Biomedical subjects

Joseph E Craft

Publications and source records attributed to Joseph E Craft.

4 recordsLinked to original sources

PubMed2026

IgA is necessary and sufficient to prevent norovirus infection in mice.

Human norovirus is the leading cause of viral gastroenteritis, yet effective vaccines and therapeutics remain elusive. Using murine norovirus as a model, we found that mucosal immunoglobulin A (IgA) is both necessary and sufficient for protection against infection, whereas CD8+ T cells are dispensable. Robust intestinal IgA production requires at least 4 weeks of enteric infection, consistent with kinetics of human norovirus RNA clearance. Systemic vaccination elicits high titers of neutralizing serum IgG but fails to prevent enteric norovirus infection, phenocopying a recent human norovirus vaccine failure. In contrast, prophylactic delivery of dimeric anti-norovirus IgA via mRNA lipid nanoparticles confers sterilizing immunity. Together, these findings define a critical role for mucosal IgA in norovirus protection and identify IgA-based treatments as a therapeutic approach for human norovirus.

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PubMed2003

STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity.

Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional mediator for many cytokines and is essential for normal embryonic development. We have generated a unique strain of mice with tissue-specific disruption of STAT3 in bone marrow cells during hematopoiesis. This specific STAT3 deletion causes death of these mice within 4-6 weeks after birth with Crohn's disease-like pathogenesis in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation. Deletion of STAT3 causes significantly increased cell autonomous proliferation of cells of the myeloid lineage, both in vivo and in vitro. Most importantly, Stat3 deletion during hematopoiesis causes overly pseudoactivated innate immune responses. Although inflammatory cytokines, including tumor necrosis factor alpha and IFN-gamma, are overly produced in these mice, the NAPDH oxidase activity, which is involved in antimicrobial and innate immune responses, is inhibited. The signaling responses to lipopolysaccharide are changed in the absence of STAT3, leading to enhanced NF-kappa B activation. Our results suggest a model in which STAT3 has critical roles in the development and regulation of innate immunity, and deletion of STAT3 during hematopoiesis results in abnormalities in myeloid cells and causes Crohn's disease-like pathogenesis.

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PubMed2003

Intrinsic T cell defects in systemic autoimmunity.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of T cell tolerance to nuclear antigens. Studies in mice and humans have demonstrated that T cells from individuals with lupus are abnormal. Here, we review the known T cell defects in lupus and their possible biochemical nature, genetic causes, and significance for lupus pathogenesis.

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PubMed2002

Transgenic overexpression of interleukin (IL)-10 in the lung causes mucus metaplasia, tissue inflammation, and airway remodeling via IL-13-dependent and -independent pathways.

To address the complex chronic effector properties of interleukin (IL)-10, we generated transgenic mice in which IL-10 was overexpressed in the lung. In these mice, IL-10 inhibited endotoxin-induced tumor necrosis factor production and neutrophil accumulation. IL-10 also caused mucus metaplasia, B and T cell-rich inflammation, and subepithelial fibrosis and augmented the levels of mRNA encoding Gob-5, mucins, and IL-13. In mice bred to have null mutations of IL-13, IL-4R(alpha), or STAT-6, transgenic IL-10 did not induce mucus metaplasia but did induce inflammation and fibrosis. IL-10 was also a critical mucin regulator of virus-induced mucus metaplasia. Thus, IL-10, although inhibiting lipopolysaccharide-induced inflammation, also causes mucus metaplasia, tissue inflammation, and airway fibrosis. These responses are mediated by multiple mechanisms with mucus metaplasia being dependent on and the inflammation and fibrosis being independent of an IL-13/IL-4R(alpha)/STAT-6 activation pathway.

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