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Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520
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Introduction |
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 Top Introduction References |
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Two roads diverged in a yellow wood,
And sorry I could not travel both
And be one traveler, long I stood
And looked down one as far as I could
To where it bent in the undergrowth;
Then took the other, as just as fair,
And having perhaps the better claim,
Because it was grassy and wanted wear;
Though as for that the passing there
Had worn them really about the same.
And both that morning equally lay
In leaves no step had trodden black.
Oh, I kept the first for another day!
Yet knowing how way leads on to way,
I doubted if I should ever come back.
I shall be telling this with a sigh,
Somewhere ages and ages hence:
Two roads diverged in a wood, and I—
I took the one less traveled by,
And that has made all the difference.
—Robert Frost
The title for my talk was chosen from a poem by Robert Frost called "The Road Not Taken." I think this poem is a wonderful metaphor for the choices we make all the time in our lives. Choices that define our paths at all forks in the road, which have irrevocable consequences for all of us, and which are often made on the merest of whims. These decisions have a profound impact on our lives, but we are usually too busy to notice this. So in my address to the members of this association, I want to review with you my life in science, especially those individuals who have influenced my choices over the years, and how I decided eventually to go into the study of the innate immune response to infection.
Looking backwards is always a temptation in these talks, and I would like to share with you my own roots in medicine and science, because these also focused my attention on the role of the immune system in protecting the body from infection.
My great-grandfather, Edward Gamaliel Janeway (Fig. 1
, left), was the
health commisioner of the City of New York and a professor of medicine
and pathology at Bellvue Hospital on Roosevelt Island. Here he is
standing beside a patient, but we don’t know if the patient is alive
or dead, as he took care of live patients and their corpses! Note the
formal dress of the medical students in the audience; I would like to
see a class at Yale with such dignity! (Of course, I would myself have
to dress up similarly to my great grandfather!) I think I inherited my
interest in medicine and research from my great-grandfather because we
both have such broad-ranging interests in science.
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, center), was a professor of medicine with interests
in cardiology and infectious disease. The eponymous Janeway’s lesions
in subacute bacterial endocarditits are named for him. He first worked
at Columbia’s College of Physicians and Surgeons, and later at John’s
Hopkins University School of Medicine, where he served as the first
full-time professor on the staff of the Johns Hopkins Hospital. In late
1917 he was asked by the United States Army to visit the encampments of
soldiers, as the rate of mortality in these camps was very high. He did
this, contracted the same pneumococcal pneumonia that accounted for the
high mortality rate among the troops, and died within a week in
December 1917; my father was 8 at the time. From this family tragedy, I
learned that in the pre-antibiotic era, infectious disease posed a real
threat to life. Fortunately, I have lived in an era that is relatively
free of infection, as key advances in antibiotic therapy of infection
and in vaccines occurred within my lifetime. If penicillin had been
available at the time of my grandfather’s illness, he could have lived
much longer; unfortunately, it was not available until 1945, and so my
grandfather died as a relatively young and otherwise healthy
man.
My father, Charles A. Janeway (Fig. 1, right), was a
professor of pediatrics and department chairman for about 30 years at
the Children’s Hospital Medical Center in Boston. During the World War
II, he worked with Dr. Edwin Cohn on the fractionation of human plasma
into various protein solutions. One of these, which I think was called
fraction V, contained a set of proteins called gammaglobulins that had
been demonstrated by Kabat and Tiselius to have antibody function. My
father studied this fraction of proteins extensively over the ensuing
years, using protein electrophoresis to define patients that lacked
gammaglobulins. He had accumulated four such patients by 1953, when
Colonel Oswald Bruton reported one case in a military recruit. My
father then reported his four cases and pointed out that they had an
unusual susceptibility to infection. He used injections of pooled
gammaglobulin to treat these patients, which protected them from
infection; this treatment is still used today. He later noted that
several distinct proteins were missing from the plasma of this patient,
thus discovering that several distinct proteins had antibody activity;
this led directly to experiments that defined the various isotypes of
human immunoglobulin. From my father, I learned that the presence of a
functioning immune system in man was an essential characteristic for a
healthy life. It should be noted that these agammaglobulinemic
individuals were only discovered once effective antibiotic therapy for
infection was available.
Thus, from many observations, and from my own personal history, it was clear that the main purpose of the adaptive immune response was resistance to infectious disease, and that, in its absence, death would occur early in life. Thus this function of the immune system was clearly of paramount evolutionary importance. These observations, as well as many chance decisions along the way, led to my initial interest in the adaptive immune system.
Several events during my early training had a great impact on my thinking. I was fortunate to train with a series of great thinkers in immunology. My first mentor, who loves to disclaim me, was Hugh McDevitt. Hugh introduced me to the subject of immunology and taught me how to read the literature. He told me that one should always attempt to construct an internal image of the universe of knowledge and then ask if a given publication can, in any significant way, modify that image. I still use this system to read papers and evaluate research proposals, although I admit that it works less well in the molecular era, as new genes define new proteins that have to be added to the list at an ever-accelerating rate. One paper that we read in class was by Marion "Bunny" Koshland on the analysis of the amino acid composition of antibodies purified from rabbits immunized with distinct antigens. I remember very well reading this paper, as it contained the first evidence of variability in protein structure in the specific case of antibody molecules. This led to a debate among my fellow students about the origin of this diversity, which was later solved by the finding made by Susumu Tonegawa that antibodies are encoded in gene segments, and that these gene segments are present in the germline in large numbers and undergo rearrangement to generate specific antibody molecules.
Hugh arranged for me to spend 2 years with John Humphrey at Mill Hill in northern London. Again, this choice had three major impacts on my life. First, it raised my interest in immunity to infection and in the science of immunology to a high level. Second, it further fed my craving for variety in my interests, as John was interested not only in all of immunology, but in country walks, in politics, and in public service. He remains a principle inspiration to me in all of these areas. Third, it got me interested in writing, as John had, together with Bob White, written one of the first textbooks of immunology, entitled "Immunology for Medical Students." I also met many of the world’s top scientists, especially in immunology, at the early age of 22. Finally, I learned from John the approach to training young scientists that I still apply today: Leave them to their own devices; if they are good, they will take care of themselves and become better scientists than they would if excessively monitored. I truly believe that this is the best way to train young scientists; it has certainly benefited me.
After working in an immunology lab for 2 years, I returned home to complete my medical studies, but with a new attitude toward them; I was more focused and more critical, which did not serve me well in clinical medicine. I realize now that people who take care of other people do not have the luxury of testing out their ideas on their patients; they simply have to make the best decision based often on the flimsiest of evidence. This bothered me, and eventually played a part in my going into science. But the immediate force that made me choose science over medicine was getting into the Public Health Service as a "yellow beret," our joking name for the group that came of age at the end of the 1960s and did not want to serve in the army in Vietnam in what we regarded as an unjust war.
I was lucky enough to be accepted into the Laboratory of Immunology at the National Institutes of Health; at the time of the decision, the head of the laboratory was Baruj Benacerraf, but on the day I arrived in Bethesda, he departed to assume the Fabyan Professorship of Pathology at Harvard Medical School. In his stead, he wisely left Bill Paul, first as an acting head of the laboratory and eventually, as the wisdom of the choice became self-evident, as lab chief. Bill became a most important mentor to me: he taught me how to write better and more carefully reasoned papers, and he, like John Humphrey, basically left me alone to follow my own interests. After 5 happy and productive years at the National Institutes of Health, I left to accept a position at Yale, but, as my laboratory was not going to be finished for a year, I obtained a fellowship from Harvard Medical School which allowed me to travel to Sweden and work with Hans Wigzell. There, I worked on cultures of mouse T cells, learning how to isolate responding T cells, which led directly to my ability to isolate cloned T cell lines. Hans often asked me, in his Swedish-accented English, if I would like it "In Jail." I had to tell him that I was not going to Jail, but to be on the faculty at Yale. Finally, I returned to Yale and set up my own group, entered the peer review system in which I met many of you, either on paper or in person, and learned how the world works.
One of the distressing things about Yale Medical School, as I learned to my amazement, was that they were one of the few medical schools in the country that had decided that they could abandon the study of infectious disease because antibiotics would soon have cleansed the earth’s surface of pathogens. This decision was made before my arrival, and has just now been reversed with the establishment of a new section of microbial pathogenesis under the leadership of Jorge Galan. In the absence of collaborators who were working on mouse or human pathogens, I turned my attention to the analysis of T cell responses to protein antigens, especially the analysis of cloned T cell lines, which we produced in large numbers. At that time, one of my collaborators said that my lab reminded him of a farm in his native Italy because we were always growing things. In any case, I worked productively in this area for some years, and at the same time taught Yale medical students, graduate students, and undergraduates. The medical students at Yale are a unique breed, full of genuine curiosity, and they were always asking naive but provocative questions about health and the immune system. In attempting to answer these questions, I was forced more and more to fall back on the primary function of the immune system, which is to fight infection. I would like to dedicate this talk to the many medical student classes that I have taught over the years for forcing this realization on me.
My personal moment of understanding of the importance of innate immunity happened in a casual conversation with my wife, Kim Bottomly, who is also a distinguished immunologist. Kim has often inspired me to think more deeply and more freely than I thought I was capable of doing. In this case, we were attending a meeting that I had organized in Steamboat Springs in January 1989. There were many issues discussed at this meeting, but one of the central issues was the regulation of the immune response by signals in the environment of the cells themselves. These signals were thought to be mediated by cytokines, and the cytokine network was a hot topic of discussion. But Kim wondered what initiated cytokine secretion in the absence of activated T cells. I glibly answered that it was undoubtedly due to infectious agents. "But how do infectious agents activate naive T cells," Kim asked? To which I blithely answered: "They do so via their effects on the innate immune system."
Once I had this idea in my head, it was impossible to let go of it, and I quickly assembled my thoughts and tried them out on many colleagues. By the time June rolled around, I could tell Adrian Hayday about my ideas in some detail as I drove him to the 1989 Cold Spring Harbor meeting on immune recognition. While at the meeting, I was asked by John Ingliss if I would be willing to write the introductory chapter to the book that is traditionally prepared from the meeting proceedings. I asked if I could write it on anything that interested me and was told yes. Meanwhile, on the last morning of the meeting, I remember Len Herzenberg, who received the American Association of Immunologists’ lifetime achievement award this year, asking me over breakfast if I could sum up the meeting in one sentence. I made an off-the-cuff comment that I thought that we were approaching the asymptote in our understanding of the central processes of adaptive immunity, but we weren’t. Although this turned out to be true, it was for different reasons. What I meant was that we needed to invest more time in work on innate immunity, which at that time was barely mentioned. So that was how I came to prepare the paper entitled: "Approaching the Asymptote: Evolution and Revolution in Immunology" (1). I always say it was the best talk I never gave. The implication of this article can best be summed up by the statement that the immune system does not just discriminate self from non-self, as Jerne, Talmage, Burnet, and many others believed, but rather that it could discriminate infectious non-self from noninfectious self.
Having a powerful idea is one thing: proving it is entirely different, and I would say that we are about one percent of the way to demonstrating that the idea has merit, but that it still represents a major advance in my knowledge, if not that of the audience. But I would like to revisit this hypothesis to explain what we now accept as true, and what is still at issue.
Let me start from the point of view of adaptive or acquired immunity. The clonal selection hypothesis, while modified in detail over the years, has been and remains a robust explanation for most of the phenomena of adaptive immunity. In fact, at the time of the first Cold Spring Harbor Symposium on immunology in 1967, Nils Jerne’s summary of the meeting was entitled: "Waiting for the end." I was tempted by this to call my introductory article at the meeting held 22 years later in 1989: "Still waiting for the end." The clonal selection hypothesis states that each lymphocyte is equipped with many identical copies of an antigen-specific receptor, and when this receptor binds a ligand with sufficient avidity, the lymphocyte is activated to undergo clonal expansion and differentiation to effector cell function. This is true of both T cells and B cells. However, for naive T cells to become activated, an additional requirement for a second or costimulatory signal was later proposed and demonstrated by many groups. In my laboratory, Yang Liu demonstrated that not only did costimulation have to be present to activate naive T cells, but that naive T cells at least needed to see the costimulatory signal on the same cell as the specific antigenic peptide to clonally expand. In this experiment, Yang used anti-CD3 antibody as a surrogate TCR ligand that has to bind to FcR, and a B7.1 gene transfected into the same cells (2). Yang also devised a system for quantitating this signal, and showed that it was induced by a variety of ligands that derived from pathogenic microbes. It is this costimulatory signal that we believe is regulated by the innate immune system via so-called pattern recognition receptors (or PRRs), which recognize pathogen-associated molecular patterns (or PAMPs).
What roles do we envision for innate immunity? We believe that innate immunity, by definition, accounts for host defense in the early phases of an infection. This occurs by processes that act immediately on the infectious agent, such as the alternative pathway of complement activation, NK cells, and the epithelial barriers of the body, as well as later when antibacterial peptides are secreted, cytokines are produced by phagocytes, and NK cells are activated by type I interferons. Second, it plays a key role in the adaptive immune response by inducing costimulatory molecules on cells that take up the pathogen. These costimulatory molecules are absolutely essential to the activation of naive T cells, as shown by Yang Liu and many others. Third, we believe that the production of cytokines by cells of the innate immune system also contributes to the type of T cell activated.
In the fruitfly Drosophila melanogaster there is clearly no
adaptive immune system; Drosophila relies solely on the
mechanisms of innate immunity to protect itself from infection. Little
was known about the mechanisms of host defense in Drosophila
until Jules Hoffman and colleagues in France began studying it,
following on from the pioneering work of Hans G. Boman of the
University of Stockholm. However, developmental mutants had been
isolated by Dr. Christine Nusslein-Volhard, and these turned out to use
many of the same elements as the immune response. When Hoffman’s group
pricked adult flies with various pathogenic microbes, they found that
flies with mutations in the Toll signaling pathway from the gene for
pro-Spaetzle to the gene for cactus could not resist infection with
fungal spores (3). Pricking adult fruit flies with fungal spores leads
to the production of the antifungal peptide called drosomycin, the only
antifungal peptide known in Drosophila. The fungal spores
activate a cascade of proteases that ends up creating the ligand for
Toll, called Spaetzle. The upstream members of the dorsoventral pattern
formation pathway that lead to Spaetzle cleavage were tested and found
not to be essential for the activation of Toll by fungal spores, so
presumably there is an independent mechanism to generate Spaetzle from
pro-Spaetzle in host defense in adult fruit flies. Ligation of Toll by
Spaetzle leads to activation of a series of proteins, some of which,
called tube and pelle, are defined, which eventually leads to
phosphorylation of cactus, degradation of the cactus protein, and
release of a rel protein that is a key promoter-binding protein for the
activation of the gene encoding drosomycin. The mammalian homologues of
cactus and rel are I
B and NFB.
Thus, as we can see from studies in Drosophila, Toll is a
key mediator of innate immunity. At the time that Hoffman’s results
were published, we had already cloned the mammalian homologue of the
Drosophila Toll protein, which we called hToll. We showed,
as I will tell you in a few minutes, that a dominant active form of
hToll induced the synthesis of B7 costimulators and pro-inflammatory
cytokines. We have also shown that Toll activates via the NFB
pathway using homologous components to tube and pelle. Furthermore, we
have data that Toll also activates the AP-1 promotor binding proteins
Fos and Jun. Finally, although the Toll ligand in the fruit fly is
known to be Spaetzle, such proteins have not been identified in
mammalian systems. However, we have recently identified candidate
activators of these pathways in both Drosophila and humans,
which have scavenger receptor domains in their N termini, and
pro-serine protease activity in their C-terminal domains.
To return to more conventional aspects of host defense for a minute,
Table I lists several characteristics of
innate immunity and contrasts them with the adaptive immune system. The
main point of this table is to contrast these two systems of host
defense. The innate immune system is ancient, being found in all
multicellular organisms down to Caenorhabditis elegans,
whereas the adaptive immune system exists only in vertebrates. The
receptors of the two systems are their biggest point of difference.
Receptors for innate immunity have evolved over an evolutionary time
scale, whereas receptors for adaptive immunity undergo gene
rearrangement and thus evolve in individual members of a vertebrate
species such as humans or the mouse. For this reason, clonal selection
of lymphocytes is a specialization unique to vertebrates. This
specialization allows us to remember those pathogens that we have
resisted before, or to vaccinate against such pathogens, so that the
initial infection that used to be required to establish protective
immunity can now be done painlessly and with few symptoms. However,
adaptive immunity can also create problems through defects in
self–non-self discrimination. As all vertebrates have some form of
adaptive immunity, the existence of immunologic memory was obviously
very important in vertebrate evolution.
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(4).
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I will now outline the published work on hToll (5) before turning to three related issues: an adaptor protein that was initially cloned as an inducer of monocyte differentiation, a TRAF homologue in Drosophila that Ruslan has recently identified, and a novel serine/threonine innate immunity kinase. Finally, I will mention briefly how we believe the upstream elements detect infection and activate a cascade of proteases that transmit the signal to Toll and hence to the nucleus.
The first issue we faced in the cloning of homologues of the dToll sequence was whether the homology was along the full length of the protein or, as in the IL-1R, only extended to the cytoplasmic domain. The sequence of hToll shows that the two genes from the fly and the human are homologous over their entire length. Thus, hToll is truly a mammalian homologue of this protein in the fly.
The ectodomain is made up of leucine-rich repeats; only one structure of a LRR domain has been solved, that of the pancreatic RNase inhibitor. This structure was determined by Johann Deisenhofer of Dallas. We don’t yet know what the hToll ectodomain will look like, but we are collaborating with Dr. Deisenhofer and we hope eventually to know its structure.
The cytoplasmic domain of both dToll and hToll are homologous to the
cytoplasmic domain of the human IL-1R, forming a so-called TIR domain
(Toll-IL-1R), which was originally thought to mediate signaling from
these receptors. However, it is now known to interact via an adaptor
protein that we have shown binds to Toll as well as to the IL-1R, as
shown earlier by Dixit’s group at Michigan and by Cao’s team at
Tularik. However, the two TIR domains signal differentially, in that
the IL-1R signals via NFB, whereas hToll signals both via NFB and
AP-1. A fourth protein that is shown in Figure 2 has leucine-rich
repeats joined to a TIR domain and is involved in host defense in
plants. This suggests a common set of building blocks in host defense
in plants, insects, and mammals, and we have also identified genes
encoding similar proteins in the worm C. elegans. The
cytoplasmic domain of hToll is more homologous to other Toll proteins
than any of the IL-1R cytoplasmic domains. The TIR domain of N protein,
as might be expected for genes that are separated by a billion years of
evolution, is distinct from both the IL-1R family and the Toll family
of cytoplasmic TIR domains.
Finally, we analyzed the cystein-rich membrane proximal domain and
found close homology with dToll in this region of hToll. It was
determined previously by Kathryn Anderson that mutation in any one of
the conserved cysteins would activate Toll signaling in
Drosophila. We took advantage of this to prepare dominantly
active hToll mutant proteins by making chimeric proteins between the
ectodomain of mouse CD4, against which many antibodies are available,
and the transmembrane and cytoplasmic domains of hToll, to produce a
construct in which three of the four conserved cysteins were replaced.
This construct was transfected into Jurkat cells. These transfectants
were tested for the induction of NFB activity using an NFB-driven
luciferase reporter gene. The signal given by the hToll dominantly
active protein is almost as strong as the positive control of PHA plus
PMA in the activation of NFB in Jurkat. We also transfected the
human monocytic cell line THP-1. We detected the transfectants by FACS
analysis with anti-mouse CD4. The existence of positive and active
transfectants allowed us to examine the production of costimulators and
pro-inflammatory cytokines by THP-1 cells transfected with the
dominantly active form of hToll, and we found that IL-1, IL-8, and, in
the presence of interferon-
, IL-6 are produced, as is IL-12. Most
importantly to our working hypothesis, we found clear induction of
B7.1, which was present at undetectable levels in parental,
nontransfected THP-1 cells, and B7.2, which was present at a low level
in THP-1 cells and was strongly induced by transfection with a
dominantly active form of hToll. Thus, many of the features predicted
for pattern recognition receptors were met by hToll. However, two
things are clear: First, the mechanism by which hToll recognizes
pathogens remains to be worked out, and second, the protease product
that forms the ligand for Toll in Drosophila is not yet
defined in mammalian systems.
We next investigated the proximal part of the hToll signaling pathway,
and determined that it involved an adapter protein called MyD88.
Overexpression of MyD88 signaled expression of an NFB reporter gene
construct that was dose-dependent. The induction of NFB by hToll was
dependent upon the intact MyD88 construct, as neither the N-terminal
death domain nor the C-terminal TIR domain could activate NFB.
Because the construct consisting only of the C-terminal domain of
MyD88, called MyDC, did not activate NFB even when it was
overexpressed, we asked whether this construct could act as a dominant
negative inhibitor of NFB activation by hToll. In this experiment,
the MyDC construct expressing only the TIR domain inhibited activation
of NFB by the dominantly active form of hToll, showing that MyD88
was downstream of hToll and upstream of NFB. Our next experiments
were designed to position IRAK and TRAF6 in the pathway, and these
showed that IRAK dominant negative mutants as well as a dominant
negative mutant of TRAF6 inhibited signals from hToll and from MyD88,
positioning IRAK downstream from MyD88 and TRAF6 downstream of IRAK. A
dominant negative mutant of TRAF2, which signals activation of NFB
by TNF-
, does not interfere with NFB activation by hToll or IL-1.
Finally, we showed that both hToll and MyD88 could induce the
transcription factor called AP-1, which is a heterodimer of Fos and
Jun. Surprisingly, in the same experiment, we failed to observe AP-1
signals in the presence of IL-1, suggesting that there is a
branch-point in this pathway downstream of TRAF6. Thus, we have defined
another member of the hToll signaling pathway as the adapter protein
MyD88.
Recently we have cloned another member of this ancient pathway of host defense in Drosophila, which is a homologue of the mammalian TRAF proteins and appears to function in the dToll signaling pathway in a way analogous to the function of TRAF6 in the mammalian host defense system. From the sequence of this protein it is not clear which mammalian TRAF protein it most closely resembles, so we call it simply dTRAF. dTRAF appears to regulate the expression of a variety of anti-microbial peptides, as shown by RT-PCR and by activation of reporter constructs driven by the promoter regions of several of these antimicrobial peptides. The role of dTRAF in host defense in Drosophila thus appears to be analogous to the role of TRAF6 in mammalian cells. Thus, we have identified a TRAF protein in Drosophila, which appears to have similar activities to mammalian TRAF6.
We have also looked for other molecules with the structural signature
of serine/threonine innate immunity kinases, similar to IRAK, pelle,
and pto (see Fig. 2). We have recently identified one such gene which
we have tentatively called CCK. When this kinase is overexpressed, it
activates the Toll signaling cascade, as shown by activating the same
NFB reporter construct. Moreover, dominant negative forms of TRAF6
inhibit NFB activation by this kinase. This positions this CCK on
the same level as all of the other serine/threonine innate immunity
kinases (see Fig. 2).
Finally, we feel that the Toll proteins are signaling molecules whose ligand is generated by a protease cascade triggered by one of many different pattern recognition receptors. We have recently identified two proteins with a similar architecture, one in Drosophila and one in mammals. These proteins have three scavenger repeats in their N-terminal halves and a pro-serine protease domain in their C-terminal halves. We suspect that proteins such as this will bind to PAMPs to initiate the cleavage of proteins that eventually generate Spaetzle in Drosophila and the Spaetzle-like ligand that we suspect will soon be defined in mammals.
In conclusion, I would like to leave you with four statements about innate immunity. It is clear to me that the innate immune system should be taken as seriously as the adaptive immune system, because it has several important functions in host defense. First, innate immunity is an essential component of host defenses against infection, and it is always on the scene when needed. Second, innate immunity can control infection until the adaptive immune response can take over. Third, innate immunity discriminates between self and non-self perfectly, as all of its components are hard-wired in the genome. Finally, innate immunity is critical for the induction and direction of the adaptive immune response, as originally discussed in my article for the 1989 Cold Spring Harbor meeting, and updated by Doug Fearon and Richard Locksley in a recent article published in Science (6). As the area of innate immunity is largely unexplored, we can look forward to many novel findings in this area in the immediate future.
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Footnotes |
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2 This work was supported in part by a grant from the Human Frontiers of Science Program; by National Institutes of Health; Grant AI-26810, National Institute of Allergy and Infectious Diseases; and by the Howard Hughes Medical Institute.
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T. Kawai, R. Eisen-Lev, M. Seki, J. W. Eastcott, M. E. Wilson, and M. A. Taubman Requirement of B7 Costimulation for Th1-Mediated Inflammatory Bone Resorption in Experimental Periodontal Disease J. Immunol., February 15, 2000; 164(4): 2102 - 2109. [Abstract] [Full Text] [PDF]
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