Stem Cells, Vol. 14, No. 3, 292-299,
May 1996
© 1996 AlphaMed Press
Granulocyte-Macrophage Colony-Stimulating Factor Overrides the Immunosuppressive Function of Corticosteroids on Rat Pulmonary Dendritic Cells
T.K. Lim,
G-H. Chen,
R.A. McDonald,
G.B. Toews
Pulmonary and Critical Care Division, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
Key Words. Pulmonary dendritic cells • Antigen presentation • Co-stimulation • Dexamethasone • GM-CSF
Dr. T.K. Lim, Division of Respiratory Medicine, Department of Medicine, National University Hospital, National University of Singapore, Lower Kent Ridge Road, Singapore 0511.
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Abstract
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Pulmonary dendritic cells (DC) are present in extremely small numbers, but they are the most potent antigen-presenting cells in the lungs. Pure populations of DC can be isolated from the lung following collagen digestion, Percoll gradient centrifugation, removal of phagocytic cells and flow cytometric sorting for cells which exhibit high levels of surface major histocompatibility complex (MHC) class II molecules. Exogenous GM-CSF enhances this immunostimulatory capacity of the pulmonary DC. Soluble factors produced by type II airway epithelial cells and interstitial macrophages also enhance the immunostimulating capacity of pulmonary DC while alveolar macrophages suppress it. Thus, the function of DC may be regulated by locally produced cytokines. Corticosteroids are widely used as immunosuppressive agents in pharmacotherapy. While these agents are known to inhibit T cell proliferation and macrophage activation, their effects on DC are not known. We found that dexamethasone (Dex) pretreatment resulted in about a 50% reduction in the immunostimulatory capacity of rat pulmonary DC. This was associated with downregulation of MHC class II (Ia) expression. Dex-induced suppression of DC function could be restored with GM-CSF. We conclude that corticosteroids downregulate antigen-presenting capacity by direct suppression of pulmonary DC. This immunosuppressive effect of corticosteroids on DC may, however, be abrogated by exogenous GM-CSF. Corticosteroids and GM-CSF are therapeutic agents with potent direct immunomodulating effects on DC.
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Introduction
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The respiratory epithelium has a large surface area for gas exchange function and is in continuous contact with the environment during respiration. It is a portal of entry for microbials and aero-allergens which are important etiologic agents for lung diseases. The lung displays a wide array of immunocompetent cells to meet this challenge [1,2]. A key initiating event in adaptive immune response is the presentation of peptide antigens in the context of major histocompatibility complex (MHC) class II molecules on antigen-presenting cells to activate clonotypic T cell receptors on helper T lymphocytes. This process generates both effector and memory lymphocytes.
Pulmonary dendritic cells (DC) are an extremely small population of cells which constitutively express MHC molecules on their surface and are the most effective antigen-presenting cells in the lung [3–6]. DC may, therefore, play important roles in host defense and immune-mediated inflammatory lung diseases. DC are characterized by their dendriform morphology, intensity of MHC class II expression, the lack of expression of markers characteristic of mature tissue macrophages and potent antigen-presenting capacity [7–9]. Pure populations of functionally mature DC with potent antigen-presenting capacity may be isolated from the lung interstitium by collagenase digestion, removal of phagocytic macrophages and flow cytometric sorting for cells expressing high levels of MHC II [10, 11]. These freshly-isolated DC may then be used for in vitro studies of factors which regulate the process of antigen presentation to immunologically naive lymphocytes. These regulating factors include interaction with neighboring cells in the lungs such as alveolar macrophages and epithelial cells and exogenous cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1) and tumor necrosis factor (TNF) [11–15].
GM-CSF is a hemopoietic growth factor which has been used as an adjunct to enhance bone marrow recovery during ablative treatment in bone marrow transplantation and cytotoxic chemotherapy [16–18]. The primary therapeutic effect of GM-CSF is to reduce the severity and duration of myelosuppression. The ability of GM-CSF to enhance host defense by acting on mature phagocytic and antigen-presenting cells has not found broad application in clinical medicine [19,20].
Corticosteroids are widely used as immunosuppressive agents in pharmacotherapy [21]. These agents have pleiotropic effects on many cell types [22]. While corticosteroids have broad anti-inflammatory and immunosuppressive activities, the specific mechanisms by which they suppress inflammation in the lung are incompletely defined. Corticosteroids are known to inhibit the access of leukocytes to inflammatory sites, T cell proliferation, macrophage activation and to modulate the production of a wide range of cytokines in surface lining cells [21,22]. The effects of corticosteroids on pulmonary DC and interaction with stimulatory cytokines such as GM-CSF remain poorly understood.
Since both corticosteroids and GM-CSF are widely used therapeutic agents, an understanding of their interactive effects on a key immunostimulatory cell such as the DC may have important clinical implications. In this article, we will review recent developments in understanding the effects of corticosteroids and GM-CSF in regulating DC phenotype and function.
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Pulmonary DC
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Pulmonary DC constitute a network layer in close association with epithelial cells which line the surface of airways and alveoli [23–29]. They are, therefore, strategically positioned for pulmonary immune surveillance. During the first weeks of postnatal life, rats accumulate DC in the respiratory epithelium with upregulation of Ia (MHC class II molecule) intensity and formation of dendriform processes [30]. Nelson et al. showed recently that the number of intra-epithelial DC and intensity of their Ia expression during developmental life is directly related to irritant dust exposure and may be further increased by an exogenous cytokine—interferon-
(IFN-) [30]. DC are also rapidly recruited to the lungs in adult rats during acute bacterial infections, following inhalation of allergens and by the administration of either endotoxin or IFN- [31,32]. DC have been termed "nature's adjuvant" and are professional accessory cells which possess the greatest capacity (when compared to B cells and macrophage-monocytes) to present peptide antigens and induce proliferation in immunologically naive T cells [33]. We have shown that freshly isolated rat pulmonary DC have 150-200x greater capacity to induce proliferation in naive T cells than either alveolar or interstitial macrophages in mixed lymphocyte reactions where the stimulator cells were isolated from Brown Norway rats (DC, alveolar and interstitial macrophages) and the responding naive T cells from Fischer rats (Fig. 1
). This is comparable to the enhanced capacity of murine DC to present peptide antigen to naive CD4+ T cells from MHC class II (I+E+) transgenic mice. The murine DC induce T cell proliferation with 1000x greater efficiency than B cells and 100x greater efficiency than macrophages [34].
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Figure 1. This figure compares the relative antigen presenting capacities of pulmonary alveolar macrophages (AM), interstitial macrophages (IM), low-density nonphagocytic cells (LDNC) and dendritic cells (DC) from Brown Norway rats isolated as described by Armstrong et al. [11]. 1,000 stimulator cells (AM, IM, LDNC and DC isolated from Brown Norway rats) and 100,000 responding naive T cells (isolated from Fischer rats) were assayed in mixed lymphocyte reactions and thymidine incorporation measured on the fifth day.
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The ability of any putative antigen-presenting cell to induce naive T cells to proliferate and secrete cytokines in response to peptide antigens is dependent upon its ability to 1) capture antigenic peptides, 2) present them on MHC class II molecules to the complimentary T cell receptor complex and 3) deliver a second signal to the T cell simultaneous with the antigen-specific signal via co-stimulatory ligand: receptor pairings such as B7(BB1):CTLA-4 and B7-2:CD28 [35, 36]. DC are antigen-presenting cells par excellence because 1) they possess high capacity micropinocytic and mannose-receptor mediated mechanisms for efficient antigenic capture, 2) they constitutively express high levels of MHC class II molecules and 3) they constitutively express co-stimulatory signals [37–44].
We have shown that the antigen-presenting capacity of pulmonary DC is enhanced in cocultures with type II airway epithelial cells and interstitial macrophages while it is suppressed by alveolar macrophages (11, 12, 45, 46). These cell-cell interactive effects persist even when the cells were separated by a permeable filter, confirming the role of soluble factors which regulate DC activity. The different functional properties of DC are thus tightly controlled by cytokines from neighboring epithelial, stromal and inflammatory cells. Cytokines which have important effects on DC phenotype and function include TNF, IL-1, IFN- and, in particular, GM-CSF.
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Effects of GM-CSF on DC
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GM-CSF has multiple effects on DC and is a key cytokine in the development and maturation of the dendritic cell system [12, 47–51]. GM-CSF generates all three lineages of myeloid cells (granulocytes, macrophages and DC) from common pluripotent bone marrow precursors during one- to two-week cultures in vitro [50, 51]. Single cell cultures of CD34+ progenitors from human bone marrow have yielded colonies containing both macrophages and dendritic cells under the influence of GM-CSF and TNF [52]. Romani et al. have shown that large numbers of DC can be generated from peripheral blood by using GM-CSF to promote proliferation and IL-4 to suppress monocyte development [53]. DC represent a differentiating pathway distinct from lymphocytes and monocytes, even though all three cell types arise from common precursors [54]. The ability to generate large numbers of DC from adult peripheral blood will greatly accelerate understanding of this otherwise trace cell type and provide an opportunity for clinical studies.
GM-CSF also enhances the viability and regulates the differentiation of freshly isolated DC into potent immunostimulatory cells by the induction of marked phenotypic and functional changes. Freshly-isolated DC "mature" in short-term (24-36 h) culture, under the influence of GM-CSF, from cells with active protein antigen-processing capacity and weak T cell stimulation activity into potent immunostimulatory cells with less avid antigen processing but marked capacity to induce proliferation and cytokine secretion in naive T cells [47–49]. Optimal stimulation of naive T cells requires antigen presentation on the peptide cleft of MHC class II molecules in conjunction with the engagement of a series of costimulating receptor:ligand molecules recently identified as B7-1(BB1):CTLA-4 and B7-2:CD28. Only GM-CSF upregulates both B7-1 and B7-2 costimulating counter receptors and enhances the stimulatory function of DC in the primary mixed lymphocyte reaction, while IFN- only induces B7-2 expression and does not enhance the immunostimulatory capacity of DC [55]. Other cytokines such as TNF-
and IL-1 do not affect B7-1 and B7-2 expression.
The effects of GM-CSF on DC cytogenesis, viability and differentiation are immunostimulatory mechanisms which may prove clinically useful in maximizing host defense.
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Effects of Glucocorticoids on DC
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Inhalation of a corticosteroid—fluticasone—reduces the number of Ia bright cells (putative DC) in the lungs of immature rats. The mechanism by which topically applied corticosteroids reduces the number of DC is unknown. It may be due to either impaired recruitment of DC to the lungs or failure of DC in situ to mature into cells with bright Ia, or a combination of both mechanisms.
We have observed that Dex treatment of freshly isolated DC enriched, low-density, non-phagocytic lung cells (LDNC) will downregulate Ia expression (Fig. 2). The suppressive effect of corticosteroids on class II MHC expression in pulmonary DC from adult rats is evident following relatively short-term treatment (24 h). This is associated with marked suppression of the antigen-presenting capacity of DC in the mixed lymphocyte reaction (Fig. 3).
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Figure 2. Incubation of LDNC with Dexamethasone (Dex) 10–7M over 20 h reduced the proportion of cells with bright Ia staining (MHC class II on DC).
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Figure 3. Dexamethasone reduced the antigen presenting capacity of DC by about 50%. DC were pretreated with Dex at 37°C for 24 h, washed 3x with fresh media and assayed in mixed lymphocyte reactions as described in Figure 1 .
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Glucocorticoids are the most effective therapy available for many forms of allergic/immune-mediated lung diseases. The cellular effects of glucocorticoids have been attributed to inhibition of many cell types involved in lung inflammation including macrophages, T lymphocytes, eosinophils and airway epithelial cells. Our observations suggest that corticosteroids also have potent direct suppressive effects on pulmonary DC. This is similar to the direct effect of corticosteroids on epidermal Langerhans' cells [56]. We cannot, however, exclude additional effects of Dex on DC recruitment to the lungs. The direct suppression of DC by corticosteroids may be an important mechanism responsible for the therapeutic effect of these agents in disease.
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Interactions between Dexamethasone and GM-CSF
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The direct suppressive effect of Dex on the immunostimulatory capacity of pulmonary DC is abrogated by GM-CSF (Fig. 4). While GM-CSF restores the capacity of DC to drive T cell proliferation to control levels (i.e., comparable with DC which received neither Dex nor GM-CSF treatment), it is clear from Figure 4 however, that Dex pretreatment prevented DC from achieving the maximal stimulatory capacity which could be induced by GM-CSF. At the concentrations which were used and under the conditions of our experimental design, the effects of GM-CSF and Dex on DC appear evenly balanced but in opposite directions.
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Figure 4. Freshly isolated rat pulmonary DC were cultured for 20 h with either Dex (10–6M) or in culture media, washed 3x, then assayed in mixed lymphocyte reactions with either 4 ng/ml of recombinant murine GM-CSF (GM-CSF and Dex + GM-CSF) or in culture media (control and Dex).
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Dex has multiple effects on different cell types in the lungs. The overall result of Dex administration in vivo would be a complex summation of concurrent and variable effects on individual cell types and their interactions with the cytokine milieu. It would thus depend upon the state of the immune system, in particular the cytokine milieu peculiar to the physiologic or disease condition.
Patients with asthma have more intra-epithelial DC in their airways, higher levels of GM-CSF in bronchial alveolar lavage fluid and greater quantities of immunoreactive GM-CSF in airway epithelial cells and T lymphocytes than nonasthmatic subjects [57–59]. These observations suggest that intrapulmonary DC and GM-CSF secreted by local epithelial cells and recruited T cells constitute a positive feedback pro-inflammatory loop which may be responsible for both the initiation and the propagation of allergenic airway inflammatory response in bronchial asthma. Similarly in an autoimmune disease such as rheumatoid arthritis, Lipsky and colleagues have shown increased numbers of DC in the synovium and synovial fluid of patients [60]. The synovial DC are phenotypically and morphologically more differentiated than DC isolated from the peripheral blood, and they also display greater autologous mixed lymphocyte response in vitro [60]. The differentiation of DC in the synovium, as in the epidermal Langerhans' cells and pulmonary intra-epithelial DC, may be mediated by locally produced cytokines such as GM-CSF and TNF-. These data suggest that DC in the synovium developed enhanced activity to stimulate autoreactive T cells after their migration into the joint and played a major role in the ongoing antigen presentation and stimulation of autoreactive T cells in rheumatoid arthritis. Thus, the clinical benefits of corticosteroids in a wide variety of immunologically mediated pulmonary disorders, including autoimmune diseases and allogenic transplant rejection, may be partly due to the result of the inhibitory effect on GM-CSF-promoted antigen presentation by DC. Conversely, this immunomodulatory effect may contribute to the increased risk of infective complications during corticosteroid treatment since antigen presentation is a necessary initiating event in the adaptive immune response to infective pathogens. Administration of exogenous GM-CSF may restore the immunostimulatory capacity of DC during corticosteroid treatment and reduce the risk of infective complications. GM-CSF is, however, a pro-inflammatory cytokine and might promote flare-up of the underlying disease for which corticosteroids were indicated in the first place. It would therefore be unlikely for GM-CSF to be a useful routine adjunct in corticosteroid therapy. It is not known, however, if patients who had acquired opportunistic infections during corticosteroid treatment would benefit from immuno-enhancement with GM-CSF administration provided the underlying inflammatory disease is in remission. This therapeutic potential of GM-CSF needs further definition in vivo.
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Conclusion
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The key position of DC in initiating and regulating the immune response is widely appreciated [7]. There has been rapid progress in our understanding of DC biology in recent years [61, 62], particularly in the areas of DC isolation, cell cultures, generation of DC cell lines, regulatory cytokines and accessory signaling molecules. DC are accessible to pharmacological manipulation using agents such as corticosteroids and GM-CSF. Further studies will determine if fine-tuning of DC function can be exploited for clinical benefit.
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References
|
|---|
-
Green GM, Jakab GJ, Low RB et al. Defense mechanisms of the respiratory membrane. Am Rev Respir Dis 1977;115:479–514.[Medline]
-
Newhouse M, Sanchis J, Bienenstock J. Lung defense mechanisms. N Engl J Med 1976;295:990–9981045–1052.[Medline]
-
Nicod LP, Libscomb MF, Weissler JC et al. Mononuclear cells in human lung parenchyma: characterization of accessory cell not obtained by broncho-alveolar lavage. Am Rev Respir Dis 1987;136:818–823.[Medline]
-
Rochester CL, Goodell EM, Stoltenborg JK et al. Dendritic cells from rat lung are potent accessory cells. Am Rev Respir Dis 1988;138:121–128.[Medline]
-
Holt P, Schon-Hegard MA, Oliver J. MHC class II antigen bearing dendritic cells in pulmonary tissues of the rat. J Exp Med 1988;167:262–274.[Abstract/Free Full Text]
-
Hance AJ. Pulmonary immune cells in health and disease: dendritic cells and Langerhans' cells. Eur Respir J 1993;6:1213–1221.[Abstract]
-
Steinman RM. The dendritic cell system and its role in immunogenicity. Ann Rev Immunol 1991;9:271–296.[Medline]
-
Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation and tissue distribution. J Exp Med 1973;137:1142–1162.[Abstract]
-
Steinman RM, Lustig DS, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. III. Functional properties in vivo. J Exp Med 1974;139:1431–1445.[Abstract]
-
Holt P, Degebrodt A, Venaille C et al. Preparation of interstitial lung cells by enzymatic digestion of tissue slices: preliminary classification by morphology and performance in functional assays. Immunology 1985;54:139–147.[Medline]
-
Armstrong LR, Christensen PJ, Paine R III et al. Regulation of the immunostimulatory activity of rat pulmonary interstitial dendritic cells by cell-cell interactions and cytokines. Am J Respir Cell Mol Biol 1994;11:682–691.[Abstract]
-
Toews GB, Christensen PJ, Armstrong L et al. Pulmonary dendritic cell immunostimulatory activity is regulated by polar secretion of alveolar cell derived granulocyte macrophage colony stimulating factor. J Cell Biochem 1995;S21A:C1–126.
-
Miyazaki H, Osawa T. Accessory functions and mutual cooperation of murine macrophages and dendritic cells. Eur J Immunol 1983;13:984–989.[Medline]
-
Naito K, Inaba K, Hirayama M et al. Macrophage factors which enhance the mixed lymphocyte reaction initiated by dendritic cells. J Immunol 1989;142:1834–1839.[Abstract]
-
Koide S, Inaba K, Steinman R. Interleukin-1 enhances T-dependent immune responses by amplifying the function of dendritic cells. J Exp Med 1987;165:515–524.[Abstract/Free Full Text]
-
Brandt SJ, Peters WP, Atwater SK et al. Effect of recombinant human granulocyte macrophage colony stimulating factor on hematopoietic reconstitution after high dose chemotherapy and autologous bone marrow transplantation. N Engl J Med 1988;318:869–876.[Abstract]
-
Reuf C, Coleman DL. Granulocyte-macrophage colony stimulating factor: pleiotropic cytokine with potential clinical usefulness. Rev Inf Dis 1990;12:41–62.[Medline]
-
Nemunaitis J, Singer JW, Buckner CD et al. Use of recombinant human granulocyte macrophage colony stimulating factor in autologous bone marrow transplantation for lymphoid malignancies. Blood 1988;72:834–836.[Abstract/Free Full Text]
-
Weiser WY, Van Niel A, Clark SC et al. Recombinant human granulocyte macrophage colony stimulating factor activates killing of Leishmania donovani by human monocyte-derived macrophages. J Exp Med 1987;166:1436–1446.[Abstract/Free Full Text]
-
Morrissey PJ, Grabstein KH, Reed SG et al. Granulocyte macrophage colony stimulating factor: a potent activation signal for mature macrophages and monocytes. Int Arch Allergy Appl Immunol 1989;88:40–45.[Medline]
-
Boumpas DT, Chrousos GP, Wilder RL et al. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med 1993,119:1198–1208.[Abstract/Free Full Text]
-
Schleimmer RP. Effects of glucocorticoids on inflammatory cells relevant to their therapeutic applications in asthma. Am Rev Respir Dis 1990;141:S59–69.[Medline]
-
Simecka JW, Davis JK, Cassel GH. Distribution of Ia antigens and T lymphocyte subpopulation in rat lungs. Immunology 1986;57:93–105.[Medline]
-
Gong J, McCarthy K, Telford J et al. Intraepithelial dendritic cells: a distinct subset of pulmonary dendritic cells obtained by microdissection. J Exp Med 1992;175:797–807.[Abstract/Free Full Text]
-
Van Rees EP, Van der Ende Sminia T. Ontogeny of macrophage subpopulations and Ia-positive cells in pulmonary tissue of rat. Cell Tissue Res 1991;263:367–375.[Medline]
-
McCarthy KM, Gong JL, Telford JR et al. Ontogeny of Ia+ accessory cells in fetal and newborn rat lung. Am J Respir Cell Mol Biol 1992;6:349–356.
-
Schon-Hegard MA, Oliver J, McMenamin PG et al. Studies in the density, distribution, and surface phenotype of intra-epithelial class II major histocompatibility complex antigen-bearing dendritic cells in the conducting airways. J Exp Med 1991;173:1345–1356.[Abstract/Free Full Text]
-
Sertl K, Takemura T, Schachler T et al. Dendritic cells with antigen presenting capability reside in airway epithelium, lung parenchyma and visceral pleura. J Exp Med 1986;163:436–451.[Abstract/Free Full Text]
-
Holt PG, Schon-Hegrad MA, Phillips MJ et al. Ia positive dendritic cells form a tightly meshed network within the human airway epithelium. Clin Exp Allergy 1989;19:597–601.[Medline]
-
Nelson DJ, McMenamin C, McWilliam A et al. Development of the airway intraepithelial dendritic cell network in the rat from class II major histocompatibility (Ia) negative precursors: differential regulation of Ia expression at different levels of the respiratory tract. J Exp Med 1994;179:203–212.[Abstract/Free Full Text]
-
McWilliam AS, Nelson DJ, Thomas JA et al. Rapid dendritic cell recruitment is a hallmark of the acute inflammatory response at mucosal surfaces. J Exp Med 1994;179:1331–1336.[Abstract/Free Full Text]
-
Holt P, Nelson DJ, McWilliam AS et al. The role of dendritic cells in regulation of immunoinflammatory responses in the lung and airways. J Cell Biochem 1995;S21A:C1–021.
-
Janeway CA Jr. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today 1992;3:11–16.
-
Levin D, Constant S, Pasqualiu T et al. Role of dendritic cells in the priming of CD4+ T lymphocytes to peptide antigen in vivo. J Immunol 1993;151:624–650.
-
Liu Y, Linsley PS. Co-stimulation of T cell growth. Curr Opin Immunol 1992;4:265–271.[Medline]
-
Robey E, Allison JP. T-cell activation: integration of signal from the antigen receptor and co-stimulatory molecules. Immunol Today 1995;16:306–310.[Medline]
-
Aiba S, Katz SI. The ability of cultured Langerhans' cells to process and present antigen is MHC-dependent. J Immunol 1991;146:2479–2487.[Abstract]
-
Nijman HW, Kleijmeer MJ, Ossevoort MA et al. Antigen capture and MHC II compartmentalization of freshly isolated and cultured human blood dendritic cells. J Exp Med 1995;182:163–174.[Abstract/Free Full Text]
-
Sallusto F, Cella M, Daniella C et al. Dendritic cells use micropinocytosis and the mannose receptor to concentrate antigen in the MHC class II compartment. J Exp Med 1995;182:279–288.[Free Full Text]
-
Pure E, Inaba M, Crowley T et al. Antigen processing by epidermal Langerhans' cells correlates with the level of biosynthesis of MHC class II molecules and expression of invariant chain. J Exp Med 1990;172:1459–1463.[Abstract/Free Full Text]
-
Kleimeer MJ, Ossevoort MA, van Veen CJ et al. MHC class II compartments and kinetics of antigen presentation in activated mouse spleen dendritic cells. 1995;154:5715–5724.
-
Young JW, Koulova L, Soergel SA et al. The B7/BB1 antigen provides one of several co-stimulatory signals for the activation of CD4+ lymphocytes by human blood dendritic cells in vivo. J Clin Invest 1992;90:229–237.
-
Wu Y, Gou Y, Liu Y. A major co-stimulatory molecule on antigen presenting cells, CLTA-4 ligand A, is distinct from B7. J Exp Med 1993;178:1753–1761.[Abstract/Free Full Text]
-
Freeman GJ, Borriello R, Hodges H et al. Murine B7-2, an alternative CTLA-4 counter-receptor that co-stimulates T cell proliferation and interleukin 2 production. J Exp Med 1993;178:2185–2196.[Abstract/Free Full Text]
-
Holt PG, Schon-Hegrad A, Oliver J. MHC class II antigen bearing dendritic cells in pulmonary tissues of the rat. Regulation of antigen presentation by endogenous macrophage population. J Exp Med 1987;167:262–274.
-
Holt PG, Oliver J, Bilyle B et al. Downregulation of the antigen presenting function of pulmonary dendritic cells in vivo by resident alveolar macrophages. J Exp Med 1993;177:397–407.[Abstract/Free Full Text]
-
Heufler C, Koch F, Schuler G. Granulocyte/macrophage colony stimulating factor and interleukin-1 mediate the maturation of murine epidermal Langerhans' cells into potent immuno-stimulatory dendritic cells. J Exp Med 1987;167:700–705.[Abstract/Free Full Text]
-
Kock FC, Heufler E, Kamgen E et al. Tumor necrosis factor- maintains the viability of murine epidermal Langerhans' cells in culture but in contrast to granulocyte/macrophage colony stimulating factor, without inducing functional maturation. J Exp Med 1990;171:159–171.[Abstract/Free Full Text]
-
Witmer-Pack M, Oliver W, Valinsky J et al. Granulocyte/macrophage colony stimulating factor is essential for viability and function of cultured murine epidermal Langerhans cells. J Exp Med 1987;166:1484–1498.[Abstract/Free Full Text]
-
Inaba K, Inaba N, Romani N et al. Generation of large numbers of dendritic cells from murine bone marrow cultures supplemented by granulocyte/macrophage colony stimulating factor. J Exp Med 1992;176:1693–1702.[Abstract/Free Full Text]
-
Inaba K, Inaba N, Deguchi M et al. Granulocytes, monocytes and dendritic cells arise from a common MHC class II—negative progenitor in mouse bone marrow. Proc Natl Acad Sci USA 1993;90:3038–3042.[Abstract/Free Full Text]
-
Reid CD, Stackpoole A, Meager A et al. Interactions of tumor necrosis factor with granulocyte-macrophage colony-stimulating factor and other cytokines in the regulation of dendritic cell growth from early bipotential CD34+ progenitors in human bone marrow. J Immunol 1992;149:2681–2688.[Abstract]
-
Romani N, Grunner S, Brang D et al. Proliferating dendritic cell precursor in peripheral blood. J Exp Med 1994;180:83–93.[Abstract/Free Full Text]
-
Kampgen E, Koch F, Heufler C et al. Understanding the dendritic cell lineage through a study of cytokine receptors. J Exp Med 1994;179:1767–1776.[Abstract/Free Full Text]
-
Larsen CP, Ritchie SC, Hendrix R et al. Regulation of immuno-stimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells. J Immunol 1994;152:5208–5219.[Abstract]
-
Furue M, Katz SI. Direct effects of glucocorticosteroids on epidermal Langerhans' cells. J Invest Dermatol 1989;92:342–347.[Medline]
-
Bellini A, Vittori E, Marini M et al. Intra-epithelial dendritic cell and selective activation of Th2 like lymphocytes in patients with atopic asthma. Chest 1993;103:997–1005.[Abstract/Free Full Text]
-
Mattoli S, Mattoso VL, Sotoperto M et al. Cellular and biochemical characteristics of bronchial alveolar lavage fluid in symptomatic non-allergic asthma. J Allergy Clin Immune 1991;87:794–802.
-
Ackerman V, Marini M, Bellini A et al. Detection of cytokines and their cell sources in bronchial biopsy specimens from asthmatic patients. Chest 1994;105:687–696.[Abstract/Free Full Text]
-
Thomas R, Davis LS, Lipsky PE. Rheumatoid synovium is enriched in mature antigen-presenting dendritic cells. J Immunol 1994;152:2613–2623.[Abstract]
-
Caux C, Liu Y-J, Banchereau J. Recent advances in the study of dendritic cells and follicular dendritic cells. Immunol Today 1995;16:2–4.[Medline]
-
Stingl G, Bergstresser PR. Dendritic cells: a major story unfolds. Immunol Today 1995;16:330–333.[Medline]
accepted for publication January 22, 1996.
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Abstract
Introduction
