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Keywords:

  • Adjuvants;
  • Antigen presentation;
  • Dendritic cells;
  • Immunogenicity;
  • Langerhans cells

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

The impetus for the discovery of dendritic cells in 1972 was to understand immunogenicity, the capacity of an antigenic substance to provoke immunity. During experiments to characterize "accessory" cells that enhanced immunity, we spotted unusual stellate cells in mouse spleen. They had a distinct capacity to form and retract processes or dendrites and were named dendritic cells (DC). DC proved to be different from other cell types and to be peculiarly immunogenic when loaded with antigens. When Langerhans cells were studied, immunogenicity was found to involve two steps: antigen presentation by immature DC and maturation to elicit immunity. Antigen-bearing DC were also immunogenic in vivo and were therefore termed "nature's adjuvants". Several labs then learned to generate large numbers of DC from progenitors, which accelerated DC research. Tolerogenicity via DC, including the control of foxp3+ suppressor T cells, was recently discovered. Two areas of current research that I find intriguing are to identify mechanisms for antigen uptake and processing, and for the control of different types of immunity and tolerance. These subjects should be studied in vivo with clinically relevant antigens, so that the activities of DC can be better integrated into the prevention and treatment of disease in patients.

Abbreviation:
LC:

Langerhans cells

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

The driving force for the first sighting of dendritic cells (DC) in 1972 was to understand immunogenicity, which a pioneer in this field, Michael Sela, defined as "the capacity of an antigen to provoke an immune response" 1. Sir MacFarlane Burnet had provided immunology with the critical clonal selection theory of immunity. It proposed that the immune system was comprised of a vast repertoire of clones, each expressing a distinct receptor to recognize an antigen. However, what stood between the administration of antigen and successful clonal selection, or immunogenicity? This remains a central theme in biology and medicine.

Sela, together with John Humphrey and Hugh McDevitt, began to unravel one critical component of immunogenicity. They had observed marked differences between strains of rabbits and mice in antibody responses to synthetic proteins that Sela had prepared 2. McDevitt then proved that immunogenicity required "Immune Response" genes, which mapped to the MHC, now MHC II 3. MHC-restricted presentation of viral antigens was then discovered by Peter Doherty and Rolf Zinkernagel for MHC I. Alain Townsend, Emil Unanue, Pam Bjorkman, Jack Strominger, and Don Wiley demonstrated that this was due to the ability of MHC I and II products to present peptide fragments from antigens, where the peptide-MHC complexes acted as ligands for the T cell antigen receptor. This seminal body of research identified a key component to immunogenicity, which is that proteins need to be processed and presented on MHC products before they can be recognized by T cells.

Discovering dendritic cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

The antigen processing and presentation arm of immunogenicity was not known when DC were discovered in 1972. Instead, there was evidence that antigens were retained as intact proteins on the surfaces of what were called dendritic macrophages in the germinal centers of lymphoid organs 4, 5 (now termed "follicular dendritic cells") or on macrophages from the peritoneal cavity 6. Together with my mentor Zanvil Cohn, a leader in macrophage cell physiology, we fed macrophages horseradish peroxidase, but we were unable to identify persistent intact antigen on the cell surface 7, 8. Instead, the macrophage internalized HRP continually over long periods, and the bulk of the antigen was catabolized down to the level of amino acids. During these studies, we discovered that endocytosis required the rapid recycling of the internalized vesicle membrane 9, 10. As revealed by Brown and Goldstein 11, the recycling of endocytic receptors allows all cells to continually capture adsorbed proteins for efficient degradation in lysosomes.

In the absence of persistent protein on the cell surface, we turned to lymphoid organs and in particular to mouse spleen, because these are the sites for the generation of immunity. We had no hypothesis about what we would find. Robert Mishell and Richard Dutton 12 had figured out how to generate primary antibody responses to sheep red blood cells using spleen cell suspensions. However, clonal selection could not take place, i.e. antibody responses would not develop, unless one added radioresistant accessory cells, along with the antigen, to mixtures of B and T lymphocytes. When I examined the populations of accessory cells, there was a Eureka moment. The accessory populations included unusual cells that did not look like any other white blood cell that had been seen before. The cells had a prominent stellate shape, and more impressively in the living state, continually extended and retracted their processes or dendrites. No other leukocyte moved in this manner. The cells lacked other key features of macrophages and lymphocytes 13, 14. The novel cells were termed dendritic cells for "treelike," from the Greek "dendron" or "dendreon" for tree (Fig. 1).

thumbnail image

Figure 1. Phase contrast micrographs of dendritic cells. Left. A mouse spleen DC cultivated 24h in a plasma clot. Right. Four successive views of a living human blood DC cultivated in liquid medium to show the rapidly changing cell shape. The figure is reproduced with permission from [14].

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A helpful choice, which took years to materialize, was to first enrich DC as a distinct cell type prior to studying their functional properties and comparing these to other cell types 15. Others were using the expression of McDevitt's immune response gene-associated (Ia) antigens as a marker for functional accessory cells, but Ia antigens did not mark a specific cell type and later proved to be the MHC II products needed to present peptides. Instead, we and others used the distinct morphology of DC to identify, enrich and begin to characterize these cells in several tissues and species, and to prepare the first monoclonals, i.e. 33D1, now anti-DCIR2 1618 and N418 anti-CD11c 19, 20. The distinct morphology that we used to guide our preparation of DC has now been observed in living lymph nodes, where each DC continually probes its environment by extending and retracting processes 21. The enriched DC also proved to have some surprising functions.

Dendritic cells as immunogens for transplantation reactions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

The immunogenic role of DC was initially noted in the setting of transplantation, in a tissue culture model for graft rejection called the mixed leukocyte reaction (MLR) 22. I like to recall that the MLR was discovered in the two places I call home, in Montreal by Barbara Bain et al. 23 and in New York by Fritz Bach and Kurt Hirschhorn, in 1964.24 The MLR detects genetic incompatibility in the MHC between prospective donors and recipients of organ transplants. Incompatibility, which is frequent because of the striking polymorphism of the MHC, reliably leads to a T cell response that is typical of graft rejection. When Maggi Pack and I added graded doses of "donor" DC to stimulate rejection by "recipient" T cells, another exciting observation was made. The DC were at least 100 times more potent than total spleen cells, which contained about 1% DC 22. Don Mason and Wesley Van Voohris 25, 26 made similar observations with DC from rat afferent lymph and human blood. We also noted that MHC II+ B cells and macrophages surprisingly were poorly immunogenic, although we later found that they were efficient in recalling a secondary MLR from T cells that had already been activated by DC 27. In addition, we could directly observe the clustering of DC with the T cells that were generating immunity, thereby directly defining a DC microenvironment for generating immunity 28, 29. The existence of DC as a powerful stimulator of the MLR had not been appreciated during the 15 years in which this test had been in active use. These observations led us to suggest in 1978 that "DC will prove to be a critical accessory cell required in the generation of many immune responses" 22.

When the 33D1 mAb was developed by Michel Nussenzweig in 1982 16, selective removal of the tiny fraction of DC became feasible. The absence of DC ablated much of the MLR stimulating activity from the total suspension of spleen cells 17. We could not interpret the residual activity in 33D1-depleted spleen cells until 7 years later, when we noted that there were two subsets of DC in mouse spleen, a major 33D1+ and a minor NLDC-145+ (now DEC-205/CD205+) subset 30. These subsets were denoted as CD8 and CD8+ by Ken Shortman 31. Because we could selectively deplete most of the MLR stimulating function by removal of DC from a fresh spleen cell suspension, we concluded that "antigens, to be immunogens, require accessory cells" 17.

Robert Lechler and Richard Batchelor did a pivotal transplant experiment in vivo. They first induced tolerance of F1 rat kidneys in a parental strain, and then they injected different types of F1 cells to try to break tolerance or induce kidney rejection. F1 DC in small numbers (104–105 per rat) induced rejection, whereas >106 lymphocytes were inactive 32. We worked with Denise Faustman et al. to treat pancreatic islets with the 33D1 mAb and complement, which selectively eliminated the few DC that could be visualized in each islet. The depleted islets could then be transplanted across an MHC barrier 33. In effect, DC were converting transplantation antigens, i.e. MHC products, into immunogens both in tissue culture and in animals. DC were needed not only for presentation of MHC products, or immune recognition, but as potent accessories for immune responsiveness.

Dendritic cells as antigen-presenting cells for autologous T cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

To analyze the capacity of DC to induce responses from autologous T cells, Nussenzweig used a system described by Gene Shearer, who had discovered that the hapten TNP was presented to CD8+ killer T cells in an MHC-restricted manner. Nussenzweig prepared TNP-coated T cells, which were not themselves immunogenic, and added them to cultures of different antigen-presenting cells and T cells. Only DC could initiate CD8+ T cell immunity to TNP 34. In retrospect, this was likely the first example of the powerful cross-presenting function of DC, in which the cells capture nonreplicating antigens and present these on MHC I. In the first review on DC in 1980, Michel and I 35 concluded "DC must belong to a separate, bone marrow-derived lineage. They exhibit distinct cytological features, surface markers and functional capacities, all of which are stable in tissue culture".

To prove that DC were required to immunize helper T cells, Kayo Inaba examined the antibody response. During her PhD thesis research in Kyoto, she had realized that some cell other than an Fc receptor-rich macrophage was critical for antibody formation in Mishell Dutton cultures 36. We joined forces after a meeting sponsored by the Naito Foundation in Tokyo in 1980. Purified DC proved to be potent accessories for antibody formation, while macrophages were weak. We also depleted fresh spleen cells of the trace DC component with 33D1 mAb and complement. Much of the antibody response in an otherwise unmanipulated spleen suspension was ablated, and could be restored by small numbers of enriched DC 37. We went on to use DC to prime helper T cells to carrier proteins like KLH and HSA 38. Again DC were required to induce (prime, sensitize) helper T cells in the afferent limb of the antibody response, while in the efferent limb, newly differentiated T cells acted on other antigen-presenting cells, here B cells, to provide the help required for antibody formation. Similar results were obtained in other systems involving the killing of targets and the activation of macrophages 39, 40, i.e. DC first activated killer and helper T cells, and then these interacted in the efferent limb with other antigen presenting cells. Thus, immune responses involved afferent and efferent limbs, each requiring antigen presentation and MHC restriction.

Other labs were obtaining evidence for cells distinct from macrophages that had active accessory function, usually with polyclonal mitogens as the T cell stimulus. William Bowers 41, 42 and Don Mason and Gordon MacPherson 25, 43 found active nonadherent accessory cells in thoracic duct lymph of rats, while Brigid Balfour, Hemmo Drexhage and Stella Knight 4446 described similar veiled cells in the afferent lymph of rabbits and guinea pigs. These early observations on distinct cells in different tissues and species were brought together in a review in 1982, where ideas of a DC system were considered 47.

Langerhans cells as immature dendritic cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

We then turned to peripheral tissues to determine if we could identify and characterize DC. Skin was chosen because several other investigators had discovered that Langerhans cells (LC) in the epidermis were leukocytes that expressed MHC class II and could present antigens. Experiments on the skin became feasible with the arrival in our lab of Gerold Schuler, a dermatologist from a leading research group in Tyrol with expertise in LC. He discovered a pivotal feature of immunogenicity, DC maturation. Surprisingly, he found that LC, in spite of their abundant MHC class II products, were poorly immunogenic in the MLR and mitogen assays 48. Instead, the LC needed to be cultured to differentiate and become potent immunogens 48, 49. When the LC were purified, it became evident that granulocyte macrophage stimulating factor (GM-CSF) was essential for LC maturation (Fig. 2) 50. Then specific protein antigens were tested by another Tyrolean, Nikolaus Romani, who made a second striking observation. The freshly isolated LC could present antigen, although only for a short time, while the mature cultured ones did not. In contrast, the mature cultured DC were powerful accessories for immunity to previously captured antigens. Thus maturation involved two steps that lead to T cell recognition (antigen processing and peptide-MHC formation) and responsiveness (often termed costimulation), and these two distinct aspects of immunogenicity could be separated in time.

thumbnail image

Figure 2. Clusters of dendritic cells (dark stellate profiles) and T lymphocytes, a microenvironment for gererating immunity. Courtesy of N Romani. The figure is reproduced with permission from 99.

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Ira Mellman, Antonio Lanzavecchia and their colleagues later showed what was going on at the level of antigen presentation in maturing DC (reviewed in 51). Immature DC were endocytic and much of the cell's MHC II products were inside the cell 52, 53. Maturation eventually led to a dampening of endocytosis, accounting for the weak endocytic activity that had been observed years before. Maturation also activated the processing machinery in late endosomes or lysosomes, and allowed for increased formation of peptide-MHC complexes 54. This was followed by transport of peptide-MHC to the cell surface 55 where degradation was avoided, probably by a newly recognized control in which mature DC turn off ubiquitination of MHC II 56. Maturation, the differentiation of DC in response to environmental stimuli, is a key to immunogenicity and can involve hundreds of changes in response to signals from microbes, immune complexes, cytokines, innate lymphocytes and a variety of endogenous stimuli currently called "danger signals" or "alarmins". Different maturation programs essentially allow DC to control the distinct qualities of the subsequent lymphocyte responses.

Dendritic cells as nature's adjuvants in vivo

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

Along with Josh Metlay, an MD-PhD student, Inaba and I 57 turned to foreign proteins to assess whether DC could serve as "nature's adjuvants" for immunogenicity in vivo. We exposed immature DC to different proteins, allowed the cells to differentiate in culture overnight, and injected the antigen-charged cells into mice. The T cells were immunized and restricted to the MHC products of the injected DC. In other words, without any Freund's or alum adjuvant, DC initiated immunity in vivo.

An important advance was to learn how to generate DC from progenitors, which became possible in several labs in the 1990′s 5862. This made DC much more accessible for research. The newly generated cells proved to be immunogenic in vivo63. Understanding the development of DC, including their various forms or subsets with different markers and functions, remains a major field.

Several scientists then used DC as adjuvants in humans 6467. Controlling DC maturation is likely to be an important component of this approach 68, 69 and requires studies in patients to analyze properly. "Active" immunotherapy with DC, which aims to stimulate patients to develop their own immunity to cancer, has a major limitation currently. It is that the injected DC migrate and persist poorly in the recipient lymphoid tissues, thereby failing to reproduce a critical homing function of DC for immunogenicity. The use of ex vivo derived DC in immunotherapy is currently an understudied but valuable approach to probe the human immune response, particularly if one could overcome this major migration obstacle and also garner support for a more vigorous and better coordinated research effort.

Tolerogenicity, another side of immunogenicity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

The function of DC in tolerance emerged when antigens were first selectively targeted to DC in situ by Nussenzweig and by Inaba. To do so, Nussenzweig engineered antigens into the anti-DEC-205 mAb 70, 71, which recognized an endocytic receptor 72 expressed by many DC in the T cell areas of lymphoid tissues 73. Additionally, Inaba studied antigens within dying cells 74. These experiments allowed one to probe DC function directly in situ, without having to isolate the cells. Following both forms of antigen targeting to DC in vivo in the steady state, i.e. using the hybrid antibodies or dying cells, antigen presentation took place but the corresponding T cells were deleted. When a stimulus for DC maturation was coadministered with the targeted antigen, clonal expansion was accompanied by differentiation to high levels of IFN-γ production 70, 71, 75. As a result, we proposed that DC could control both immunity and tolerance.

The role of DC as tolerogens is thought to be essential to balance their role as immunogens, because when DC capture dying infected cells and mature, they simultaneously present microbial antigens as well as harmless self and environmental antigens 76, 77. Through tolerance, DC orchestrate the lymphocyte repertoire to dampen the danger of subsequent self reactivity. Then, when infection strikes, maturing DC focus immunity to the microbe.

A newly discovered facet of tolerance by DC is that they induce suppressor T cells, which are often termed "T regs" by the research community. DC can differentiate T regs in the thymus 78 and in the periphery 79, and expand them once the T regs have formed 8082. Antigen-specific T regs are much more effective than polyclonal populations in suppressing immunity in vivo79, 8183. For many years, the major approach to the induction of peripheral tolerance has been to inject very large doses of antigen. Nowadays, the efficient and more physiologic induction of antigen-specific tolerance is becoming feasible by directing antigens to DC and controlling their maturation state.

New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

Antigen handling, i.e. capture, processing and presentation, is a key step in the antigen-specific control of immunity and tolerance, but for many years, antigen capture was not manipulated directly. Instead, sizeable doses of antigen were administered to reveal the effective antigen processing capacities of DC in vivo, e.g. 84. It is now evident that DC express many potential receptors for antigen uptake, including the first two markers recognized by anti-DC antibodies, 33D1 to DCIR2 18, and NLDC-145 to DEC-205 72, 85. These receptors are expressed by distinct subsets of DC in the mouse. When antigen is incorporated into these antibodies and targeted to the corresponding receptors in mice 18, 70, 8690, presentation is increased more than 100-fold. Reciprocally, if one simply injects nontargeted antigen, one is under-exploiting the capacity of DC to control immunity and tolerance by 100-fold. DC also take up dying cells in vivo, including tumor cells 74, 9193, and this likewise greatly increases the efficiency of antigen presentation, although the receptors for uptake remain unidentified. In both instances, uptake of DEC-205 ligands and dying cells, DC are able to cross-present antigens on MHC class I products to CD8+ T cells. A fascinating recent example has been provided in the case of HIV gag protein delivered within antibodies to human DEC-205. For the first time, it has been shown that cross-presentation is able to extract defined peptides for presentation to CD8+ T cells across a spectrum of MHC haplotypes 94. I am excited about this new field of receptor-based antigen targeting to DC, which allows one to analyze DC function -- both antigen processing and subsequent interactions with lymphocytes -- directly in vivo, without the need for cell isolation.

Another critical component of immunogenicity, DC maturation, also needs to be pursued to identify the molecular mechanisms that maturing DC utilize to differentiate T cells along one pathway or another. Maturation, the stimulus-dependent differentiation of DC that leads to different types of immunity and tolerance, allows DC to tailor the immune response so that it is appropriate to the pathogen or other stimulus. Maturation entails the expression of numerous families of membrane-associated costimulatory molecules, cytokines, chemokines and other active metabolites. It has become clear that a traditional model, i.e. signal one (peptide-MHC) and signal two (B7 costimulators), is insufficient to explain immunogenicity, because DC are competent in both and can still require additional functions, e.g. through CD40 signals 75. Recently, it was found that the up-regulation of CD70 was essential for one subset of DEC-205+ DC to induce the Th1 pathway of CD4+ T cell differentiation 90. The function of DC subsets is not emphasized here, but clearly, subsets differ in their expression of uptake receptors, processing capacities, and responses to maturation stimuli. By understanding and controlling antigen handling and maturation of DC and their subsets in vivo, it should be possible to better control antigen-specific immune resistance and silencing.

Dendritic cells as a pivotal force in medicine

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

Immunology is pivotal to major problems in medicine, which are also increasing in prevalence. Many clinically relevant antigens are known and/or being identified, but it is still necessary to uncover the required pathways for immunogenicity and tolerogenicity, i.e. to identify antigen-specific therapies that can either enhance (as in infection and cancer) or dampen (as in autoimmunity, allergy, and transplantation) the immune response. The knowledge derived from DC biology about innate and adaptive immune responses, and about their roles in medicine, helps one to think more concretely about the specific driving forces for disease, both pathogenesis and the design of preventions and treatments, e.g. in HIV-1 infection 88, 95, 96.

Regrettably, research on patients remains an underrepresented field, one that suffers from many obstacles 97. This lack of activity occurs despite strong evidence that antibody-based, immune therapies are the most successful and prominent new therapy for cancer and other diseases, and that cell-mediated immunity also has significant potential to provide nontoxic and highly specific treatments. We need to build a new research enterprise, without damaging the existing one, to breed investigators who study the immunology of disease in humans and to provide them with a supportive culture and research funds.

Dendritic cells as part of the tapestry of immunology and medicine

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discovering dendritic cells
  5. Dendritic cells as immunogens for transplantation reactions
  6. Dendritic cells as antigen-presenting cells for autologous T cells
  7. Langerhans cells as immature dendritic cells
  8. Dendritic cells as nature's adjuvants in vivo
  9. Tolerogenicity, another side of immunogenicity
  10. New developments in antigen handling and maturation of dendritic cells, two critical aspects of immunogenicity
  11. Dendritic cells as a pivotal force in medicine
  12. Dendritic cells as part of the tapestry of immunology and medicine

Many threads of research by scientists from many countries contributed to the discovery of the DC system 98. This personal article explains some of the experiments that we did, why we did them and our interpretations of the findings. However, our discipline is like a tapestry, because immunology uses different sources, colors and weaves of materials to create an array of beautiful and valuable products. This was certainly the case for all the events related in this summary. At each point, we depended on reagents and discoveries from other distinct areas of research. The rich tapestry of immunology and biology has allowed the theme of immunogenicity to expand its impact and to identify new mechanisms. I am grateful to the National Institutes of Health and to several foundations for research support and to the Rockefeller University for support and stimulating traditions in cell biology, patient-based research, and immunology.

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    WILEY-VCH

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