Selective Reduction of Post-Selection CD8 Thymocyte Proliferation in IL-15Rα Deficient Mice

ABSTRACT The outcome of viral infections is dependent on the amount of tissue destruction caused either by direct lysis of infected cells and/or by immunopathology resulting from the immune response to the virus. We investigated whether induction of tolerance to only one viral protein could reduce immunopathology caused by nonlytic lymphocytic choriomeningitis virus (LCMV) in perforin-deficient hosts. Earlier studies had shown that LCMV infection results in aplastic anemia and death in most of these mice and that this is associated with bone marrow infiltration by antiviral cytotoxic T lymphocytes (CTL) that secrete inflammatory cytokines. We report here that perforin-deficient mice exhibit severe immunopathology in multiple organs that is characterized by infiltration of anti-LCMV CTL that secrete large amounts of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Importantly, this immunopathology is significantly reduced and long-term survival of LCMV infection is increased in perforin-deficient mice expressing LCMV nucleoprotein (NP) in the thymus (and therefore deleting most of their LCMV-NP CTL) compared to the situation in thymus nonexpressors. This is due to the selective reduction of NP-specific CTL responses and their inflammatory-cytokine (IFN-γ and TNF-α) secretion and to a lack of pathogenetically relevant compensatory responses to other viral proteins. Thus, “selective reduction” of the antiviral immune response to only one viral protein can significantly reduce inflammatory immunopathology and might be a therapeutic possibility for certain nonlytic infections.

Download Full-text

Selective reduction in microglia density and function in the white matter of colony-stimulating factor-1-deficient mice

Journal of Neuroscience Research ◽

10.1002/jnr.22096 ◽

2009 ◽

Vol 87 (12) ◽

pp. 2686-2695 ◽

Cited By ~ 30

Author(s):

Yoichi Kondo ◽

Ian D. Duncan

Keyword(s):

White Matter ◽

Selective Reduction ◽

Colony Stimulating Factor ◽

And Function ◽

Stimulating Factor ◽

Deficient Mice

Download Full-text

Hippocampal Network Hyperactivity After Selective Reduction of Tonic Inhibition in GABAA Receptor α5 Subunit–Deficient Mice

Journal of Neurophysiology ◽

10.1152/jn.01122.2005 ◽

2006 ◽

Vol 95 (5) ◽

pp. 2796-2807 ◽

Cited By ~ 134

Author(s):

Joseph Glykys ◽

Istvan Mody

Keyword(s):

Selective Reduction ◽

Tonic Inhibition ◽

Therapeutic Approaches ◽

Field Recordings ◽

Phasic Inhibition ◽

Pyramidal Layer ◽

Hippocampal Network ◽

Deficient Mice ◽

Selective Impairment

Functionally, γ-aminobutyric acid receptor (GABAR)–mediated inhibition can be classified as phasic (synaptic) and tonic (extrasynaptic). The GABARs underlying tonic inhibition assemble from subunits different from those responsible for phasic inhibition. We wanted to assess the excitability of hippocampal pyramidal cell (PC) networks following a selective impairment of tonic inhibition. This is difficult to accomplish by pharmacological means. Because the GABAR α5 subunits mostly mediate the tonic inhibition in CA1 and CA3 PCs, we quantified changes in tonic inhibition and examined network excitability in slices of adult gabra5−/− mice. In gabra5−/− CA1 and CA3 PCs tonic inhibitory currents were 60 and 53%, respectively, of those recorded in wild type (WT), with no alterations in phasic inhibition. The amount of tonic inhibition recorded in slices was significantly affected by the method of slice storage (interface or submerged chamber). Field recordings in gabra5−/− CA3 pyramidal layer showed an increased network excitability that was decreased by the GABAR agonist muscimol at a concentration that restored the tonic inhibition of gabra5−/− PCs to the WT level without altering phasic inhibition. Through a battery of pharmacological experiments, we have identified δ subunit–containing GABARs as the mediators of the residual tonic inhibition in gabra5−/− PCs. Our study is consistent with an important role of tonic inhibition in the control of hippocampal network excitability and highlights selective enhancers of tonic inhibition as promising therapeutic approaches for diseases involving network hyperexcitability.

Download Full-text

ICAM-2 mediates neutrophil transmigration in vivo: evidence for stimulus specificity and a role in PECAM-1–independent transmigration

Blood ◽

10.1182/blood-2005-11-4683 ◽

2006 ◽

Vol 107 (12) ◽

pp. 4721-4727 ◽

Cited By ~ 77

Author(s):

Miao-Tzu Huang ◽

Karen Y. Larbi ◽

Christoph Scheiermann ◽

Abigail Woodfin ◽

Nicole Gerwin ◽

...

Keyword(s):

Direct Evidence ◽

Leukocyte Adhesion ◽

Neutrophil Migration ◽

Selective Reduction ◽

Leukocyte Transmigration ◽

Tnf Α ◽

Peritonitis Model ◽

Deficient Mice

AbstractICAM-2 has been implicated in leukocyte transmigration in vitro, but there is little in vivo evidence to support this. To address this, neutrophil migration was investigated in ICAM-2–deficient mice (KO) and in wild-type (WT) mice treated with an anti–ICAM-2 blocking monoclonal antibody (mAb) (3C4). In a peritonitis model, IL-1β–induced accumulation of neutrophils was significantly reduced in mice treated with 3C4 (51% inhibition) and in KO mice (41% inhibition). In contrast, TNF-α– or thioglycolate-induced responses were not suppressed in KO mice. Analysis of IL-1β–induced leukocyte responses in cremasteric venules of KO animals by intravital microscopy indicated a defect in transmigration (44% inhibition) but not rolling or adhesion. As found before, TNF-α–induced leukocyte transmigration was unaltered in the KO mice. WT mice treated with the anti–ICAM-2 mAb also exhibited a selective reduction in leukocyte transmigration in response to IL-1β while an anti–ICAM-1 mAb inhibited both leukocyte adhesion and transmigration. Interestingly, mAb 3C4 significantly suppressed IL-1β–induced neutrophil transmigration in PE-CAM-1 KO animals in the peritonitis model but not in the cremaster muscle. The findings provide direct evidence for the involvement of ICAM-2 in neutrophil transmigration in vivo, though this role appears to be stimulus specific. Furthermore, ICAM-2 appears capable of mediating PECAM-1–independent leukocyte transmigration.

Download Full-text

Comparison of localization of metallothionein in tissues of metallothionein-deficient mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100141585 ◽

1995 ◽

Vol 53 ◽

pp. 1042-1043

Author(s):

H. Nishimura ◽

R Nishimura ◽

D.L. Adelson ◽

A.E. Michaelska ◽

K.H.A. Choo ◽

...

Keyword(s):

Metal Binding ◽

Immunohistochemical Staining ◽

Squamous Epithelium ◽

Rabbit Antiserum ◽

Slight Modification ◽

Positive Control ◽

Heavy Metal Binding ◽

Critical Organ ◽

Metal Binding Protein ◽

Deficient Mice

Metallothionein (MT), a cysteine-rich heavy metal binding protein, has several isoforms designated from I to IV. Its major isoforms, I and II, can be induced by heavy metals like cadmium (Cd) and, are present in various organs of man and animals. Rodent testes are a critical organ to Cd and it is still a controversial matter whether MT exists in the testis although it is clear that MT is not induced by Cd in this tissue. MT-IV mRNA was found to localize within tongue squamous epithelium. Whether MT-III is present mainly glial cells or neurons has become a debatable topic. In the present study, we have utilized MT-I and II gene targeted mice and compared MT localization in various tissues from both MT-deficient mice and C57Black/6J mice (C57BL) which were used as an MT-positive control. For MT immunostaining, we have used rabbit antiserum against rat MT-I known to cross-react with mammalian MT-I and II and human MT-III. Immunohistochemical staining was conducted by the method described in the previous paper with a slight modification after the tissues were fixed in HistoChoice and embedded in paraffin.

Download Full-text