Mast Cell Biology: Contemporary and Emerging Topics

311 Pages·2011·8.88 MB·English

by  Alasdair M. Gilfillan

Mast Cell Biology
ADVVVANCES INEXPERIMENTTTALMEDICINEAND BIOLOGY
Editorial Board:
NATHAAANBACK,State University of New York at Buffalo
IRUUUNR. COHEN, The Weizmann Institute of Science
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research
JOHN D. LAMBRIS,University of Pennsylvania
RODOLFO PAOLETTI,University of Milan
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Robin L. Thurmond
Volume 710
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Eleftherios Mylonakis
Volume 711
EPIGENETIC CONTRIBUTIONS IN AUTOIMMUNE DISEASE
Esteban Ballestar
Volume 712
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Mark W. Robinson and John P. Dalton
Volume 713
CELL FUSION IN HEALTH AND DISEASE, I: CELL FUSION IN HEALTH
Thomas Dittmar
Volume 714
CELL FUSION IN HEALTH AND DISEASE, II: CELL FUSION IN DISEASE
Thomas Dittmar
Volume 715
BACTERIAL ADHESION: BIOLOGY, CHEMISTRY AND PHYSICS
Dirk Linke and Adrian Goldman
Volume 716
MAST CELL BIOLOGY: CONTEMPORARY AND EMERGING TOPICS
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Mast Cell Biology
Contemporary and Emerging TTTopics
Edited by
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Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, Maryland, USA
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Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, Maryland, USA
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and biology ; v. 716.
[DNLM: 1. Mast Cells. W1AD559 v.716 2011 / QS 532.5.C7]
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DEDICAAATION
The editors would like to dedicate this work to the many present and former
members of the Laboratory of Allergic Diseases who have contributed to the
success of the clinical and basic research programs in theLAD since the inception
of the Laboratory in 1995. We feel privileged to have worked with so many
talented and enthusiastic fellows, nurses, administrators and senior scientists.
AA special thanks to Dr. Anthony Fauci, the Director of the National Institute
of Allergy and Infectious Diseases who, along with Dr. TTTom Kindt, then the
Director of the NIAID Division of Intramural Research, supported the creation
of the LAD; and to Dr. Katherine Zoon for her encouragement and support in
the contemporary expansion of the clinical research program of the LAD. We
are especially indebted to the patients who have participated in clinical research
protocols directed at understanding and treating allergic diseases and systemic
mast cell disorders.
v
FOREWORD
The editors of this book, Drs. Gilfillan and Metcalfe, have enlisted an outstanding
group of investigators to discuss the emerging concepts in mast cell biology with respect
to development of these cells, their homeostasis, their activation, as well as their roles
in maintaining health on the one hand and on the other, their participation in disease.
As noted by several of the contributors, there have been extraordinary advances in
our understanding of these phenomena over the past 40 years since the tools became
available to analyze these aspects at a molecular level. Initially, this ability was made
possible by the use of so-called model systems by which phenomena such as the allergic
response involving the IgE-mediated activation of mast cells, and the related basophils,
could be investigated. The discovery of a rat mucosal mast cell tumor analog –the “rat
basophilic leukemia” (RBL) cells—and the development of lines of IgE myeloma protein
producing cell lines, permitted a rigorous analysis of the cellular receptor that triggered
the explosive release of a variety of potent mediators. This was soon followed by the
initial identification of the proximal post-receptor molecules that were activated when
the receptor-bound IgE was aggregated by antigen or bivalent anti-IgE. As knowledge
about similar systems expanded, extraordinarily powerful cell biological methods were
developed. That knowledge and those methods have been productively applied to analyze
those model systems and, increasingly, their normal counterparts in rodent cells and, even
more recently, in human cells. At the same time, less reductive more physiological studies
have vastly increased our insight into the role mast cells play in a variety of aspects of
the immune response.
These new insights not only expand our knowledge of cell biology in general but
hopefully will be therapeutically applicable. Indeed, almost without exception, the
authors of each of the articles in this compendium end their presentations by noting
that their studies have helped to define new targets to which drugs could be directed in
order to alleviate some of the pathological phenomena that are mediated by mast cells.
However, as noted for example in the contribution byTsai et al, the fact that mast cells
have both positive and negative immunomodulatory functions present the challenge of
whether such functions can be manipulated for therapeutic ends by suppressing those
vii
viii FOREWORD
actions that result in disease without interfering with those functions that promote health
by enhancing beneficial immune responses.
TTTwo recent events underscore this dilemma.On the down side is the case of Alzheimer
disease. It has long been posited that the disease is caused by the accumulation of so-
called amyloid beta plaques in the brain. Because gamma secretase is believed to play
an important role in formation of the plaque, a drug designed to inhibit the activity of
that enzyme was thought to be promising. Indeed, a trial of such a drug, Eli Lilly’s
semagacestat, had advanced to a Phase III clinical trial involving some 2600 patients.
But in August of this year the multi-million dollar trial had to be abruptly halted when
the developing data showed that the drug not only failed to slow progression of the
disease, but was associated with a worsening of cognition and the ability to perform the
tasks of daily living.
On the other hand, a more hopeful conclusion is prompted by a report published
that same month by the laboratory of TTTak Mak.1That group has been studying the MAP
kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) -protein serine/ threonine kinases that
are activated by ERKK or p38 and which phosphorylate eIF4E, a component involved in
the initiation of cap-dependent translation. Surprisingly, they found that Mnk1/2 double
knockout mice not only exhibited normal cell growth and development despite an absence
of eIF4E phosphorylation, but that the tumorigenesis occurring in a mouse model was
suppressed by the loss of Mnk1/2.Furthermore, stable knockdown of Mnk1 in a human
glioma cell line resulted in dramatically decreased tumor formation when these cells
were injected into athymic nude mice.Thus, their data demonstrate an oncogenic role
for Mnk1/2 in tumor development, and highlight these molecules as potential anticancer
drug targets that could be inactivated with minimal side effects.Clearly, translating such
findings to warrant a clinical trial will require many more steps but it shows that despite
the complexity of cellular biochemical pathways it may be possible to pin-point specific
components that though participating in normal functions can be dispensed with when
they become involved in pathological processes. Many other results from clinical trials
of rationally designed therapeutics, some disappointing, others successful such as the
inhibitor of theABLL tyrosine kinase, imatinib (Gleevec®) and the anti-tumor necrosis
factor monoclonals infliximab (Remicade®) and adalimumab (Himura®), could be cited.
So how realistic are the proposals that our increased insight into mast cell biology
can be translated to yield therapeutic benefits?TTTo state my own cautious optimism in
semi-quantitative terms, I believe that whereas our knowledge can be expected to continue
to expand exponentially, the applicability of that knowledge will proceed only linearly
and with a rather shallow slope. The enormous expense of clinical trials makes it critical
that pre-clinical investigations should be exhaustive, and we must be careful not to let
those who pay for our research, whether it be the general public or private investors, be
encouraged to believe otherwise.
Henry Metzger
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health, Bethesda, Maryland, USA
(cid:2) (cid:28)(cid:11)(cid:2)’(cid:16)(cid:7)(cid:5)*(cid:30)(cid:31)(cid:5)(cid:6)(cid:5)<(cid:8)(cid:10)(cid:30)=(cid:4)(cid:8)(cid:5)(cid:3)>(cid:16)(cid:17)(cid:5)(cid:4)(cid:11)@(cid:21)(cid:25)(cid:20)(cid:8)(cid:14)(cid:16)(cid:7)(cid:7)(cid:16)(cid:13)(cid:18)(cid:8)(cid:16)(cid:14)(cid:18)(cid:23)(cid:19)(cid:21)(cid:9)(cid:10)(cid:3)\<(cid:8)(cid:14)(cid:5)(cid:6)(cid:16)^(cid:8)(cid:14)(cid:17)(cid:16)(cid:9)(cid:5)(cid:18)(cid:17)(cid:8)(cid:14)(cid:22)<(cid:8)(cid:14)(cid:5)(cid:6)(cid:16)(cid:28)(cid:5)(cid:14)(cid:7)_
(Mnk1 and Mnk2) delays tumor development. Proc NatlAcad Sci USAA 2010; 107:13964-13990.
ABOUT THE EDITORS...
ALASDAIR GILFILLAAAN, PhD received a BSc from the University of Strathclyde,
Glasgow, Scotland and MSc and PhD degrees in Pharmacology from theUniversity of
Manchester, England.Following completion of his PhD, he moved to the United States
to undertake research in Cell Biology and Biochemistry in the Department of Pediatrics,
Yale University Medical School; initially as a Postdoctoral Fellow, then as anAssociate
Research Scientist. From there, Dr. Gilfillan moved toF. Hoffman-La Roche Ltd (Nutley,
NewJersey,USA) where he spent several years conducting preclinical research in the
areas of allergy and inflammation. In 1999, he joined theLaboratory of Allergic Diseases
(LAD), at the National Institute of Allergy and Infectious Diseases (Bethesda, Maryland,
USA), where he currently helps direct the basic research efforts within the Mast Cell
Biology Section. Dr. Gilfillan has had a long term interest in mast cell biology, and his
current research focuses on the elucidation of signaling mechanisms associated with the
activation of mast cells throughFc(cid:2)RI, KIT and other receptors, in health and disease.
Dr. Gilfillan is the author of more than 90 scientific articles, and more than 50 abstracts.
From 1994-2001, he was on the editorial board of the Journal of Pharmacology and
Experimental Therapeutics. He currently serves on the editorial boards of Journal of
Immunology, Immunology Letters, The Open Immunology Journal, The Open Allergy
Journal, and theWorld Journal of Biological Chemistry.
ix
ABOUT THE EDITORS...
DEAAAN METCALFE, MD, received a BS from Northern Arizona University and an
MD from theUniversity of TTTennessee. He completed a residency in Internal Medicine at
the University of Michigan and received a MS in Microbiology from the University of
Michigan. Dr. Metcalfe was a Fellow in Allergy and Immunology at NIHand a Fellow in
RRRheumatology and Immunology at the Robert Brigham Hospital and the Harvard Medical
School. In 1979, he returned to NIHas a Senior Clinical Investigator. His subsequent career
has been devoted to research and public service at the NIH. There he combines clinical and
basic research, patient care and administrative duties, as well as scholarly activities in the
form of teaching, writing, and speaking on areas related to allergic diseases. In 1995, Dr.
Metcalfe was appointed the first Chief of the newly created Laboratory of Allergic Diseases
(LAD), NIAID. He is also Chief of the Mast Cell Biology Section/LAD and Associate
Director of the NIHClinicalCenter Allergy and Immunology ClinicalFellowship Program
which is administered through theLAD. Dr. Metcalfe is an author on over 490 scientific
papers and 230 abstracts; and an editor on 12 books on mast cell biology, systemic mast
cell disorders, food allergy and asthma. He is a past Chairman of the American Board of
Allergy and Immunology; a past President of the American Academy of Allergy, Asthma
and Immunology; and a past Chairman of theACGME-RRC for Allergy and Immunology.
Dr. Metcalfe has been elected to membership in theAmerican Clinical and Climatological
Association, the Collegium Internationale Allergologicum, the American Society for Clinical
Investigation, and theAmerican Association of Physicians.
xi
PARTICIPPPANTS
Soman N.Abraham Peter Bradding
Departments of Pathology, Immunology, Department of Respiratory Medicine
and Molecular Genetics (cid:12)(cid:4)(cid:16)(cid:14)(cid:13)(cid:16)(cid:4)(cid:7)‘(cid:21)(cid:6)(cid:26)(cid:8)(cid:17)(cid:5)(cid:4)
and Microbiology Leicester
DukeUniversity Medical Center UK
Durham, North Carolina
USA GeorgeH.Caughey
Department of Medicine
Sarah J.Austin Pulmonary and CriticalCare Division
Laboratory of Allergic Diseases University of California at San Francisco
National Institute of Allergy San Francisco, California
and Infectious Diseases USA
National Institutes of Health
Bethesda, Maryland Enrico Crivellato
USA Department of Medical
and Morphological Research
MichaelA. Beaven Section of Anatomy
Laboratory of Molecular Immunology University of Udine Medical School
National Heart, Lung Udine
and Blood Institute Italy
National Institutes of Health
Bethesda, Maryland Maria Ekoff
USA Clinical Immunology and Allergy
Department of Medicine
Ulrich Blank Karolinska Institutet
InsermU699, Université Paris 7 Stockholm
and Sweden
Faculté de Médecine Paris Diderot
Site Xavier Bichat Stephen J. Galli
Paris Department of Pathology
France Department of Microbiology
and Immunology
Stanford University School of Medicine
Stanford, California
USA
xiii