No abstract

Acute kidney injury (AKI) following ischemia–reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking kynurenine 3-monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active kynurenine metabolites 3-hydroxykynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.

No abstract

T cell protective immunity is associated with multifunctional memory cells that produce several different cytokines. Currently, our understanding of when and how these cells are generated is limited. We have used an influenza virus mouse infection model to investigate whether the cytokine profile of memory T cells is reflective of primary responding cells or skewed toward a distinct profile. We found that, in comparison to primary cells, memory T cells tended to make multiple cytokines simultaneously. Analysis of the timings of release of cytokine by influenza virus‐specific T cells, demonstrated that primary responding CD4 T cells from lymphoid organs were unable to produce a sustained cytokine response. In contrast CD8 T cells, memory CD4 T cells, and primary responding CD4 T cells from the lung produced a sustained cytokine response throughout the restimulation period. Moreover, memory CD4 T cells were more resistant than primary responding CD4 T cells to inhibitors that suppress T cell receptor signaling. Together, these data suggest that memory CD4 T cells display superior cytokine responses compared to primary responding cells. These data are key to our ability to identify the cues that drive the generation of protective memory CD4 T cells following infection.

No abstract

This paper examines the efficacy of 10% lambdacyhalothrin-impregnated plastic tags and a deltamethrin pour-on preparation in protecting red grouse chicks from parasitism by ticks and subsequent infection with the louping-ill virus. In 1995, ten red grouse hens (Lagopus Zugopus scoticus) in a free-living population in north-east Scotland were fitted with lambdacyhalothrin-impregnated plastic tags, glued to radio transmitters. Chicks of more than 10 days of age from a further ten untreated radio-collared hens were caught and fitted with individual tags to the ptagium. Both treatments significantly reduced tick burdens in the short term. The number of larvae and nymphs on chicks up to 45 days was less under both treatments than on control chicks and tagged chicks had fewer nymphs than chicks from treated hens. Nevertheless, treatments did not reduce viral infection rates nor increase survival to 10 weeks, possibly explained by incomplete treatment of tagged broods and/or direct or indirect mortality due to tags. In 1996 chicks in ten broods from hens with radio transmitters were individually treated at 14 days of age at a rate of lmgkg of chick with a deltamethrin pour-on preparation. This preparation significantly reduced the number of larvae and nymphs on grouse chicks 7-10 days after application below the number on untreated controls. At 20 days from application, however, only larval numbers were lower on treated chicks. Nevertheless louping-ill virus infection prevalences were significantly reduced at 35 days of age and survival of chicks to 10 weeks increased.

Reinforcing defective tolerogenic processes slows progression of autoimmune (AI) diseases and has potential to promote drug-free disease remission. Previously, we reported that DNA nanoparticles (DNPs) and cyclic dinucleotides (CDNs) slow progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, by activating the Stimulator of Interferon Genes (STING) signaling adaptor to stimulate interferon type 1 (IFN-I) production, which induced dendritic cells to express indoleamine 2,3 dioxygenase (IDO) and acquire immune regulatory phenotypes. Here, we show that therapeutic responses to DNPs depend on DNA sensing via cyclic GAMP synthase (cGAS) and interactions between Programmed Death-1 (PD-1) and PD-1 ligands. To investigate how increased tryptophan (Trp) metabolism by IDO promotes therapeutic responses mice were co-treated at EAE onset with DNPs and drugs that inhibit kynurenine aminotransferase-II (KatII) or 3-hydroxyanthranilic acid dioxygenase (HAAO) activity downstream of IDO in the kynurenine (Kyn) pathway. DNP and KatII or HAAO inhibitor co-treatments suppressed EAE progression more effectively than DNPs, while KatII inhibition had no significant therapeutic benefit and HAAO inhibition attenuated but did not prevent EAE progression. Moreover, therapeutic responses to co-treatments were durable as EAE progression did not resume after co-treatment. Thus, using STING agonists to boost IDO activity and manipulating the Kyn pathway downstream of IDO is an effective strategy to enhance tolerogenic responses that overcome autoimmunity to suppress EAE progression.

The opisthosomal integument and associated secretory organs of Rhipicephalus appendiculatus Neumann larvae, nymphs, females and males, both unfed and fed were examined by light and electron microscopy. Type 1 dermal glands were found on the alloscutum and scutum of all ticks. They were undeveloped in unfed ticks and reached full development in engorging ticks. They produced secretory granules from 2 glandular cells but without accumulation of a reservoir of secreted material. Type 2 dermal glands were found in all ticks, with pores on the alloscutum, edge of scutum, and on anal plates. These glands produced secretion during feeding and accumulated large reservoirs of secreted material that were present in engorging, recently detached and questing ticks. Spiracular glands were found in all ticks below the spiracle plate. They produced small amounts of secretion and had pores to the exterior by way of spiracle goblets. No obvious cycle of secretory activity was recorded. Foveal glands were present and produced secretions in nymphs, females, and males. They were largest in females with an accumulation of secretory vesicles in feeding ticks. The potential function of these glands is discussed in the context of the chemical ecology of this tick.