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• W1982245851 abstract "The expression of inflammatory mediators by various cells following in vitro CD40 ligation is well known. However, knowledge of the role and interaction with these cells in the establishment and maintenance of in vivo immune-mediated inflammation is limited. In this report, a chimeric mouse model based on CD40 knockout and wild-type mice was used to assess the role of bone marrow (BM)-derived and non-BM-derived cells in a CD40-mediated pulmonary inflammation response. CD40+ BM-derived cells were required for initial cell recruitment, pulmonary edema, and weight loss associated with this response. The structural CD40+ non-BM-derived cells of the lung, such as fibroblasts, epithelial cells, and endothelial cells, could not by themselves establish any level of pulmonary inflammation. However, both the CD40+ BM-derived cells and the structural CD40+ non-BM-derived cells of the lung were required to maximize the level of pulmonary inflammation. Both B cells and T cells played a contributing role in macrophage recruitment and pulmonary edema but neither contributed to the inflammation-associated weight loss. These experiments indicate that CD40+ BM-derived cells were critical to the induction of pulmonary inflammation and that alveolar macrophages, B cells, and T cells contributed to selective aspects of the response. The expression of inflammatory mediators by various cells following in vitro CD40 ligation is well known. However, knowledge of the role and interaction with these cells in the establishment and maintenance of in vivo immune-mediated inflammation is limited. In this report, a chimeric mouse model based on CD40 knockout and wild-type mice was used to assess the role of bone marrow (BM)-derived and non-BM-derived cells in a CD40-mediated pulmonary inflammation response. CD40+ BM-derived cells were required for initial cell recruitment, pulmonary edema, and weight loss associated with this response. The structural CD40+ non-BM-derived cells of the lung, such as fibroblasts, epithelial cells, and endothelial cells, could not by themselves establish any level of pulmonary inflammation. However, both the CD40+ BM-derived cells and the structural CD40+ non-BM-derived cells of the lung were required to maximize the level of pulmonary inflammation. Both B cells and T cells played a contributing role in macrophage recruitment and pulmonary edema but neither contributed to the inflammation-associated weight loss. These experiments indicate that CD40+ BM-derived cells were critical to the induction of pulmonary inflammation and that alveolar macrophages, B cells, and T cells contributed to selective aspects of the response. The CD40 receptor is constitutively expressed on a variety of bone marrow (BM)1Banchereau J Bazan F Blanchard D Briere F Galizzi JP van Kooten C Liu YJ Rousset F Saeland S The CD40 antigen and its ligand.Annu Rev Immunol. 1994; 12: 881-922Crossref PubMed Google Scholar and non-BM2Fries KM Sempowski GD Gaspari AA Blieden T Looney RJ Phipps RT CD40 expression by human fibroblasts.Clin Immunol Immunopathol. 1995; 77: 42-51Crossref PubMed Scopus (149) Google Scholar, 3Galy AH Spits H CD40 is functionally expressed on human thymic epithelial cells.J Immunol. 1992; 149: 775-782PubMed Google Scholar, 4Hollenbaugh D Ochs HD Noelle RJ Ledbetter JA Aruffo A The role of CD40 and its ligand in the regulation of the immune response.Immunol Rev. 1994; 138: 23-37Crossref PubMed Scopus (84) Google Scholar derived cells. These cell types include B cells,5Laman JD Claassen E Noelle RJ Functions of CD40 and its ligand, gp39 (CD40L).Crit Rev Immunol. 1996; 16: 59-108Crossref PubMed Google Scholar dendritic cells,6Van Den Berg TK Habold J Renardel C de Lavalette EA Dijkstra CD Klaus GGB Properties of mouse CD40: differential expression of CD40 epitopes on dendritIc cells and epithelial cells.Immunology. 1996; 88: 294-300Crossref PubMed Scopus (13) Google Scholar monocytes,7Alderson MR Armitage RJ Tough TW Strockbine L Fanslow WC Spriggs MK CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40.J Exp Med. 1993; 178: 669-674Crossref PubMed Scopus (539) Google Scholar macrophages, epithelial cells,3Galy AH Spits H CD40 is functionally expressed on human thymic epithelial cells.J Immunol. 1992; 149: 775-782PubMed Google Scholar, 8Atsuta J Sterbinsky SA Pitt J Schwiebert LM Bochner BS Schleimer RP Phenotyping and cytokine regulation of the BEAS-2B human bronchial epithelial cell: Demonstration of inducible expression of the adhesion molecules VCAM-1 and ICAM-1.Am J Respir Cell Mol Biol. 1997; 17: 571-582Crossref PubMed Scopus (117) Google Scholar and endothelial cells.9Hollenbaugh D Mischel-Petty N Edwards CP Simon JC Denfeld RW Kiener PA Aruffo A Expression of functional CD40 by vascular endothelial cells.J Exp Med. 1995; 182: 33-40Crossref PubMed Scopus (388) Google Scholar The CD40-ligand CD154 is expressed predominantly on activated CD4+ T cells in a transient manner,10Yellin MJ Sippel K Inghirami G Covey LR Lee JJ Sinning J Clark EA Chess L Lederman S CD40 molecules induce down-modulation, and endocytosis of T cell surface T cell-B cell activating molecule/CD40L.J Immunol. 1994; 152: 598-608PubMed Google Scholar although eosinophils,11Ohkawara Y Lim KG Xing Z Glibetic M Nakano K Dolovich J Croitoru K Weller PF Jordana M CD40 Expression by human peripheral blood eosinophils.J Clin Invest. 1996; 97: 1761-1766Crossref PubMed Scopus (136) Google Scholar, 12Gauchat JF Henchoz S Fattah D Mazzei G Aubry JP Jomotte T Dash L Page K Solari R Aldebert D Capron M Dahinden C Bonnefoy JY CD40 ligand is functionally expressed on human eosinophils.Eur J Immunol. 1995; 25: 863-865Crossref PubMed Scopus (123) Google Scholar basophils, mast cells,13Gauchat JF Henchoz S Mazzel G Aubry JP Brunner T Blasey H Life P Talabot D Flores-Romo L Thompson J Kishi K Butterfield J Dahinden C Bonnefoy JY Induction of human IgE synthesis in B cells by mast cells and basophils.Nature. 1993; 365: 340-343Crossref PubMed Scopus (579) Google Scholar and CD8+ T cells14Hermann P Van-Kooten C Gaillard C Banchereau J Blanchard D CD40 ligand-positive CD8+ T cell clones allow B cell growth and differentiation.Eur J Immunol. 1995; 25: 2972-2977Crossref PubMed Scopus (68) Google Scholar are also capable of activation-induced CD154 expression. Repetitive CD40-CD154 interactions involving these various cells during their response to immunological stimuli result in an enhancement of their cellular activation level.15Karmann K Hughes CCW Schechner J Fanslow W Pober JS CD40 on human endothelial cells: inducibility by cytokines and functional regulation of adhesion molecule expression.Proc Natl Acad Sci USA. 1995; 92: 4342-4346Crossref PubMed Scopus (426) Google Scholar, 16Kiener PA Moran-Davis P Rankin BM Wahl AF Aruffo A Hollenbaugh D Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes.J Immunol. 1995; 155: 4917-4925PubMed Google Scholar In the context of innate immunity, this interaction triggers cytocidal activity and inflammatory mediator production,7Alderson MR Armitage RJ Tough TW Strockbine L Fanslow WC Spriggs MK CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40.J Exp Med. 1993; 178: 669-674Crossref PubMed Scopus (539) Google Scholar, 17Sempowski GD Chess PR Moretti AJ Padilla J Phipps RP Blieden TM CD40 mediated activation of gingival and periodontal ligament fibroblasts.J Periodont. 1997; 68: 284-292Crossref PubMed Scopus (47) Google Scholar, 18Yellin MJ Winikoff S Fortune SM Baum D Crow MK Lederman S Chess L Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) up-regulation and IL-6 production and proliferation.J Leukoc Biol. 1995; 58: 209-216PubMed Google Scholar which may contribute to the immunopathology associated with autoimmune and inflammatory diseases.The CD40-CD154 interaction is a well known critical component in the activation of adaptive immune responses.19Grewal IS Flavell RA CD40 and CD154 in cell-mediated immunity.Adv Immunol. 1998; 16: 111-135Crossref Scopus (1322) Google Scholar, 20Foy MT Aruffo A Bajorath J Buhlmann JE Noelle RJ Immune regulation by CD40 and its ligand gp39.Annu Rev Immunol. 1996; 14: 591-617Crossref PubMed Scopus (571) Google Scholar Of potentially equal importance, but less well defined, is the in vivo role of CD40-CD154 interaction in innate immunity and its association with the development of immune-mediated inflammation. In vitro activation of endothelial cells and lung fibroblasts by CD40 ligation results in the up-regulated expression of cellular adhesion molecules and increased production of proinflammatory cytokines.21Sempowski GD Chess PR Phipps RP CD40 is a functional activation antigen and B7-independent T cell costimulatory molecule on normal human lung fibroblasts.J Immunol. 1997; 158: 4670-4677PubMed Google Scholar, 22Dechanet J Grosset C Taupin JL Merville P Banchereau J Ripoche J Moreau JF CD40 ligand stimulates proinflammatory cytokine production by human endothelial cells.J Immunol. 1997; 159: 5640-5647PubMed Google Scholar Ligation of CD40 on human monocytes in vitro results in enhanced tumoricidal activity, induction of a state of activation, and production of proinflammatory cytokines.7Alderson MR Armitage RJ Tough TW Strockbine L Fanslow WC Spriggs MK CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40.J Exp Med. 1993; 178: 669-674Crossref PubMed Scopus (539) Google Scholar These findings have led to speculation that CD40+ cells contribute to the activation and regulation of immune-mediated inflammation.23Stout RD Suttles J The many roles of CD40 in cell-mediated inflammatory responses.Immunol Today. 1996; 17: 487-492Abstract Full Text PDF PubMed Scopus (252) Google Scholar The extent to which these in vitro findings have been extrapolated to in vivo models has remained incomplete. In vivo modeling of CD40 involvement in inflammation is also warranted by the potential for application of a CD154 plasmid construct as a transgenic adjuvant in vaccination therapies.24Mendoza RB Cantwell MJ Kipps TJ Cutting edge: Immunostimulatory effects of a plasmid expressing CD40 ligand (CD154) on gene immunization.J Immunol. 1997; 159: 5777-5781PubMed Google Scholar Consideration must be given to the nonspecific stimulation of unrelated CD40+ cells that encounter the CD154-transfected cells. The consequences of unrestricted CD40-CD154 interactions have been demonstrated in a CD154 transgenic mouse model.25Clegg CH Rulffes JT Haugen HS Hoggatt IH Aruffo A Durham SK Farr AG Hollenbaugh D Thymus dysfunction and chronic inflammatory disease in gp39 transgenic mice.Int Immunol. 1997; 9: 1111-1122Crossref PubMed Scopus (78) Google Scholar In vivo models to study the role of CD40-CD154 interactions in the establishment and maintenance of inflammation are needed to further understand how this interaction could impact immune-mediated inflammatory diseases.We have recently shown that instilling soluble CD154 into the lungs of mice results in an inflammatory response similar to that which occurs during human pulmonary immune responses.26Wiley JA Geha R Harmsen AG Exogenous CD40 ligand induces a pulmonary inflammation response.J Immunol. 1997; 158: 2932-2938PubMed Google Scholar Our in vivo model of CD40 ligation is useful for the investigation of immune-mediated pulmonary inflammation. In this paper, we report on the involvement of different CD40+ cells in establishing and maintaining a pulmonary inflammatory response induced by a specific anti-CD40 monoclonal antibody (mAb). Our evidence demonstrates that CD40+ BM-derived cells in the lung (macrophages, B cells, and possibly dendritic cells) were critical to the establishment of this response, but were not by themselves capable of sustaining the full extent of the inflammation. CD40+ non-BM-derived cells of the lung (endothelial cells, epithelial cells, and fibroblasts) were not capable of establishing this response in the absence of CD40+ BM-derived cells. In the absence of B cells, macrophage recruitment and pulmonary edema associated with this CD40 ligation-dependent inflammation were diminished; they were diminished further in the absence of B and T cells. The results indicate that CD40+ BM-derived cells were critical to the establishment of CD40-induced pulmonary inflammation and that CD40+ non-BM-derived cells of the lung were also required to maximize the inflammatory response.Materials and MethodsMiceMale and female C57BL/6 wild-type (+/+) mice, approximately 9 weeks of age, were obtained from the Trudeau Institute animal breeding facility for use in this study. CD40−/− breeder pairs were obtained from Dr. R. Geha27Hollander GA Castigli E Kulbacki R Su M Burakoff SJ Gutierrez-Ramos JC Geha RS Induction of alloantigen-specific tolerance by B cells from CD40-deficient mice.Proc Natl Acad Sci USA. 1996; 93: 4994-4998Crossref PubMed Scopus (58) Google Scholar and bred at the Trudeau Institute animal breeding facility. Male CD40 knockout (−/−) mice used in this study were approximately 10–12 weeks of age. Breeding pairs of μMT mice on a C57BL/6 background were obtained from The Jackson Laboratory (Bar Harbor, ME) and bred at the Trudeau Institute breeding facility. Male μMT mice used in this study were approximately 10–12 weeks of age. Ten-week-old male SCID mice on a C57BL/6 background were obtained directly from The Jackson Laboratory for this study.Production of Anti-CD40 AntibodyThe hybridoma cell line which secretes the rat IgG anti-CD40 mAb, 1C10, was obtained by permission from DNAX Corporation (Palo Alto, CA). The cell line was cultured in RPMI 1640 media (Gibco BRL, Grand Island, NY) supplemented with 3–10% fetal calf serum, 200 U/ml penicillin, 200 ug/ml streptomycin, and 20 mmol/L HEPES buffer. The cells were grown in a CellMax artificial capillary cell culture system (Spectrum Labs, Laguna Hills, CA) for three months, during which time tissue culture supernatant was recovered regularly. The antibody was purified using an AvidChrom IgPure column (Unisyn Technologies, Hopkinton, MA). The control mAb used in these procedures was a rat IgG mAb specific for horseradish peroxidase (HRPN) which was grown and purified in the same manner as the anti-CD40 mAb.Chimeric MiceChimeric mice were made by reconstituting the BM compartment of +/+ or CD40−/− mice following irradiation. Recipient mice were irradiated (9.5 Gy) and then immediately reconstituted by i.v. injection of 107 +/+ or CD40−/− donor BM cells. The animals were then housed for 1 month, under sterile conditions when required, to allow re-establishment of their BM compartment. After this time, peripheral blood samples were taken from the reconstituted animals. B cells were stained for the presence or absence of CD40 using FITC-anti-CD40 and phycoerythin-anti-B220 (PharMingen, San Diego, CA) and analyzed by flow cytometry.Experimental DesignAnti-CD40 mAb was given in 60-ug doses by intratracheal administration to mice under light halothane anesthesia. The mAb was given daily for 3 consecutive days and then every second day for 6 days. The mice were then exsanguinated by perforation of the abdominal aorta following deep halothane anesthetization. The difference between the starting and final body weight of each mouse was recorded as the change in body weight over the duration of the experiment. The lungs of the mice were lavaged as previously described.28Harmsen AG Role of alveolar macrophages in lipopolysaccharide-induced neutrophil accumulation.Infect Immun. 1988; 56: 1858-1863PubMed Google Scholar Briefly, the trachea was exposed, cannulated, and washed incrementally with five 1-ml volumes of Hanks' balanced salt solution:EDTA (3 mmol/L). Using this lung lavage technique, at least 85% of the lavage fluid was retrieved. The total number of cells recovered in the lung lavage fluid was recorded and an aliquot of the cells obtained from each animal was stained using Diff-Quik (Baxter, Miami, FL). Measurements of the serum albumin levels found in the lung lavage fluids have been used as indicators of tissue injury and subsequent transudation of proteins from the bloodstream.29Pendino KJ Meidhof TM Heck DE Laskin JDD Laskin DL Inhibition of macrophages with gadolinium chloride abrogates ozone-induced pulmonary injury and inflammatory mediator production.Am J Respir Cell Mol Biol. 1995; 13: 125-132Crossref PubMed Scopus (99) Google Scholar Serum albumin levels found in the lung lavage fluids were determined using an albumin colorimetric assay (Sigma Diagnostics, St. Louis, MO). Color absorbency was read at 630 nm and albumin concentration was reported as ug/ml of lung lavage fluid. Lung tissue sections were cut from lungs fixed in phosphate-buffered 10% formalin, embedded in paraffin, and stained with hematoxylin and eosin for histological assessment.Flow CytometryCells obtained from lung lavage were stained with the following fluorochrome-conjugated mAbs: phycoerythrin-anti-B220, cychrome-anti-CD4, biotinylated-anti-CD8, phycoerythrin-anti-CD44 (PharMingen, San Diego, CA), streptavidin-allophycocyanin (Caltag Laboratories, Burlingame, CA), FITC-anti-IgG, A, M (Organon Teknika, West Chester, PA), and FITC-anti-CD62L (Trudeau Institute, Saranac Lake, NY). The cells were washed and resuspended in phosphate-buffered saline (PBS) containing 1% bovine serum albumin-0.1% sodium azide. The cells were stained for 30 minutes at 4°C. Confinement of the analysis to the lymphocyte population was accomplished by establishing forward and side scatter settings to exclude other cell populations. Surface marker phenotypes were detected on a FACS caliber cytofluorometer (Becton Dickinson, San Jose, CA) and analyzed using CellQuest software (Becton Dickinson).StatisticsData are expressed as the mean ± standard deviation (SD). The results reported here are from one experiment that was representative of two independent experiments. The sample size of each group is as stated for each experiment. Differences between the designated groups were determined using Mann-Whitney rank sum analysis or a pairwise Dunn's ANOVA on the difference of rank means. Differences were considered significant if P < 0.05.ResultsSpecificity of the Anti-CD40 mAbThe specificity of the anti-CD40 mAb and its ability to induce a pulmonary inflammatory response are shown (Table 1). Treatment of +/+ mice with anti-CD40 mAb induced a significant cellular infiltration that was not observed in similarly treated CD40−/− mice. A substantial accumulation of cells in the alveolar space as well as significant levels of perivascular and peribronchiolar cuffing were evident in the +/+ mice treated with anti-CD40 mAb (Figure 1a). Treatment of CD40−/−mice with anti-CD40 mAb (Figure 1b) and treatment of +/+ mice (Figure 1c) and CD40−/− mice with anti-HRPN mAb elicited none of the above indications of pulmonary histopathology. A significant transudation of serum albumin into the alveolar space (Figure 2a) and the development of a wasting syndrome characterized by body weight loss (Figure 2b) were observed only in the +/+ mice treated with anti-CD40 mAb. In fact, a slight weight gain was observed over the duration of the experiment in the CD40−/− mice treated with anti-CD40 mAb and in the +/+ mice treated with the control anti-HRPN mAb.Table 1Cellular Infiltration into Lungs of Mice Following Anti-CD40 mAb TreatmentMiceAntibody treatmentTotal macrophages (×106)Total lymphocytes (×106)Total PMN (×106)+/+*n = 5 mice/group.Anti-CD401.57 ± 0.798.19 ± 3.375.20 ± 1.67CD40−/−Anti-CD400.25 ± 0.13†Statistically significant differences were observed relative to the +/+ mice treated with anti-CD40 MAb, P< 0.05.0.01 ± 0.01†Statistically significant differences were observed relative to the +/+ mice treated with anti-CD40 MAb, P< 0.05.0.10 ± 0.05†Statistically significant differences were observed relative to the +/+ mice treated with anti-CD40 MAb, P< 0.05.+/+Anti-HRPN0.32 ± 0.110.20 ± 0.082.10 ± 0.67CD40−/−Anti-HRPN0.66 ± 0.420.11 ± 0.112.04 ± 0.97Measurements are means ± SD, n = 6 mice/group except where noted otherwise.* n = 5 mice/group.† Statistically significant differences were observed relative to the +/+ mice treated with anti-CD40 MAb, P< 0.05. Open table in a new tab Figure 2A: Serum albumin levels in lung lavage fluids of +/+ or CD40−/− mice following treatment with anti-CD40 or anti-HRPN mAb. Statistically significant reductions were found relative to +/+ mice treated with anti-CD40 mAb, P < 0.05. Sample size was 5–6 mice per group. B: Change in body weight of +/+ or CD40−/− mice following treatment with anti-CD40 or anti-HRPN mAb. Statistically significant difference was found relative to +/+ mice treated with anti-CD40 mAb, P < 0.05. Sample size was 5–6 mice per group.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Treatment of Chimeric Mice with Anti-CD40 mAbAnti-CD40 mAb treatment of the +/+ mice that received +/+ BM-derived cells elicited an intense pulmonary cellular infiltrate (Table 2). Similar treatment of the +/+ or CD40−/− mice given CD40−/− BM-derived cells or of the CD40−/− mice given +/+ BM-derived cells resulted in reduced pulmonary cellular infiltration levels. However, the total numbers of lymphocytes and polymorphonuclear cells (PMNs) recovered from the CD40−/− mice that received +/+ BM-derived cells were significantly greater than those recovered from +/+ mice or CD40−/− mice that received CD40−/− BM-derived cells. Thus, the cellular infiltration was greatest in the +/+ mice given +/+ BM-derived cells, slightly elevated in the CD40−/− mice given +/+ BM-derived cells, and nearly undetectable in either the +/+ mice or CD40−/− mice given CD40−/− BM-derived cells.Table 2Cellular Infiltration into Lungs of Wild-type/CD40 Chimeric Mice Treated with Anti-CD40 mAbMiceDonor BM-derived cellsAntibody treatmentTotal macrophages (×106)Total lymphocytes (×106)Total PMN (×106)+/+ mice+/+Anti-CD404.81 ± 4.5423.70 ± 12.2710.19 ± 4.05CD40−/−Anti-CD400.25 ± 0.190.10 ± 0.08†Statistically significant difference was observed relative to +/+ cells → CD40−/− mice group, P < 0.05.0.24 ± 0.15†Statistically significant difference was observed relative to +/+ cells → CD40−/− mice group, P < 0.05.CD40−/− mice+/+Anti-CD400.49 ± 0.34*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.053.00 ± 0.98*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.053.36 ± 0.76*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.05CD40−/−Anti-CD400.14 ± 0.080.02 ± 0.010.19 ± 0.07Measurements are means ± SD, n = 5 to 7 mice/group.* Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.05† Statistically significant difference was observed relative to +/+ cells → CD40−/− mice group, P < 0.05. Open table in a new tab T and B cell infiltration occurred only in mice that were given +/+ BM-derived cells; the +/+ recipients had significantly more lymphocytes than the CD40−/− recipients (Table 3). Little detectable lymphocyte infiltration occurred in the mice given CD40−/− BM-derived cells regardless of whether the recipients were +/+ or CD40−/− mice. In mice that received +/+ cells, the level of CD8+ T cell infiltration was greater than that of the CD4+ T cells. In both the CD4+ and CD8+ T cell subsets, the activation phenotype CD44high/CD62Llow predominated.Table 3Phenotype of Infiltrating Lymphocyte Population (×106) Following Anti-CD40 mAb TreatmentCD4+CD8+MiceDonor BM-derived cellsB cellsCD4+CD44highCD62LlowCD8+CD44highCD62Llow+/++/+7.50 ± 4.112.95 ± 1.652.61 ± 1.552.44 ± 1.556.35 ± 2.845.36 ± 2.504.51 ± 2.40CD40−/−0.01 ± 0.00†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.05 ± 0.03†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.06 ± 0.03†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.05 ± 0.02†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.03 ± 0.03†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.03 ± 0.03†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.03 ± 0.02†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.CD40−/−+/+0.27 ± 0.11*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.050.81 ± 0.19*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.050.75 ± 0.19*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.050.67 ± 0.20*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.051.50 ± 0.53*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.051.38 ± 0.51*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.051.20 ± 0.50*Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.05CD40−/−0.00 ± 0.00†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.02 ± 0.01†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.02 ± 0.01†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.02 ± 0.01†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.01 ± 0.00†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.01 ± 0.00†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.0.01 ± 0.00†Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05.Measurements are means ± SD, n = 5 to 7 mice/group.* Statistically significant differences were observed relative to the +/+ cells→ +/+ mice group, P < 0.05† Statistically significant differences were observed relative to +/+ cells→ CD40−/− mice group, P < 0.05. Open table in a new tab Significant serum albumin levels were noted in the lung lavage fluids of the +/+ mice that received +/+ BM-derived cells (Figure 3a). The only other mice to show detectable albumin levels in their lung lavage fluids were the CD40−/− mice that received +/+ BM-derived cells. In a similar manner, only those mice reconstituted with +/+ BM-derived cells showed a significant loss in body weight (Figure 3b).Figure 3A: Serum albumin levels in lung lavage fluids of chimeric mice following treatment with anti-CD40 mAb. Statistically significant differences relative to +/+ cells → +/+ mice group, P < 0.05, statistically significant difference relative to +/+ cells → CD40−/− mice group, P < 0.05. Sample size was 5–7 mice per group. B: Change in body weight of chimeric mice following treatment with anti-CD40 mAb. Statistically significant differences relative to +/+ cells → +/+ mice group, P < 0.05, statistically significant differences relative to +/+ cells → CD40−/− mice group, P < 0.05. Sample size was 5–7 mice per group.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Treatment of μMT and SCID Mice with Anti-CD40 mAbMacrophage infiltration into the lungs of anti-CD40 mAb-treated μMT and SCID mice was substantially reduced relative to similarly treated +/+ mice (Table 4). As expected, the lymphocyte infiltration level into the lungs of the anti-CD40 mAb-treated SCID mice was significantly reduced compared to the +/+ mice. Although the PMN influx in the anti-CD40 mAb-treated μMT mice was significantly greater than that for the +/+ mice in this experiment, the PMN influx in the repeat experiment was equivalent among the three strains of mice. The levels of serum albumin in the lung lavage fluids of the treated μMT and SCID mice were both significantly reduced relative to the similarly treated +/+ mice, with that for the SCID mice being significantly lower than that for the μMT mice (Figure 4a). The +/+, μMT, and SCID mice all lost equivalent amounts of body weight (Figure 4b).Table 4Cellular Infiltration into Lungs of Wild-type, μMT, and SCID Mice Treated with Anti-CD40 mAbMiceAntibody treatmentTotal macrophages (×106)Total lymphocytes (×106)Total PMN (×106)+/+Anti-CD401.80 ± 0.735.36 ± 2.461.37 ± 0.52μMTAnti-CD401.02 ± 0.483.81 ± 1.833.79 ± 1.34*Statistically significant differences were observed relative to the +/+ mice, P < 0.05.SCIDAnti-CD400.85 ± 0.54*Statistically significant differences were observed relative to the +/+ mice, P < 0.05.0.16 ± 0.07*Statistically significant differences were observed relative to the +/+ mice, P < 0.05.1.99 ± 0.91Measurements are means ± SD, n = 7 to 8 mice/group.* Statistically significant differences were observed relative to the +/+ mice, P < 0.05. Open table in a new tab Figure 4A: Serum albumin" @default.
• W1982245851 created "2016-06-24" @default.
• W1982245851 creator A5002470243 @default.
• W1982245851 creator A5088118263 @default.
• W1982245851 date "1999-03-01" @default.
• W1982245851 modified "2023-10-16" @default.
• W1982245851 title "Bone Marrow-Derived Cells Are Required for the Induction of a Pulmonary Inflammatory Response Mediated by CD40 Ligation" @default.
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• W1982245851 doi "https://doi.org/10.1016/s0002-9440(10)65339-4" @default.
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