Type I IFN Receptor Signaling on B Cells Promotes Antibody Responses to Polysaccharide Antigens.

We previously reported monophosphoryl lipid A (MPL) and synthetic cord factor trehalose-6,6'-dicorynomycolate (TDCM) significantly increase Ab responses to T cell-independent type 2 Ags (TI-2 Ags) in a manner dependent on B cell-intrinsic TLR4 expression, as well as MyD88 and TRIF proteins. Given the capacity of MPL to drive type I IFN production, we aimed to investigate the extent to which type I IFN receptor (IFNAR) signaling was required for TI-2 responses and adjuvant effects. Using Ifnar1-/- mice and IFNAR1 Ab blockade, we found that IFNAR signaling is required for optimal early B cell activation, expansion, and Ab responses to nonadjuvanted TI-2 Ags, including the pneumococcal vaccine.

The PD-1 Regulatory Axis Inhibits T Cell-Independent B Cell Memory Generation and Reactivation.

The inability of T cell-independent type 2 (TI-2) Ags to induce recall responses is a poorly understood facet of humoral immunity, yet critically important for improving vaccines. Using normal and VB1-8 transgenic mice, we demonstrate that B cell-intrinsic PD-1 expression negatively regulates TI-2 memory B cell (B) generation and reactivation in part through interacting with PDL1 and PDL2 on non-Ag-specific cells. We also identified a significant role for PDL2 expression on B in inhibiting reactivation and Ab production, thereby revealing a novel self-regulatory mechanism exists for TI-2 B This regulation impacts responses to clinically relevant vaccines, because PD-1 deficiency was associated with significantly increased Ab boosting to the pneumococcal vaccine after both vaccination and infection.

B Cell Subsets Differentially Contribute to the T Cell-Independent Memory Pool.

The roles distinct B cell subsets play in clonal expansion, isotype switching, and memory B cell differentiation in response to T cell-independent type 2 Ags (TI-2 Ags) has been understudied. Using sorted B cells from VB1-8 knock-in mice, we evaluated B-1b, marginal zone, and follicular B cell responses to the TI-2 Ag, NP-Ficoll. All subsets extensively divided in response to NP-Ficoll.

Ochratoxin A: in utero exposure in mice induces adducts in testicular DNA.

Ochratoxin A (OTA) is a nephrotoxin and carcinogen that is associated with Balkan endemic nephropathy and urinary tract tumors. OTA crosses the placenta and causes adducts in the liver and kidney DNA of newborns. Because the testis and kidney develop from the same embryonic tissue, we reasoned that OTA also may cause adducts transplacentally in the testis.

Strain-specific induction of murine lung tumors following in utero exposure to 3-methylcholanthrene.

Fetal mice are more sensitive to chemical carcinogens than are adults. We previously demonstrated that resistant offspring of a DBA/2 x (C57BL/6 x DBA2) backcross exhibited a high incidence of lung tumors 12-13 mo after transplacental exposure to 3-methylcholanthrene (MC). We compared the effects of in utero treatment with MC on lung tumor incidence in the offspring of intermediately susceptible BALB/c (C), resistant C57BL/6 (B6), and reciprocal crosses between these strains.

Coordinate inhibition of cytokine-mediated induction of ferritin H, manganese superoxide dismutase, and interleukin-6 by the adenovirus E1A oncogene.

Adenovirus E1A sensitizes cells to the cytotoxic action of tumor necrosis factor alpha (TNF-alpha). This effect has been attributed to direct blockade of NF-kappaB activation, as well as to increased activation of components of the apoptotic pathway and decreases in inhibitors of apoptosis. In this report we evaluated the mechanism by which E1A modulates the expression of the cytokine-inducible cytoprotective genes manganese superoxide dismutase (MnSOD), interleukin-6 (IL-6), and ferritin heavy chain (FH).

Genetic and epigenetic alterations in lung tumors from bitransgenic Ki-rasG12C expressing mice.

Mutations in Ki-ras occur in approximately 30-50% of patients with adenocarcinoma (AC) of the lung. We previously reported the development of a bitransgenic mouse model that expressed the human Ki-ras(G12C) allele in a lung-specific, tetracycline-inducible manner and gave rise to benign lung tumors. In the current study, these benign tumors, which represent relatively early lesions in neoplastic progression, were analyzed for molecular alterations secondary to mutant Ki-ras expression to determine the gene(s) that contribute to adenoma (AD) development.