Major contributions
- Purification, characterization and function of human lung mast cells
(1982).
- Inhibitory effects of glucocorticoids on basophils, mast cells and
eosinophils (1981-1991) and other cells during allergic inflammation
(1981-)
- Demonstrated that pro-inflammatory cytokines like IL-1 and TNF cause
endothelial cells to acquire adhesiveness for granulocytes (1986)
while type 2 cytokines selectively induce adherence of eosinophils and
basophils, but not neutrophils, to endothelium via induction of VCAM-1
(1992)
- Role of airway epithelial cells in allergic diseases (1995-)
- Understanding pathogenesis of chronic rhinosinusitis (2005-)
- Mentorship of over 50 trainees including more than 10 full professors
This issue honors Robert (Bob) Paul Schleimer, PhD for his scientific
accomplishments. Bob has been studying the mechanisms of inflammation,
especially in the context of disease of the airways of humans, for over
40 years and is a world-renowned expert on the role of immune and
structural cells in type 2 inflammatory diseases including asthma,
allergic rhinitis and chronic rhinosinusitis (CRS). Bob was born on
April 8, 1952 in New York City. He received his PhD in pharmacology and
toxicology at the University of California, Davis in 1980 followed by a
postdoctoral fellowship at The Johns Hopkins University School of
Medicine under the primary mentorship of Dr. Lawrence Lichtenstein. Bob
first became interested in the role of basophils and mast cells, key
effector cells in the allergic response. Importantly, Bob was on the
team that developed the first method to purify human mast cells from
lung tissue. For over 30 years Bob has studied basophils and mast cells
and published many important and impactful papers describing the
regulation of their signaling, activation and products especially in
human allergic diseases.
One of his key contributions to this field was the discovery of the
action of glucocorticoids in allergic reactions. Bob was the first to
demonstrate that glucocorticoids inhibit human basophil-mediated, but
not mast cell-mediated, allergic release of histamine (Figure
1).1,2 This very important finding explains why
glucocorticoid treatment does not interfere with the allergen-induced
immediate early phase response by mast cells but does inhibit the
basophil’s contribution to the late phase response. Bob has continued to
study the mechanisms of action of glucocorticoids in allergic diseases
for over 30 years as a principal investigator in NIH research grants and
received a MERIT award focusing on this subject.
Recruitment of leukocytes by adhesion and migration is a key event to
induce an inflammatory cascade. Bob was the first to show that cytokines
including TNF and IL-1 cause endothelial cells to acquire adhesiveness
for neutrophils.3 This important finding ultimately
led other groups to clone endothelial adhesion molecules such as
E-selectin and VCAM-1. Together with one of his early mentees Bruce
Bochner, Bob then focused on the mechanisms of selective recruitment for
eosinophils and basophils in allergic diseases and identified several
important mechanisms such as the fact that IL-4 and IL-13 selectively
induced VCAM-1 on endothelial cells, a ligand for VLA-4 on eosinophils
and basophils but not neutrophils.4 His laboratory was
the first to characterize the adhesion molecules and chemokines that
mediate transendothelial migration, including work by Motohiro Ebisawa
and others.5 These findings contributed to the
rationale for drug discovery that targeted CCR3, IL-4, IL-13, IL-4Rα,
VCAM-1 and α4 integrins (ligands for VCAM-1). Indeed, many such drugs
are under development or are already approved for the treatment of
allergic and other diseases.
In the mid 1990s, Bob continued to explore chemokine biology and began
to focus on the role of airway epithelial cells in allergic diseases.
Besides working with Lisa Beck to show that RANTES caused eosinophil
accumulation in the skin, his lab was actually among the first to
describe epithelial cells as important producers of chemokines including
MCP-4 (discovered by Cristiana Stellato in the Schleimer laboratory),
RANTES and eotaxin.6,7 His laboratory also found that
type 2 cytokines, especially in the presence of proinflammatory
cytokines, induce expression of MCP-4 and eotaxin as well as an adhesion
molecule VCAM-1 in airway epithelial cells. Expression and induction of
these molecules in epithelial cells are now widely recognized as an
essential event in leukocyte recruitment in both physiological and
disease situations. Bob’s group also made the important observation that
glucocorticoids enhanced innate immunity and host defense molecules in
airway epithelial cells while they reduced pro-inflammatory mediators.
In addition, his laboratory was among the first to describe that airway
epithelial cells are an important source of cytokines including BAFF,
TSLP and IL-36 that directly and indirectly activate innate and adaptive
immune cells and participate in several airway diseases, including work
by Atsushi Kato.
In the late 1990’s, the Schleimer laboratory, once again working
together with Bruce Bochner’s laboratory, co-discovered Siglec-8 (or
sialoadhesin factor-2, SAF-2).8 Siglec-8 is
selectively expressed on human eosinophils and mast cells, and the
engagement of Siglec-8 with a monoclonal antibody or its natural ligands
induces the death of eosinophils and inhibits mast cell degranulation.
Anti-Siglec-8 antibody (AK002, lirentelimab) is currently in clinical
trials for several eosinophilic disorders.9
In 2004, Bob moved to Northwestern University Feinberg School of
Medicine and became the chief in the division of Allergy and Immunology
and a Roy & Elaine Patterson Professor of Medicine. Although there was
only a CLIA laboratory in this division before his arrival, Bob
successfully recruited multiple faculty members and developed several
research laboratories in this division. Bob, together with Dr. Robert
Kern, a surgeon and Chairman of the Department of Otolaryngology,
developed the Sinus and Allergy Center at Northwestern to focus on
translational research in chronic rhinosinusitis (CRS). At the time,
basic research in CRS was far behind compared to other airway
inflammatory diseases including asthma and allergic rhinitis especially
in the US. Bob contributed to the CRS field for 16 years and has
published over 100 manuscripts on CRS.10 He also
currently serves as the program director for the Chronic Rhinosinusitis
Integrative Studies Program funded by NIH/NIAID. Bob is now one of the
key leaders in this field in the world.
Dr. Schleimer has published over 390 peer-reviewed papers with an H
index of 88 and has been recognized by the ISI as being among the top
0.5% of the most highly cited investigators over the last 20 years. He
actively contributes to research on the mechanisms of allergic diseases
and chronic rhinosinusitis, and true to his background in pharmacology,
several of his discoveries served as underpinnings for drug development
in allergic and other diseases. Between his time at Johns Hopkins and at
Northwestern, he trained over 50 highly successful scientists, many of
whom are full professors and leaders in
Allergy/Immunology/Respiratory/Dermatology fields throughout the world.
His impact on current and future generations of physicians and
scientists will be long-lasting.