Bronchoalveolar lavage fluid from mice with experimentally induced allergic pulmonary inflammation contains a novel 9.4 kDa cysteine‐rich secreted protein, FIZZ1 (found in inflammatory zone). Murine (m) FIZZ1 is the founding member of a new gene family including two other murine genes expressed, respectively, in intestinal crypt epithelium and white adipose tissue, and two related human genes. In control mice, FIZZ1 mRNA and protein expression occur at low levels in a subset of bronchial epithelial cells and in non‐neuronal cells adjacent to neurovascular bundles in the peribronchial stroma, and in the wall of the large and small bowel. During allergic pulmonary inflammation, mFIZZ1 expression markedly increases in hypertrophic, hyperplastic bronchial epithelium and appears in type II alveolar pneumocytes. In vitro, recombinant mFIZZ1 inhibits the nerve growth factor (NGF)‐mediated survival of rat embryonic day 14 dorsal root ganglion (DRG) neurons and NGF‐induced CGRP gene expression in adult rat DRG neurons. In vivo, FIZZ1 may modulate the function of neurons innervating the bronchial tree, thereby altering the local tissue response to allergic pulmonary inflammation.
BLys , a key cytokine that sustains B cell maturation and tolerance, binds three receptors: BR3, BCMA, and TACI. Results from knockout mice implicate a major functional role for BR3 and a redundant one for BCMA in B cell function. TACI's role is controversial based on defects in TI antibody responses accompanied by B cell hyperplasia in knockout mice. We have presently characterized a precise role for TACI in vivo. TACI(-/-) mice develop fatal autoimmune glomerulonephritis, proteinurea, and elevated levels of circulating autoantibodies. Treatment of B cells with TACI agonistic antibodies inhibits proliferation in vitro and activation of a chimeric receptor containing the TACI intracellular domain induces apoptosis. These results demonstrate the critical requirement for TACI in regulating B cell homeostasis.
Background & Aims
Direct-acting anti-viral agents suppress hepatitis B virus (HBV) load but must be given
lifelong. Stimulation of the innate immune system could increase its ability to control the virus
and have long lasting effects, after a finite regimen. We investigated the effects of immune
activation with GS-9620—a potent and selective orally active small molecule agonist of
Toll-Like Receptor (TLR)7—in chimpanzees with chronic HBV infection.
Methods
GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks
at 1 mg/kg and, after a 1 week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and
liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters:
interferon (IFN)-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural
killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored
to determine the safety and tolerability of GS-9620.
Results
Short-term oral administration of GS-9620 provided long-term suppression of serum and
liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of
the end of GS-9620 administration; reductions of greater than 1 log persisted for months. Serum
levels of HB surface antigen and HB e antigen, and numbers of HBV antigen-positive hepatocytes, were
reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of
IFN-α and other cytokines and chemokines, and activated ISGs, natural killer cells, and
lymphocyte subsets.
Conclusions
The small molecule GS-9620 activates TLR-7 signaling in immune cells of chimpanzees to
induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients
with chronic HBV infection.
The tumor necrosis factor (TNF)-related ligand B lymphocyte stimulator (BLyS) binds two TNF receptor family members, transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI) and B cell maturation molecule (BCMA). Mice that are transgenic for BLyS show B cell accumulation, activation and autoimmune lupus-like nephritis. The existence of at least two distinct BLyS receptors raises the question of the relative contribution of each to B cell functions. We therefore generated mice that were deficient in TACI. TACI-/- mice showed increased B cell accumulation and marked splenomegaly. Isolated TACI-/- B cells hyperproliferated and produced increased amounts of immunoglobulins in vitro. In vivo antigen challenge resulted in enhanced antigen-specific antibody production. Thus, TACI may play an unexpected inhibitory role in B cell activation that helps maintain immunological homeostasis.
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