheral blood mononuclear cell-derived B cells to create immune organoids that maintain GC B cells and plasma cells longer than tonsil-derived ones. The study also investigates the effects of chemical inhibition of transcriptional and epigenetic processes on plasma cell formation and the impact of polarized CXCL12 protein on GC responses in healthy donor and lymphoma-derived B cells. The primary objective of the study is to develop a controlled and rapid model for studying immune responses and B cell disorders.

Comparative Analysis & Findings

  • The study found that immune organoids derived from peripheral blood mononuclear cells maintain GC B cells and plasma cells longer than tonsil-derived ones. The study also identified unique B cell programming in peripheral blood mononuclear cell-derived immune organoids, including GC compartments, somatic hypermutation, immunoglobulin class switching, and B cell clones. Chemical inhibition of transcriptional and epigenetic processes enhances plasma cell formation. However, integrating polarized CXCL12 protein in a lymphoid organ-on-chip modulates GC responses in healthy donor B cells but fails with B cells derived from patients with lymphoma. These findings suggest that the synthetic hydrogels developed in the study can be used to study B cell disorders and their programming.

Implications and Future Directions

  • The study's findings have significant implications for the development of new immunotherapies for B cell lymphoma and other B cell disorders. The study's synthetic hydrogels can be used to study the effects of immunotherapies on B cell responses and their programming. The study also identifies unique B cell programming in peripheral blood mononuclear cell-derived immune organoids, which can be used to develop new immunotherapies targeting specific B cell subsets. The study's lymphoid organ-on-chip model can be used to study the effects of different cytokines and chemokines on B cell responses and their programming. The study's findings also highlight the limitations of current ex vivo models for studying B cell responses and their programming, and the need for more advanced models that can sustain long-term GC reactions and effectively test B cell responses.
Read Full Article