Article
Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease.
Graduate School of Biological Science, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Blood (impact factor:
9.9).
08/2008;
112(5):2101-10.
DOI:10.1182/blood-2007-12-126987
Source: PubMed
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Article: Acute graft-versus-host disease does not require alloantigen expression on host epithelium.
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ABSTRACT: Alloantigen expression on host antigen-presenting cells (APCs) is essential to initiate graft-versus-host disease (GvHD); therefore, alloantigen expression on host target epithelium is also thought to be essential for tissue damage. We tested this hypothesis in mouse models of GvHD using bone-marrow chimeras in which either major histocompatibility complex class I or class II alloantigen was expressed only on APCs. We found that acute GvHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents acute GvHD. These results pertain particularly to CD4-mediated GvHD but also apply, at least in part, to CD8-mediated GvHD. These results challenge current paradigms about the antigen specificity of GvHD effector mechanisms and confirm the central roles of both host APCs and inflammatory cytokines in acute GvHD.Nature Medicine 07/2002; 8(6):575-81. · 22.46 Impact Factor -
Article: Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease.
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ABSTRACT: Alloantigen expression on host APCs is essential to initiate graft-vs-host disease (GVHD); however, critical APC subset remains to be elucidated. We compared the ability of dendritic cells (DCs) and B cells to initiate acute GVHD by an add-back study of MHC class II-expressing APCs (II(+/+)) into MHC class II-deficient (II(-/-)) mice that were resistant to CD4-dependent GVHD. Injection of host-derived, but not donor-derived, II(+/+) DCs or host-derived II(+/+) B cells, was sufficient to break GVHD resistance of II(-/-) mice and induced lethal acute GVHD. By contrast, host-derived II(+/+) B cells, both naive and LPS stimulated, failed to induce activation or tolerance of donor CD4(+) T cells. Similarly, in a model of CD8-dependent GVHD across MHC class I mismatch injection of allogeneic DCs, but not B cells, induced robust proliferation of donor CD8(+) T cells and broke GVHD resistance of chimeric recipients in which APCs were syngeneic to donors. These results demonstrate that host-derived DCs are critical in priming donor CD4(+) and CD8(+) T cells to cause GVHD, and selective targeting of host DCs may be a promising strategy to prevent GVHD.The Journal of Immunology 07/2004; 172(12):7393-8. · 5.79 Impact Factor -
Article: Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense.
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ABSTRACT: Bacterial pneumonia is an increasing complication of HIV infection and inversely correlates with the CD4(+) lymphocyte count. Interleukin (IL)-17 is a cytokine produced principally by CD4(+) T cells, which induces granulopoiesis via granulocyte colony-stimulating factor (G-CSF) production and induces CXC chemokines. We hypothesized that IL-17 receptor (IL-17R) signaling is critical for G-CSF and CXC chemokine production and lung host defenses. To test this, we used a model of Klebsiella pneumoniae lung infection in mice genetically deficient in IL-17R or in mice overexpressing a soluble IL-17R. IL-17R-deficient mice were exquisitely sensitive to intranasal K. pneumoniae with 100% mortality after 48 h compared with only 40% mortality in controls. IL-17R knockout (KO) mice displayed a significant delay in neutrophil recruitment into the alveolar space, and had greater dissemination of K. pneumoniae compared with control mice. This defect was associated with a significant reduction in steady-state levels of G-CSF and macrophage inflammatory protein (MIP)-2 mRNA and protein in the lung in response to the K. pneumoniae challenge in IL-17R KO mice. Thus, IL-17R signaling is critical for optimal production of G-CSF and MIP-2 and local control of pulmonary K. pneumoniae infection. These data support impaired IL-17R signaling as a potential mechanism by which deficiency of CD4 lymphocytes predisposes to bacterial pneumonia.Journal of Experimental Medicine 09/2001; 194(4):519-27. · 13.85 Impact Factor
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Keywords
acute GVHD
acute GVHD model
allogeneic recipients
ameliorate acute GVHD
augmented Th1 differentiation
donor T cells
donor Th17 cells
host DCs
identified T-cell lineage
IFN-gamma production
induced exacerbated acute GVHD
inflammatory autoimmune diseases
inflammatory chemokines
mediating autoimmune diseases
neutralizing IFN-gamma
recombinant IL-17
secretes proinflammatory cytokine IL-17
Severe tissue damage
Th1 infiltration
treatments neutralizing proinflammatory cytokine IL-17
