Alveolar macrophage dysfunction in human bone marrow transplant recipients

Winston, Drew J.; Territo, Mary; Ho, Winston G.; Miller, Marjorie J.; Gale, Robert Peter; Golde, David W.

doi:10.1016/0002-9343(82)90777-x

Cited by 78 publications

(34 citation statements)

References 27 publications

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“…This is likely due, in part, to innate immune defects noted in AMs of patients post transplant [10]. Our previous work established a murine model of BMT (TBI + T), which was characterized by overproduction of PGE 2 , impaired AM phagocytosis and diminished host defense [4,8].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Conditioning Regimens for Alveolar Macrophage Reconstitution and Innate Immune Function Post Bone Marrow Transplant

Hubbard

Ballinger

Wilke

et al. 2008

Experimental Lung Research

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The authors compared efficiency of alveolar macrophage (AM) reconstitution from donor bone marrow post transplant following 4 chemotherapy conditioning regimens and 2 total body irradiation (TBI) regimens. TBI regimens are more effective in inducing AM reconstitution from donor marrow. However, mice conditioned with 13 Gy split-dose TBI or a dual-chemotherapy regimen (25 mg/kg busulfan × 4 days plus cyclophosphamide 100 mg/kg × 2 days) both demonstrate significant AM repopulation from donor marrow. Additionally, both protocols resulted in impaired pulmonary host defense associated with overproduction of prostaglandin E 2 and I 2 by AMs and impaired AM phagocytosis post bone marrow transplant. Keywords phagocytosis; prostaglandin; P. aeruginosaThe lung has the largest interface with the outside environment of any internal organ in the body. As such, the lung is constantly bombarded with foreign particles and pathogens. Active host defense requires the orchestration of innate immune cells and immune mediators such as cytokines, chemokines, and eicosanoids to aid in the recognition, containment, and clearance of microorganisms [1]. Unfortunately, patients who have undergone stem cell transplantation are at risk for pulmonary infections [2][3][4][5] and pneumonia remains the leading infectious cause of death following stem cell transplantation despite the implementation of numerous prophylactic strategies and advances in diagnosis and treatment [6]. These transplant patients manifest increased susceptibility to infections for periods of time (months to years) post transplantation, extending long after engraftment of leukocytes from donor sources [2,7].We have previously established a murine model of gram-negative bacterial infection following bone marrow transplantation (BMT) and have shown that these mice are more susceptible to pulmonary infection with the gram-negative pathogen Pseudomonas aeruginosa due to defects in innate immune cells. these studies involved 13 Gy of total body irradiation (TBI) followed by reconstitution with 5 × 10 6 whole bone marrow (BM) cells + 1 × 10 6 syngeneic splenic T cells. We demonstrated that AMs from these mice were >87% donor-derived by 3 weeks post BMT [4]. Despite the fact that the alveolar macrophages (AMs) were largely donor derived, the AMs were defective in their ability to both phagocytose and kill bacteria [4,8]. In this model, AMs post BMT produced elevated amounts of prostaglandin E 2 (PGE 2 ), which is known to inhibit host defense [4,8,9]. However, one caveat to the extrapolation of these findings is that the experimental conditioning regimen utilized in our previous studies does not mimic human clinical practice. Thus, to determine the applicability of these findings to BMT performed following different conditioning regimens, we compared the level of AM reconstitution and prostaglandin production following multiple TBI and chemotherapy preparative regimens. Our results demonstrate that significant reconstitution of AMs from donor BM following either TBI or c...

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Section: Discussionmentioning

confidence: 99%

Comparison of Conditioning Regimens for Alveolar Macrophage Reconstitution and Innate Immune Function Post Bone Marrow Transplant

Hubbard

Ballinger

Wilke

et al. 2008

Experimental Lung Research

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“…Winston et al (1982) have reported abnormal alveolar macrophage function for several months after BMT in patients receiving TBI at dose-rates 0.06 Gy/min. Although etiology of IP is multifactorial, in order to achieve a successful BMT with improved survival and quality of life, low dose-rate fractionated TBI may be the reliable conditioning regimen resulting in less pulmonary morbidity.…”

Section: Discussionmentioning

confidence: 99%

Effect of Dose-Rate and Lung Dose in Total Body Irradiation on Interstitial Pneumonitis after Bone Marrow Transplantation

Beyzadeoğlu

Oysul

Dırıcan

et al. 2004

Tohoku J. Exp. Med.

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“…We have also reported that levels of Ht-A-DQ and HLA-DP are signiiicanlly increased on alveolar macrophages in EAA and sarcoidosis compared with controls [9]. Alveolar macrophages are mainly derived from blood monoeytes, which migrate to the lungs where they complete their ditferentiation to mature alveolar macrophages [10,11]; and there is evidence that the infiltration of monocytes is increased in the lungs of patients with EAA [12]. Cells of the mononuclear phagocyte lineage show considerable phenotypic diversity, suggesting the existence of a variety of differentiation programmes associated with the expression of different gene products [13].…”

Section: Introductionmentioning

confidence: 84%

Enhancement of the antigen-presenting function of monocytes by cholesterol: possible relevance to inflammatory mechanisms in extrinsic allergic alveolitis and atherosclerosis

Hughes¹,

Townsend²,

Haslam³

1992

Clinical and Experimental Immunology

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SUMMARYExtrinsic allergic alveolitis (EAA) (synonym: hypcrsensilivity pneumonitis) is a hypersensitivity lung disease characterized by lymphocylic infiltrates in the pulmonary interstitial tissues. We have previously reported thai the numbers of lymphocytes in bronchoalveoiar iavage (BAL) samples in this disease correlate wilh leveis ofcholesierol and neutral lipid-ladcn 'foamy' macrophages. We have also reported that the macrophages express an increased density of MHC class II antigens (in particular HLA-DQ) which areknovtn lobe essential for antigen recognition by T lymphocytes. The aim of the present study was to explore whether cholesteroi is capable of enhancing the antigenpresenting function of mononuciear phagocytes by moduiating the expression of HLA-D region products. Ineubation of purified monocytes from heaithy volunteers with cholesterol in serum-free medium induced a significant increase in bolh ihe percentages of monocyles expressing HLA-DQ (P< 002) and in Ihe intensity of expression of the three HLA-D sub-region products, HLA-DQ,-DP and -DR {P<0Q2. <001, <005, respeetiveiy). The choieslerol pre-incubated monocytes also exhibited enhanced antigen-presenting function (/'<005), compared with controls pre-incubated without cholesterol. These findings indicate that increases in cholesterol in the extracellular milieu may augmeni aniigen presentation by modulating the expression of HLA-D region products on anligen-preseniing cells. Apart from EAA. this observation may also have relevance lo inflammatory mechanisms in atherosclerosis, where 'foamy' macrophages also occur in association with hypercholesterolaemia.

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Alveolar macrophage dysfunction in human bone marrow transplant recipients

Cited by 78 publications

References 27 publications

Comparison of Conditioning Regimens for Alveolar Macrophage Reconstitution and Innate Immune Function Post Bone Marrow Transplant

Comparison of Conditioning Regimens for Alveolar Macrophage Reconstitution and Innate Immune Function Post Bone Marrow Transplant

Effect of Dose-Rate and Lung Dose in Total Body Irradiation on Interstitial Pneumonitis after Bone Marrow Transplantation

Enhancement of the antigen-presenting function of monocytes by cholesterol: possible relevance to inflammatory mechanisms in extrinsic allergic alveolitis and atherosclerosis

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