Science - USA (2022-02-25)

SCIENCE science.org 25 FEBRUARY 2022 • VOL 375 ISSUE 6583 830-B

By Lisa Wagar

T

he investigation of how

the specialized microen-

vironment of lymphoid

tissues regulates adaptive

immune responses forms

the foundation of my laboratory’s re-

search. At present, I am using human tonsil

organoids to predict immunogenicity and

immunodominance for vaccines and infec-

tious diseases and then leveraging this new

information to improve vaccine design. We

are also using tumor organoids (derived from

primary human biopsies or excisional surger-

ies) to investigate the dynamics of tumor–

immune cell interactions to dissect the mech-

anisms by which immunotherapies contrib-

ute to tumor control.

At present, there are two major chal-

lenges that limit our ability to rationally de-

sign new immune therapeutics for humans.

First, although numerous animal models

exist to study adaptive immunity, translat-

ing these foundational discoveries into vac-

cines and immunotherapies remains ineffi-

cient. Vaccine efficacy for some of the most

well-studied human pathogens (e.g., HIV,

Mycobacterium tuberculosis, Plasmodium

falciparum, influenza) ranges from 0 to

60%, indicating our inability to predict in

vivo immunogenicity on the basis of pre-

clinical data. The second major challenge

is that most preclinical studies fail to ad-

equately account for the extent of interindi-

vidual immune variation. I have studied the

effects of demographic and environmental

factors (e.g., age, sex, immune history, mi-

crobial environment) on human adaptive

immunity and repeatedly found that they

play a crucial role ( 1 – 3 ). Studying this vari-

ability can help us to understand why some

people respond differently to the same drug

as well as to develop more broadly effective

immune therapeutics. Immune organoids

are an optimal strategy to overcome these

challenges because they enable us to study

the factors that contribute to adaptive im-

munity in a high-throughput way while

controlling for interindividual variation.

Organoid technologies have revolution-

ized our ability to study complex tissues

in a physiologically relevant

microenvironment. Immune

organoid models offer a dis-

tinctive opportunity to track

the early events in lymphoid

tissues that lead to protective

responses. In the laboratory,

we use tonsils as a source of accessible

lymph node–like tissues from humans.

Tonsillectomy surgeries are common, and

the excised tissue is usually discarded.

Lymph nodes are one of the most impor-

tant tissue types for understanding the

maturation of vaccine-induced adaptive

immunity. Tonsils are exposed to both res-

piratory and alimentary antigens and are a

key access point for studying the response

to both oral and nasal vaccines. We devel-

oped an immune organoid model, derived

from primary human lymphoid tissues

(principally tonsils but also lymph nodes

and spleen), to improve the translational

value of preclinical vaccine studies and to

increase our appreciation of how interin-

dividual differences contribute to immune

variation ( 4 ). Our organoids are derived

from tonsil tissue collected from children

(≥2 years old) and adults of ethnically di-

verse backgrounds, with males and females

represented equally. Tonsils are collected

from relatively healthy individuals, but we

do not exclude those with common condi-

tions such as diabetes and heart disease.

We are now screening a large panel of US

Food and Drug Administration–approved

vaccines in tonsil organoids to build an

integrated model of vaccine immunogenic-

ity and make predictions about the magni-

tude and quality of the response in people.

Previous techniques for producing in vi-

tro models of human adaptive immunity,

though successful, have not been widely

adopted because of reliance on specialized

equipment, challenging technical protocols,

poor throughput, a lack of evidence for an-

tigen-specific responses, and/or the absence

of cells known to be crucial to important fea-

tures of adaptive immunity ( 5 – 12 ). Contrary

to previous immune organoid methods, our

tonsil organoid system holistically captures

the original cell composition and complete

functional capabilities of donor tissues.

Research published last year details how

these immune organoids respond to influ-

enza and other viral vaccines and patho-

IMMUNOLOGY

Small centers of defense

Deciphering immune responses to viruses and vaccines

using human tonsil organoids

Institute for Immunology, University of California, Irvine,
PHOTO: ANDREW SORN Irvine, CA 92697, USA. Email: [email protected]

FINALIST

Lisa Wagar

Lisa Wagar

received

a BSc from

the University

of Ontario

Institute of Technology and

a PhD from the University of

Toronto. After completing her

postdoctoral fellowship at

Stanford University, she started

her laboratory in 2020 in the

Department of Physiology and

Biophysics at the University

of California, Irvine, where she is

currently an assistant profes-

sor. Her research focuses on

translational human immunol-

ogy and the use of organoids

to understand the complex

interactions that occur between

immune cells upon vaccination

and infection in humans.

http://www.science.org/doi/10.1126/

science.abn9652

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