Experimental Hypersensitivity Research Articles

Co-modulation of T cells and B cells enhances the inhibition of inflammation in experimental hypersensitivity pneumonitis

BackgroundHypersensitivity pneumonitis (HP) is an interstitial lung disease characterized by antigen-triggered neutrophilic exacerbations. Although CD4+ T cells are sufficient for HP pathogenesis, this never translated into efficient T cell-specific therapies. Increasing evidence shows that B cells also play decisive roles in HP. Here, we aimed to further define the respective contributions of B and T cells in subacute experimental HP.MethodsMice were subjected to a protocol of subacute exposure to the archaeon Methanosphaera stadmanae to induce experimental HP. Using models of adoptive transfers of B cells and T cells in Rag1-deficient mice and of B cell-specific S1P1 deletion, we assessed the importance of B cells in the development of HP by evaluating inflammation in bronchoalveolar lavage fluid. We also aimed to determine if injected antibodies targeting B and/or T cells could alleviate HP exacerbations using a therapeutic course of intervention.ResultsEven though B cells are not sufficient to induce HP, they strongly potentiate CD4+ T cell-induced HP‑associated neutrophilic inflammation in the airways. However, the reduction of 85% of lung B cells in mice with a CD19-driven S1P1 deletion does not dampen HP inflammation, suggesting that lung B cells are not necessary in large numbers to sustain local inflammation. Finally, we found that injecting antibodies targeting B cells after experimental HP was induced does not dampen neutrophilic exacerbation. Yet, injection of antibodies directed against B cells and T cells yielded a potent 76% inhibition of neutrophilic accumulation in the lungs. This inhibition occurred despite partial, sometimes mild, depletion of B cells and T cells subsets.ConclusionsAlthough B cells are required for maximal inflammation in subacute experimental HP, partial reduction of B cells fails to reduce HP-associated inflammation by itself. However, co-modulation of T cells and B cells yields enhanced inhibition of HP exacerbation caused by an antigenic rechallenge.

S1P1 Contributes to Endotoxin-enhanced B-Cell Functions Involved in Hypersensitivity Pneumonitis.

In a proportion of patients with hypersensitivity pneumonitis, the biological and environmental factors that sustain inflammation are ill defined, resulting in no effective treatment option. Bioaerosols found in occupational settings are complex and often include Toll-like receptor ligands, such as endotoxins. How Toll-like receptor ligands contribute to the persistence of hypersensitivity pneumonitis, however, remains poorly understood. In a previous study, we found that an S1P1 (sphingosine-1-phosphate receptor 1) agonist prevented the reactivation of antigen-driven B-cell responses in the lung. Here, we assessed the impact of endotoxins on B-cell activation in preexisting hypersensitivity pneumonitis and the role of S1P1 in this phenomenon. The impact of endotoxins on pre-established hypersensitivity pneumonitis was studied in vivo. S1P1 levels were tracked on B cells in the course of the disease using S1P1-eGFP knockin mice, and the role of S1P1 on B-cell functions was assessed using pharmacological tools. S1P1 was found on B cells in experimental hypersensitivity pneumonitis. Endotoxin exposure enhanced neutrophil accumulation in the BAL of mice with experimental hypersensitivity pneumonitis. This was associated with enhanced CD69 cell-surface expression on lymphocytes in the BAL. In isolated B cells, endotoxins increased cell-surface levels of costimulatory molecules and CD69, which was prevented by an S1P1 agonist. S1P1 modulators also reduced TNF production by B cells and their capacity to trigger T-cell cooperation ex vivo. An S1P1 ligand directly inhibited endotoxin-induced B-cell activation.

The effects of bovine colostrum supplementation on in vivo immunity following prolonged exercise: a randomised controlled trial

BackgroundBovine colostrum (COL) has been advocated as a nutritional countermeasure to exercise-induced immune dysfunction, but there is a lack of research with clinically relevant in vivo measures.AimTo investigate the effects of COL supplementation on in vivo immunity following prolonged exercise using experimental contact hypersensitivity (CHS) with the novel antigen diphenylcyclopropenone (DPCP).MethodsIn a double-blind design, 31 men were randomly assigned to COL (20 g/day) or placebo (PLA) for 58 days. Participants ran for 2 h at 60% maximal aerobic capacity on day 28 and received a primary DPCP exposure (sensitisation) 20 min after. On day 56, participants received a low-dose-series DPCP challenge to elicit recall of in vivo immune-specific memory (quantified by skinfold thickness 24 and 48 h later). Analysis of the dose–response curves allowed determination of the minimum dose required to elicit a positive response (i.e., sensitivity).ResultsThere was no difference in summed skinfold thickness responses between COL and PLA at 24 h (p = 0.124) and 48 h (p = 0.405). However, sensitivity of in vivo immune responsiveness was greater with COL at 24 h (p < 0.001) and 48 h (p = 0.023) with doses ~ twofold greater required to elicit a positive response in PLA.ConclusionsCOL blunts the prolonged exercise-induced decrease in clinically relevant in vivo immune responsiveness to a novel antigen, which may be a mechanism for reduced illness reports observed in the previous studies. These findings also suggest that CHS sensitivity is highly relevant to host defence.

A sphingosine-1-phosphate receptor 1 agonist inhibits tertiary lymphoid tissue reactivation and hypersensitivity in the lung.

Hypersensitivity pneumonitis is characterized by pulmonary accumulation of B-cell-rich tertiary lymphoid tissues (TLTs), which are alleged sites of amplification for antigen-specific responses. The sphingosine-1-phosphate receptor 1 (S1P1) regulates key mechanisms underlying lymphoid tissue biology and its chemical modulation causes lymphocyte retention in lymph nodes. Given the putative immunopathogenic impact of lymphocyte accumulation in TLTs, we investigated whether or not chemical modulation of S1P1 caused lymphocyte retention within TLTs in a model of hypersensitivity pneumonitis. Mice were exposed subchronically to Methanosphaera stadtmanae (MSS) in order to induce an hypersensitivity pneumonitis-like disease. MSS exposure induced B-cell-rich TLTs surrounded by S1P1-positive microvessels. Upon MSS rechallenge, the S1P1 agonist RP001 prevented the pulmonary increase of CXCL13, a chief regulator of B-cell recruitment in lymphoid tissues. This was associated with a complete inhibition of MSS rechallenge-induced TLT enlargement and with a 2.3-fold reduction of MSS-specific antibody titers in the lung. Interference with TLT reactivation was associated with a 77% reduction of neutrophil accumulation and with full inhibition of protein-rich leakage in the airways. Thus, an S1P1 agonist hinders TLT enlargement upon antigenic rechallenge and inhibits key pathognomonic features of experimental hypersensitivity pneumonitis.

Cathelicidin related antimicrobial peptide, laminin, Toll-like receptors and chemokines levels in experimental hypersensitivity pneumonitis in mice

IntroductionHypersensitivity pneumonitis (HP) is an interstitial lung disease caused by unresolved inflammation and tissue repair pathologies triggered by repeated organic dust exposure. The aim of the study was to investigate changes in levels of the cathelicidin related antimicrobial peptide (CRAMP), laminin (LAM-A1), selected Toll-like receptors (TLR) and chemokines in experimental HP in mice. Materials and methodsThree and 18-month-old female C57BL/6J mice underwent inhalations of the saline extract of Pantoea agglomerans cells, Gram-negative bacterium common in organic dust and known for its pathogenic impact. The inhalations were repeated daily (28 days). ELISA was used for measuring in lung tissue homogenates concentration of CRAMP, LAM-A1, TLR2, TLR4, TLR8, CXCL9 (chemokine [C-X-C motif] ligand) and CXCL10. ResultsLevels of TLR2, TLR4 and CXCL9 were significantly higher in both young and old mice lungs already after 7 days of inhalations, while significant increase of LAM-A1 and CXCL10 was noted after 28 days, compared to untreated samples. TLR8 level was significantly augmented only in young mice. Only CRAMP level significantly declined. Significantly higher TLR8 and CXCL9 concentration in untreated samples were noted in old animals compared to young ones. ConclusionSignificant alterations of the examined factors levels indicate their role in HP pathogenesis.

Role of IL-17A and neutrophils in fibrosis in experimental hypersensitivity pneumonitis

Chronic hypersensitivity pneumonitis is characterized by pulmonary inflammation and fibrosis in response to repeated inhalation of mainly organic antigens. It is recognized that IL-17A is crucial for the development of pulmonary inflammation in murine models of experimental hypersensitivity pneumonitis, but its role in the development of pulmonary fibrosis has not been determined. Furthermore, the main cell type(s) that produce IL-17A in experimental hypersensitivity pneumonitis have not yet been identified. Our objectives were to test the hypothesis that IL-17A plays a central role in the development of pulmonary fibrosis in experimental hypersensitivity pneumonitis and to determine the main inflammatory cell type(s) responsible for IL-17A production. We used a mouse model of experimental hypersensitivity pneumonitis in which IL-17A was inhibited or neutrophils were depleted. We also used IL-17RA-deficient and RAG-2-deficient mice. Lung IL-17A-producing cells were identified by fluorescence-activated cell sorting of myeloid versus lymphoid cell populations, intracellular IL-17A staining, flow cytometry, and quantitative reverse transcription PCR for IL-17A mRNA. We found that the development of pulmonary fibrosis depended on IL-17A and was significantly attenuated by neutrophil depletion. Neutrophils and monocytes/macrophages were the main cell types that expressed IL-17A in our model. We have identified the central roles of IL-17A and neutrophils in the pathogenesis of fibrosis in experimental hypersensitivity pneumonitis. We have also established that nonlymphocytic innate immune cells, specifically neutrophils and monocytes/macrophages, rather than TH17 lymphocytes, are the predominant source of IL-17A in experimental hypersensitivity pneumonitis.

Nitric oxide regulates T cell responses

We reveal a previously unrecognized subset of CD4 + CD25 + Tregs derived from CD4 + CD25 − T cells induced by nitric oxide (NO). The induction of Tregs (NO-Tregs) is independent of cGMP but dependent on p53, IL-2 and OX40. NO-Tregs suppressed the proliferation of CD4 + CD25 − T cells in vitro and attenuated colitis and collagen-induced arthritis in vivo in an IL-10-dependent manner. NO-Tregs were also induced in vivo in SCID mice adaptively transferred with CD4 + CD25 − T cells in the presence of LPS and IFN γ and the induction was completely inhibited by L-NMMA. We also found that NO-Treg preferentially suppresses the polarization and established Th17 but not Th1 cells and attenuates experimental autoimmune encephalomyelitis (EAE). Furthermore NO can directly suppress the polarization of Th17 cells. In contrast NO can switch CD4 + T cells from a Th17 phenotype to that of Th9 phenotype and exacerbates experimental airway hypersensitivity. The molecular mechanism and the function of NO in modulating T cells will be discussed.

Toll‐like receptor 6 drives interleukin‐17A expression during experimental hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is a T-cell-driven disease that is histologically characterized by diffuse mononuclear cell infiltrates and loosely formed granulomas in the lungs. We have previously reported that interleukin-17A (IL-17A) contributes to the development of experimental HP, and that the pattern recognition receptor Toll-like receptor 6 (TLR6) might be a factor in the initiation of this response. Using a well-established murine model of Saccharopolyspora rectivirgula-induced HP, we investigated the role of TLR6 in the immunopathogenesis of this disease. In the absence of TLR6 signalling, mice that received multiple challenges with S. rectivirgula-antigen (SR-Ag) had significantly less lung inflammation compared with C57BL/6 mice (wild-type; WT) similarly challenged with SR-Ag. Flow cytometric analysis of whole lung samples from SR-Ag-challenged mice showed that TLR6(-/-) mice had a decreased CD4(+) : CD8(+) T-cell ratio compared with WT mice. Cytokine analysis at various days after the final SR-Ag challenge revealed that whole lungs from TLR6(-/-) mice contained significantly less IL-17A than lungs from WT mice with HP. The IL-17A-driving cytokines IL-21 and IL-23 were also expressed at lower levels in SR-Ag-challenged TLR6(-/-) mice, when compared with SR-Ag-challenged WT mice. Other pro-inflammatory cytokines, namely interferon-gamma and RANTES, were also found to be regulated by TLR6 signalling. Anti-TLR6 neutralizing antibody treatment of dispersed lung cells significantly impaired SR-Ag-induced IL-17A and IL-6 generation. Together, these results indicate that TLR6 plays a pivotal role in the development and severity of HP via its role in IL-17A production.

The possible involvement of immune complexes in pulmonary granuloma formation in experimental hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is a disease caused by inhaled organic dust. The alveolitis and granuloma are characteristic features of HP. The precise mechanism of granuloma formation is still unclear. The roles of immune complexes and primed T cell in relation to granuloma formation were studied. Local lymph node cells were obtained from C57BL/6 mice immunized by injection of ovalbumin (OA) or keyhole limpet haemocyanin (KLH) emulsified in complete Freund's adjuvant into footpads. Thereafter enriched T cells were obtained by passage through nylon wool columns. Antigens (OA, KLH) were chemically coupled to Sepharose 4B beads (OA-beads, KLH-beads). The immune complex was made by the incubation of the antigen-coupled beads and the immunized mouse serum at 37 degrees C for 2 hours. The recipient mouse irradiated by 6.5 Gy was transferred with 3 X 10(7) T cells and challenged with intratracheal instillation of 1 X 10(4) antigen-coupled beads or 1 X 10(4) immune complex-coupled beads. The recipient mice were sacrificed day 3 after cell transfer and challenge. The radius of pulmonary granuloma was measured by microscopic examination of the HE-stained section. The radius of granuloma increased in the recipient mouse which received the primed T cell and was challenged with immune complex-coupled beads compared with any other combination of cell transfer and antigen challenge. This result suggests that not only T cell but also immune complexes play an important role in granuloma formation in HP.

Experimental hypersensitivity pneumonitis and enhancement of granuloma formation by low dose irradiation with increased interleukin-1 activity of granuloma in genetically low responder mouse (C3H)

Possible enhancing effects by low dose total body irradiation on pulmonary granuloma formation induced by intratracheal injection of ovalbumin-coupled beads in low responder C3H mouse were studied. The low dose (3.5 Gy) irradiation increased the size of granuloma in low responder C3H mouse as large as the granuloma formed in high responder C57BL/10 mouse. The resolution of granuloma which usually disappeared within 9 days was also prolonged by the irradiation. Increase in IL-1 activity of lung extracts but not IL-2 activity was parallel to the enhancement of granuloma formation and/or the delayed resolution of granuloma. These results indicated that the radiation-sensitive cells might regulate IL-1 producing cell, possibly macrophages which made pulmonary granuloma.

Establishment of an experimental hypersensitivity pneumonitis model in mice

Establishment of an experimental hypersensitivity pneumonitis model in mice

Galectin‐9 expands immunosuppressive macrophages to ameliorate T‐cell‐mediated lung inflammation

Galectin-9 (Gal-9) plays pivotal roles in the modulation of innate and adaptive immunity to suppress T-cell-mediated autoimmune models. However, it remains unclear if Gal-9 plays a suppressive role for T-cell function in non-autoimmune disease models. We assessed the effects of Gal-9 on experimental hypersensitivity pneumonitis induced by Trichosporon asahii. When Gal-9 was given subcutaneously to C57BL/6 mice at the time of challenge with T. asahii, it significantly suppressed T. asahii-induced lung inflammation, as the levels of IL-1, IL-6, IFN-gamma, and IL-17 were significantly reduced in the BALF of Gal-9-treated mice. Moreover, co-culture of anti-CD3-stimulated CD4 T cells with BALF cells harvested from Gal-9-treated mice on day 1 resulted in diminished CD4 T-cell proliferation and decreased levels of IFN-gamma and IL-17. CD11b(+)Ly-6C(high)F4/80(+) BALF Mphi expanded by Gal-9 were responsible for the suppression. We further found in vitro that Gal-9, only in the presence of T. asahii, expands CD11b(+)Ly-6C(high)F4/80(+) cells from BM cells, and the cells suppress T-cell proliferation and IFN-gamma and IL-17 production. The present results indicate that Gal-9 expands immunosuppressive CD11b(+)Ly-6C(high) Mphi to ameliorate Th1/Th17 cell-mediated hypersensitivity pneumonitis.

Interleukin-17–mediated Immunopathogenesis in Experimental Hypersensitivity Pneumonitis

T cells play a critical role in the development of Saccharopolyspora rectivirgula-induced hypersensitivity pneumonitis (HP) but little is known about the role of IL-17A in this disease. We examined the role of IL-17A in a murine model of S. rectivirgula antigen (SR-Ag)-induced HP. Experimental HP was induced by oropharyngeal instillation of SR-Ag in wild-type and IL-17 gene-deficient mice. SR-Ag-induced murine HP was characterized by increased transcript levels of IFN-gamma and IL-12p35 compared with saline-treated control mice. Furthermore, mice with HP showed increased IL-17 in lung homogenates, bronchoalveolar lavage fluid, and ex-vivo lung cultures compared with control mice. Flow cytometric analysis of SR-Ag-challenged lungs revealed increased Th17 and CD11c(+) cells. The role of IL-17 in SR-induced HP was examined in IL-17 deficient (IL17(-/-)) and in wild-type (IL-17(+/+)) mice immunodepleted of IL-17. Histological examination of IL17(-/-) mice challenged with SR-Ag revealed reduced inflammatory cell infiltration, decreased CD11c(+) cells, and reduced levels of inflammatory mediators such as IL-12p70, CCL3, and CXCL9 compared with similarly treated IL17(+/+) mice. Anti-IL-17 antibody treatment of IL-17(+/+) mice with HP resulted in reduced inflammation and a lower percentage of CD11c(+) cells compared with IgG-treated IL-17(+/+) mice with HP. SR-Ag-induced IL-17 plays a pivotal role in the immunopathology of HP and targeting IL-17 is an attractive therapeutic option for this disease.

The Role of MIP-1? in Experimental Hypersensitivity Pneumonitis

S. rectivirgula (SR) causes Farmer's Lung Disease, a classic example of hypersensitivity pneumonitis (HP). We utilized a model of experimental hypersensitivity pneumonitis (EHP), antibody to MIP-1alpha and MIP-1alpha -/- mice, to test the hypothesis that MIP-1alpha is essential in the development of EHP. Treatment of C57BI/6 mice with anti-MIP-1alpha antibody did not change the extent of pulmonary histology abnormalities, BALF cell number or characteristics, or BALF concentration of IL12p40, TNF, IL1alpha and IL6, after an i.t. challenge with SR. MIP-1alpha -/- animals responded similarly to wild-type (wt) animals in the extent and nature of pulmonary histologic changes and BALF cell number and type after a single i.t. injection of SR There was a dose-response relationship between the amount of SR and BALF IL12p40, MCP-1 and IL6 in both strains, and MIP-1alpha in wild-type animals. We next transferred SR cultured spleen cells from SR sensitized mice (both wt and MIP-1alpha -/-) to naive recipients. Lung histology and BALF characteristics after SR i.t. challenge of the recipients were used to determine if adoptive transfer had occurred. Cultured cells from MIP-1alpha -/- animals were fully capable of transferring EHP to recipients. There was no difference of BALF TNF, IL6 and IL1alpha between the strains, but there was more MCP-1 and IL12p40 in the MIP-1alpha -/- mice than in the control mice. MIP-1alpha is not necessary for the recruitment of cells into the lung and BALF after i.t. administration of SR, or the development of cells able to adoptively transfer EHP.

Experimental hypersensitivity pneumonitis: cellular requirements.

We previously demonstrated that Thy1.2+, CD4+, Ia-T cells are responsible for transfer of murine adoptive experimental hypersensitivity pneumonitis (adoptive EHP). To characterize the culture conditions necessary for development of these cells, we depleted cell cultures of Thy1.2+, CD4+, CD8+, or Ia+ cells using MoAbs and complement or magnetic beads, prior to culture of sensitized C3H/HeJ murine spleen cells (SC) with Micropolyspora faeni. After culture, cells were transferred to recipients which were later challenged intratracheally with M. faeni. The extent of pulmonary inflammatory changes in these animals was determined 4 days after intratracheal (i.t.) challenge with M. faeni. Cultured M. faeni-sensitized SC which had been treated before culture with media, complement only, anti-CD8 plus complement or magnetic beads alone could transfer EHP to naive animals. SC treated with anti-Thy1.2 or anti-CD4 plus complement could not transfer EHP. Treatment of SC with anti-Iak plus magnetic beads diminished the ability of cultured cells to transfer EHP. We conclude that the ability to produce cells able to adoptively transfer EPH is dependent on the presence of Thy1.2+, CD4+, and Ia+ cells, but not CD8+ cells, at the onset of culture.

Is IL12 necessary in experimental hypersensitivity pneumonitis?

Inhalation of Saccharopolyspora rectivirgula (SR) can cause the disease Farmer's Lung, a classic example of hypersensitivity pneumonitis. Th1, but not Th2, cell lines can adoptively transfer experimental hypersensitivity pneumonitis (EHP). Substantial amounts of IL12 appear in bronchoalveolar lavage fluid (BALF) after a single intratracheal (IT) injection of SR, and SR-induced IL12 secretion by both a macrophage cell line and alveolar macrophages. We tested the hypothesis that IL12 is essential for the development of EHP by addition of anti-IL12 to cultured cells, and adoptive transfer of EHP in IL12p40-/- animals. We transferred SR cultured spleen and lung associated lymph node cells from SR sensitized mice (both IL12p40-/- and wild type), to naïve recipients (both wild type and IL12p40-/-). The addition of anti-IL12 to cultures of sensitized cells could not ablate the ability of these cells to transfer EHP. Cultured cells from IL12p40-/- animals were fully capable of transferring EHP. In contrast, IL12p40-/- recipients of both wild type and IL12p40-/--cultured cells were less able to express EHP (lung histology and BALF characteristics) than wild type mice, and had more eosinophils in both lung tissue and BALF. We conclude that IL12 is not necessary for development of cells able to adoptively transfer EHP, but that it is required for full expression of EHP in recipient animals.

Fc gamma RIII-mediated production of TNF-alpha induces immune complex alveolitis independently of CXC chemokine generation.

We recently demonstrated a codominant role of C5aR and FcgammaRIII in the initiation of IgG immune complex-mediated inflammation in mice. In this study, we investigated the relative contribution of FcgammaRIII in the generation of several cytokines during experimental hypersensitivity pneumonitis/alveolitis in vivo. Induction of immune complex-alveolitis in C57BL/6 mice resulted in strong accumulation of neutrophils into the lung and enhanced chemotactic activity within bronchoalveolar lavage fluid accompanied by an increased production of the proinflammatory cytokines TNF-alpha and IL-1beta as well as the ELR-CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC). FcgammaRIII-deficient C57BL/6 mice (FcgammaRIII(-/-)) showed a marked reduction of the inflammatory response due to decreased production of TNF-alpha, IL-1beta, and MIP-2. Results obtained in C57BL/6 mice either lacking the TNF-alpha class I receptor (TNF-alphaRI(-/-)) or treated with neutralizing anti-TNF-alpha mAb demonstrated an essential contribution of TNF-alpha for mediating IL-1beta release, neutrophil influx, and hemorrhage. Surprisingly, MIP-2 and KC chemokine levels remained largely unaffected in TNF-alphaRI(-/-) mice or after functional inhibition of TNF-alpha. These data suggest that in immune complex alveolitis, the activation of FcgammaRIII may induce divergent downstream effector pathways with TNF-alpha acting independently of CXC chemokines to trigger the inflammatory response in C57BL/6 mice.

Immunologic orchestration of hypersensitivity pneumonitis

Immunologic orchestration of hypersensitivity pneumonitis

Experimental Hypersensitivity Pneumonitis Induced by Fusarium kyushuense in Mice

Experimental Hypersensitivity Pneumonitis Induced by Fusarium kyushuense in Mice: Koichi Harada, et al. Department of Hygiene, Kumamoto University School of Medicine—Arecently described Fusarium species, Fusarium kyushuense, was isolated from dead leaves of egg plant in a greenhouse where a female farmer who developed hypersensitivity pneumonitis (HP) with progressing lung lesions had been working. The freeze dried fungus was exposed to specific pathogen‐free, 6‐week‐old female C57Black/6J mice under light ether anesthesia. Each mouse received 40 pi of the suspended fungal solution by dropping it onto its nostrils in 5 consecutive days a week for 4 wk. The control group received 40 μl of 0.1 M sterilized phosphate buffered saline. The mice were killed on the 4th day after the final exposure. The lung indices increased dose dependently in the fungus exposed mice groups. The specific IgG anti‐Fkyushuense levels in sera of the high dose group were significantly higher than in the control group (P &lt;0.05 by Ryan's multiple comparison test). Histologically, the lungs of both low and high dose groups showed signs of atelectasis with granulomatous lesions containing multinuclear giant cells and activated macrophages. This is the first report that mice developed HP induced by repeated exposure to freeze dried F. kyushuense.

Fusarium kyushuense暴露によりマウスに誘発した実験的過敏性肺炎

Fusarium kyushuense暴露によりマウスに誘発した実験的過敏性肺炎