134 research outputs found
Function and fate of certain white blood cells in exper imentally-induced polyarthritis
No full textA/Pr Graham Mayrhofer$AUD 292,927.15NHMRC Project GrantsStandard Project Gran
A new concept in mucosal defence
No full textA/Pr Graham Mayrhofer$AUD 127,860.10NHMRC Project GrantsStandard Project Gran
Mechanisms of accumulation of t lymphocytes in normal a nd inflamed joints
No full textA/Pr Graham Mayrhofer$AUD 191,863.21NHMRC Project GrantsStandard Project Gran
The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro
No full textCopyright © 2008 Elsevier Inc. All rights reserved.Dasatinib (BMS-354825) is a Src/ABL tyrosine kinase inhibitor currently approved for the treatment of chronic myeloid leukemia. Dasatinib has increased potency against ABL compared to the current therapy imatinib, and is effective in many cases where disease is resistant to imatinib. Dasatinib also inhibits many Src-family tyrosine kinases. We have demonstrated in this study that dasatinib is able to block the function of normal human T-lymphocytes in vitro at clinically relevant concentrations. T-cell functions including proliferation, activation and cytokine production were all uniformly inhibited in the presence of dasatinib. We also demonstrated inhibition of TCR signalling through Src-family kinase LCK, and predicted that inhibition of LCK and other kinases involved in T-cell signalling by dasatinib is responsible for the suppression of T-cell function. These findings raise the concern about potential T-cell inhibition in patients taking dasatinib, and suggest a possible application for the treatment of T-cell mediated immune disorders.Stephen Blake, Timothy P. Hughes, Graham Mayrhofer and A. Bruce Lyon
Impaired clearance of herpes simplex virus type 1 from mice lacking CD1d or NKT cells expressing the semivariant Valpha14-Jalpha 281 TCR
No full textCopyright © 2003 by The American Association of ImmunologistsAg-presenting molecule CD1 and CD1-restricted NKT cells are known to contribute to defense against a range of infectious pathogens, including some viruses. CD1-restricted NKT cells, a distinct subpopulation of T cells, have striking and rapid effector functions that contribute to host defense, including rapid production of IFN-y and IL-4, and activation of NK cells. Consideration of the important contributions of innate and adaptive immunity to clearance of HSV prompted us to investigate the role of CD1 and of NKT cells expressing the Vα14-Jα281 TCR in the pathogenesis of HSV infection. To address this issue, we compared infection in wild-type mice with that in CD1 gene knockout (GKO) and Jα281 GKO mice. In this study, we report impaired clearance of virus and viral Ags, and more florid acute infection in mice lacking CD1 (and by inference, CD1-restricted T cells), in comparison with parental C57BL6 mice. In Jα281 GKO mice there was also impairment of virus clearance, resembling that seen in CD1 GKO mice. These results imply roles for the Vα14-Jα281 subset of NKT cells and for CD1d in control of HSV infection.Branka Grubor-Bauk, Anthony Simmons, Graham Mayrhofer and Peter G. Spec
Adoptive transfer of peripheral immune cells potentiates allodynia in a graded chronic constriction injury model of neuropathic pain
No full textRecent evidence demonstrates that peripheral immune cells contribute to the nociceptive hypersensitivity associated with neuropathic pain by infiltrating the central nervous system (CNS). We have recently developed a rat model of graded chronic constriction injury (CCI) by varying the exposure of the sciatic nerve and control non-nerve tissue to surgical placement of chromic gut. We demonstrate that splenocytes can contribute significantly to CCI-induced allodynia, as adoptive transfer of these cells from high pain donors to low pain recipients potentiates allodynia (P<0.001). The phenomenon was replicated with peripheral blood mononuclear cells (P<0.001). Adoptive transfer of allodynia was not achieved in sham recipients, indicating that peripheral immune cells are only capable of potentiating existing allodynia, rather than establishing allodynia. As adoptively transferred cells were found by flow cytometry to migrate to the spleen (P<0.05) and potentiation of allodynia was prevented in splenectomised low pain recipients, adoptive transfer of high pain splenocytes may induce the migration of host-derived immune cells from the spleen to the CNS as observed by flow cytometry (P<0.05). Importantly, intrathecal transfer of CD45(+) cells prepared from spinal cords of high pain donors into low pain recipients led to potentiated allodynia (P<0.001), confirming that infiltrating immune cells are not passive bystanders, but actively contribute to nociceptive hypersensitivity in the lumbar spinal cord.Peter M. Grace, Mark R. Hutchinson, Alan Bishop, Andrew A. Somogyi, Graham Mayrhofer, Paul E. Rola
Genetic diversity within the morphological species Giardia intestinalis and its relationship to host origin
No full textA genetic analysis of Giardia intestinalis, a parasitic protozoan species that is ubiquitous in mammals worldwide, was undertaken using organisms derived from a variety of mammalian hosts in different geographical locations. The test panel of 53 Giardia isolates comprised 48 samples of G. intestinalis, including representatives of all known genetic subgroups, plus an isolate of G. ardeae and four isolates of G. muris. The isolates were compared by allozymic analysis of electrophoretic data obtained for 21 cytosolic enzymes, representing 23 gene loci. Neighbour Joining analysis of the allelic profiles supported the monophyly of G. intestinalis but showed that the species encompasses a rich population substructure. Seven major clusters were evident within G. intestinalis, corresponding to lineages designated previously as genetic assemblages A–G. Some genotypes, e.g. those defining assemblage A, are found in divergent host species and may be zoonotic. However other genotypes, e.g. those defining assemblages C–G, appear to be confined to particular hosts or host groups. The findings reinforce other evidence that G. intestinalis, which was defined on the basis of morphological criteria only, is a species complex.Paul T. Monis; Ross H. Andrews; Graham Mayrhofer; and Peter L. Eyhttp://www.elsevier.com/wps/find/journaldescription.cws_home/621317/description#descriptio
Interleukin-5 transgenic mice show enhanced resistance to primary infections with Nippostrongylus brasiliensis but not primary infections with Toxacara caris
No full textIn this study, interleukin-5 (IL-5) transgenic mice with lifelong eosinophilia were assessed for resistance to primary infections with two tissue-invading nematodes, Nippostrongylus brasiliensisand Toxocara canis. Relative to nontransgenic littermates, three lines of IL-5 transgenic mice with varying degrees of eosinophilia all displayed enhanced resistance to N. brasiliensis. Although the timing of final worm expulsion was similar in transgenic and nontransgenic hosts, intestinal worms in transgenic mice were fewer in number throughout infection, failed to increase in size over the course of the infection, and were much less fecund. In contrast, T. canis larvae were recovered in similar numbers from tissues of transgenic mice with “low” or “high” eosinophilia and from nontransgenic mice. These results and other data suggest that eosinophils can contribute to host resistance to some parasite species. Parasite transit time through the host may correlate with relative sensitivity to eosinophils.Lindsay A. Dent, Christine M. Daly, Graham Mayrhofer, Trudy Zimmerman, Ann Hallett, Leon P. Bignold, Jenette Creaney, and Jim C. Parson
Uterine epithelial cells synthesize granulocyte-macrophage colony-stimulating factor and interleukin-6 in pregnant and nonpregnant mice
No full textCytokine secretion by endometrial cells from estrous and mated mice was measured using specific bioassays. The granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) contents of uterine intraluminal fluid were elevated greater than 20-fold and 250-fold respectively following mating, and both cytokines were synthesized in abundance in vitro by uterine cells harvested at estrus and on Day 1 of pregnancy. Synthesis was not impaired in genetically lymphocyte-deficient nude, SCID, or beige mice. To determine the cellular origin of the cytokines, a panning technique employing monoclonal antibodies against a range of leukocyte and other lineage markers was used to isolate uterine cell subsets in vitro. These experiments identified glandular and/or luminal epithelial cells as the major source of GM-CSF and IL-6 in estrous and pregnant uteri. Stromal fibroblasts also synthesized IL-6, as did macrophages in mated mice. Epithelial cells harvested from midgestation uteri secreted GM-CSF and IL-6 in quantities similar to those of cells from estrous and mated mice. Bioactivities of both cytokines derived from epithelial cells were neutralized by specific antibodies, and size-exclusion chromatography of conditioned media from uterine cells revealed peaks of GM-CSF and IL-6 bioactivity with M(r) 23,000 and 23,000-26,000, respectively. Bioassay of luminal fluids and culture supernatants were negative for the cytokines interleukin-1, interleukin-2, interleukin-3, and tumor necrosis factor-alpha. These studies identify murine uterine epithelium as a potent source of the cytokines GM-CSF and IL-6, which we postulate have potentially important functions in pregnancy through actions on target cells in both the uterus and the conceptus.Sarah A. Robertson, Graham Mayrhofer, and Robert F. Seamar
Trapping and immobilization of Nippostrongylus brasiliensis larvae at the site of inoculation in primary infections of interleukin-5 transgenic mice
No full textInterleukin-5 (IL-5) transgenic mice are highly resistant to primary infections with the intestinal nematode Nippostrongylus brasiliensis; few parasites are found in the intestines of infected animals, and egg production is minimal. While adult worms may be damaged in the intestine, larval migration, development, and viability may also be impaired in other tissues. This study addresses the migration of N. brasiliensis larvae through the skin and lungs and associated cellular responses in primary infections of IL-5 transgenic mice. Although some larvae may have been trapped and killed in the lungs of IL-5 transgenic mice, most apparently failed to reach this site. Two or more hours after infection of IL-5 transgenic mice, eosinophils were a major component of the cellular infiltrate at the subcutaneous site of injection, and localized eosinophil degranulation was extensive. Seventy-five to ninety-five percent of the larvae injected into subcutaneous air pouches in IL-5 transgenic mice were retained there for at least 24 h. In contrast, in nontransgenic mice, less than 20% of larvae could be recovered from the skin 2 or more h postinjection, and eosinophil activity was modest at all times. The data strongly suggest that eosinophils can restrict the movement of N. brasiliensis larvae in the first few hours of a primary infection and that this has profound effects on later stages of parasite development. Preexisting eosinophilia, due either to allergy or to infection with tissue-invasive helminth species, may therefore confer some degree of immediate and nonspecific resistance in primary infections with parasitic worms.Christine M. Daly, Graham Mayrhofer, and Lindsay A. Den
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