title: CD4+ cell-dependent granuloma formation in humanized mice infected with mycobacteria.
abstract: We have used humanized mice, in which human immune cells differentiate de novo from transplanted cord blood progenitor cells, to study the human immune responses to infection with Mycobacterium bovis bacillus Calmette-Guérin and Mycobacterium tuberculosis. Granulomas with a core containing giant cells, human CD68(+) macrophages, and high bacilli numbers surrounded by a layer of CD3(+) T cells and a fibrotic response encapsulating the lesions were observed in livers and lungs from bacillus Calmette-Guérin-infected humanized mice but not in nonhumanized infected controls. Paradoxically, humanized mice contained higher mycobacterial numbers in organs than nonhumanized controls. The enhancement of bacterial load was mediated by human CD4(+) cells and associated to an increased expression of Programmed Death-1 protein and CD57 on T cells, molecules associated with inhibition and senescence. The lesions from mice depleted of CD4(+) cells were scarcer, minimal, and irregular compared with those from mice depleted of CD8(+) cells or nondepleted controls. Granulomas of bacillus Calmette-Guérin-infected humanized mice administered with a TNF-neutralizing TNF receptor fusion molecule preserved their structure, but contained higher levels of intracellular bacilli. Extended necrosis was observed in granulomas from M. tuberculosis- but not bacillus Calmette-Guérin-infected humanized mice. Our data indicate that humanized mice can be used as a model to study the formation and maintenance of human granuloma in tuberculosis and other infectious or noninfectious diseases.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology and Center for Infectious Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Frank
authors.initials: F
authors.lastname: Heuts
authors.forename: Dolores
authors.initials: D
authors.lastname: Gavier-Widén
authors.forename: Berit
authors.initials: B
authors.lastname: Carow
authors.forename: Julius
authors.initials: J
authors.lastname: Juarez
authors.forename: Hans
authors.initials: H
authors.lastname: Wigzell
authors.forename: Martin E
authors.initials: ME
authors.lastname: Rottenberg
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D036101:Cord Blood Stem Cell Transplantation; D005434:Flow Cytometry; D006099:Granuloma / Q000150:complications / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009163:Mycobacterium bovis; D009169:Mycobacterium tuberculosis; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014376:Tuberculosis / Q000150:complications / Q000276:immunology*
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