Hepatic injury due to cold storage followed by reperfusion remains a major cause of morbidity and mortality after orthotopic liver transplantation (OLT). CD4 T cell TIM-1 signaling co-stimulates a variety of immune responses in allograft recipients. This study analyzes mechanisms by which TIM-1 affects liver ischemia-reperfusion injury (IRI) in a murine model of prolonged cold storage followed by OLT. Livers from C57BL/6 mice, preserved at 4°C in UW solution for 20h, were transplanted to syngeneic recipients. There was an early (1h) increased accumulation of TIM-1+ activated CD4 T cells in the ischemic OLTs. Disruption of TIM-1 signaling with a blocking mAb (RMT1-10) ameliorated liver damage, evidenced by reduced sALT levels and well-preserved architecture. Unlike in controls, TIM-1 blockade diminished OLT expression of Tbet/IFN-γ, but amplified IL-4/IL-10/IL-22; abolished neutrophil and macrophage infiltration/activation; and inhibited NF-κB while enhancing Bcl-2/Bcl-xl. Although adoptive transfer of CD4 T cells triggered liver damage in otherwise IR-resistant RAG−/− mice, adjunctive TIM-1 blockade reduced Tbet transcription, and abolished macrophage activation, restoring homeostasis in IR-stressed livers. Further, transfer of TIM-1HiCD4+, but not TIM-1LoCD4+ T cells, recreated liver IRI in RAG−/− mice. Thus, TIM-1 expressing CD4 T cells are required in the mechanism of innate immune-mediated hepatic IRI in OLTs.
Water quality benchmarks
for fecal indicator bacteria (FIB) are
often exceeded in many urban streams in southern California. Possible
sources of elevated stream FIB concentrations within urban areas include
sanitary sewer exfiltration, sanitary sewer overflows (SSOs), illegal
discharges, and human or animal fecal material on the ground surface.
Teasing apart the different sources remains a challenge, especially
when untreated wastewater and runoff from open defecation sites both
contain human fecal material. To distinguish the various sources of
microbial contamination in an urban stream, temporal trends in biological
and chemical markers of anthropogenic contamination were evaluated
in the San Diego River and its tributaries during storm events in
two consecutive hydrologic years. Temporal trends in FIB, HF183, pepper
mild mottle virus (PMMoV), caffeine, sucralose, chloride, bromide,
specific ultraviolet absorbance, and fluorescence index indicated
that untreated wastewater flushed from the vadose zone was the main
source of microbial pollution to the San Diego River, while open defecation
near homeless encampments in the river margins was not a major source.
We demonstrated that the combined use of caffeine/sucralose ratios
and HF183 and PMMoV holds promise for identifying sewage inputs to
surface waters. These findings highlight the need for maintenance
and repair of aging sewer infrastructure.
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