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P Toby H Coates

Publications and source records attributed to P Toby H Coates.

12 recordsLinked to original sources
PubMed2006

Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients.

BACKGROUND: Dendritic cell (DC) subsets play critical roles in regulation of innate and adaptive immune responses. These important antigen-presenting cells have not been extensively analyzed in chronic renal failure (CRF), during dialysis, or before and after renal transplantation. METHODS: The incidence of circulating precursor (pre)-DC subsets relative to total peripheral blood mononuclear cells was analyzed in healthy controls, haemodialysis patients, peritoneal dialysis patients, CRF patients, and renal transplant (RT) recipients. DC subsets were identified and characterized phenotypically by multicolour flow cytometric analysis and purified by immunomagnetic bead isolation respectively. Cytokine production and circulating DC mobilizing cytokines were determined by ELISA. RESULTS: The incidence of circulating prePDC was reduced in all patients, but the incidence of circulating preMDC was comparable in RT and dialysis patients compared to healthy controls. CRF patients exhibited the lowest incidence of circulating preMDC and prePDC. Immunomagnetic bead-isolated preMDC and prePDC from haemodialysis patients were functionally impaired (reduced expression of surface costimulatory molecules and interleukin-12p70 production following bacterial lipopolysaccharide stimulation, and reduced interferon-alpha production following herpes simplex virus stimulation respectively, compared to healthy controls and RT recipients. Glomerular filtration rate correlated significantly with the incidence of circulating preMDC, but not prePDC. CONCLUSIONS: Deficiencies in the incidence and function of precursor DC can be reversed with successful renal transplantation achieving normal renal function. However, the finding of reduced incidence of circulating prePDC in the peripheral blood in RT recipients may be of significance in the pathogenesis of infections and malignancies.

Adult↗
PubMed2006

Neglected nephropathy.

BACKGROUND: Diabetic nephropathy is a significant contributor to the morbidity, mortality and health care cost among patients with diabetes. With increasing understanding of this problem, the natural progression of diabetic nephropathy can potentially be changed. OBJECTIVE: This article examines the natural history of diabetic nephropathy and provides guidelines on detection, management and future treatment possibilities of this complication. DISCUSSION: Prevention and slowing progression are the most important aspects of the management of diabetic nephropathy. This involves monitoring renal function and risk factors for renal damage and early active intervention. The angiotensin converting enzyme inhibitors and receptor antagonists are important components of therapy, both for controlling hypertension and for slowing the progression of micro and macroalbuminuria. When microalbuminuria occurs, intensive intervention on a range of risk factors can halve the number of those suffering a cardiovascular event or progressing to macroalbuminuria. When renal insufficiency occurs, particularly when creatinine clearance is >30 mL/minute, referral to an nephrologist should be considered.

Australia↗
PubMed2005

Cross-reactivity of anti-human chemokine receptor and anti-TNF family antibodies with common marmoset (Callithrix jacchus) leukocytes.

The common marmoset (Callithrix jacchus) is a New World primate species frequently employed for immunological models of human disease. We used flow cytometry to screen a panel of new anti-human antibodies from the HLDA8 workshop to establish cross-reactivity with marmoset peripheral blood mononuclear cells. Seventy-seven antibodies were screened of which nine antibodies showed binding. Cross-reactivity of anti-human monoclonal antibodies with CC and CXC chemokine receptors CCR3, CCR6, CCR7, and CCR8 was demonstrated on untreated marmoset mononuclear cells. Stimulation of marmoset mononuclear cells with ConA and/or PMA-ionomycin resulted in an up-regulated expression of CXCR1, CXCR3, and CXCR4. The expression of TNF-family related molecules TACI and APRIL on marmoset mononuclear cells was also identified. These studies extend the range of cross-reactive antibodies to now include anti-chemokine and anti-TNF family antibodies for this important pre-clinical model species and should provide useful tools for investigation of immunological processes in marmoset monkey models.

Animals↗
PubMed2005

The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo.

The pro-drug FTY720 is undergoing phase III clinical trials for prevention of allograft rejection. After phosphorylation, FTY720 targets the G protein-coupled-sphingosine-1-phosphate receptor 1 (S1PR1) on lymphocytes, thereby inhibiting their egress from lymphoid organs and their recirculation to inflammatory sites. Potential effects on dendritic cell (DC) trafficking have not been evaluated. Here, we demonstrate the expression of all five S1PR subtypes (S1PR1-5) by murine DCs. Administration of FTY720 to C57BL/10 mice markedly reduced circulating T and B lymphocytes within 24 h, but not blood-borne DCs, which were enhanced significantly for up to 96 h, while DCs in lymph nodes and spleen were reduced. Numbers of adoptively transferred, fluorochrome-labeled syngeneic or allogeneic DCs in blood were increased significantly in FTY720-treated animals, while donor-derived DCs and allostimulatory activity for host naïve T cells within the spleen were reduced. Administration of the selective S1PR1 agonist SEW2871 significantly enhanced circulating DC numbers. Flow analysis revealed that CD11b, CD31/PECAM-1, CD54/ICAM-1 and CCR7 expression on blood-borne DCs was downregulated following FTY720 administration. Transendothelial migration of FTY720-P-treated immature DCs to the CCR7 ligand CCL19 was reduced. These novel data suggest that modulation of DC trafficking by FTY720 may contribute to its immunosuppressive effects.

Animals↗
PubMed2004

In vivo-mobilized kidney dendritic cells are functionally immature, subvert alloreactive T-cell responses, and prolong organ allograft survival.

BACKGROUND: Migratory antigen-presenting cells resident in kidneys may have tolerogenic potential. Difficulties inherent in their isolation have limited their characterization. The authors examined the phenotype and function of murine kidney dendritic cells (DC) mobilized in vivo by systemic administration of fms-like tyrosine 3 kinase ligand (Flt3L). METHODS: Monoclonal antibody staining was used to characterize DC subsets in situ, immediately after their isolation, and after lipopolysaccharide stimulation. Cytokine and CC chemokine receptor (CCR) gene expression was analyzed by RNase protection assay. Mixed leukocyte reactions were performed to assess DC allostimulatory ability and also the function of putative T-regulatory cells. In vivo DC trafficking was monitored by fluorescence imaging of dye-labeled cells and the influence of renal DC on vascularized heart allograft survival was determined. RESULTS: Flt3L induced a marked increase both in CD11cCD8alpha and in CD11cCD8alpha DC within the renal cortex and medulla. Rarer, CD11cB220 (precursor plasmacytoid) DC were also detected. Bulk freshly isolated DC exhibited no interleukin (IL)-12p35 mRNA, low surface co-stimulatory molecule expression, and CCR transcripts, consistent with immaturity. They elicited only weak allogeneic T-cell proliferative responses, and repeated stimulation induced CD4CD25 IL-10 T cells. In vivo, the freshly isolated DC failed to prime T cells of naive allogeneic hosts for anti-donor cytotoxic T-cell responses. When infused systemically, 1 week before organ transplantation, they prolonged graft survival without immunosuppressive therapy. CONCLUSIONS: Hematopoietin-mobilized renal DC are functionally immature and exhibit tolerogenic potential. Mobilization of DC within kidneys is likely to affect their antigen-handling capacity, immunogenicity, and tolerogenic ability.

Animals↗
PubMed2004

CCR and CC chemokine expression in relation to Flt3 ligand-induced renal dendritic cell mobilization.

BACKGROUND: We investigated the expression and function of CC chemokine receptors (CCR) on highly-purified kidney and blood dendritic cells isolated from mice in which dendritic cells were mobilized with fms-like tyrosine 3 kinase ligand (Flt3L). METHODS: CCR and CC chemokine expression were determined by RNase protection assay or flow cytometry, and dendritic cell migratory responses assayed using Transwell chambers. Chemokine production in renal tissue was detected by immunofluorescence staining. Trafficking of fluorochrome-labeled dendritic cells was monitored in vivo. RESULTS: Freshly-isolated renal dendritic cells expressed mRNA for CCR1, 2, 5, and 7 and CCR1 and 5 protein. They did not migrate to inducible chemokines--CCL3 [macrophage inflammatory protein (MIP)-1alpha], CCL5 [regulated upon activation, normal T cell expressed and secreted (RANTES)], or CCL20 (MIP-3alpha). Following lipopolysaccharide (LPS) stimulation, the dendritic cells down-regulated CCR1, 2, and 5 expression, up-regulated or sustained signals for CCR7, and migrated to the constitutively expressed ligands CCL19 (MIP-3beta) and CCL21 (secondary lymphoid tissue chemokine). Normal kidneys expressed weak message for CCL2, 3, and 4, with stronger signals for CCL5 and 19. Intrarenal CCL5 production was enhanced by Flt3L administration, in association with marked increases in interstitial CD45+ mononuclear cells. Mobilized blood dendritic cells migrated to CCR2 and CCR5 ligands and trafficked to renal intertubular sites following adoptive (intravenous) transfer. Their migration to the CCR5 ligand MIP-1beta (CCL4) and homing to kidneys of Flt3L-treated recipients were inhibited by CCR5 antagonism. CONCLUSION: These data implicate specific CCR and their ligands in regulation of the dendritic cell constituency of the kidney. CCR5 antagonism inhibits their directed migration and intrarenal accumulation.

Animals↗
PubMed2003

Dendritic cell subsets in blood and lymphoid tissue of rhesus monkeys and their mobilization with Flt3 ligand.

We provide phenotypic and functional evidence of premonocytoid dendritic cells (DCs) and preplasmacytoid DCs in blood and of corresponding DC subsets in secondary lymphoid tissue of rhesus monkeys. Subsets were identified and sorted by 4-color flow cytometry using antihuman monoclonal antibodies cross-reactive with rhesus monkey. To mobilize pre-DC subsets, fms-like tyrosine 3 kinase ligand (Flt3L; 100 microg/kg subcutaneously) was administered for 10 days. Presumptive pre-DC subsets were identified within the lineage- (Lin-) major histocompatibility complex (MHC) class II+ fraction of blood mononuclear cells. Premonocytoid DCs were CD11c+CD123- (interleukin-3Ralpha- [IL-3Ralpha-]). Preplasmacytoid DCs were characterized as CD11c-CD123++ Flt3L increased the CD11c+ pre-DC (7-fold) and CD123++ pre-DC subsets (3-fold) in blood. The freshly isolated CD11c+ pre-DC subset induced modest proliferation of naive allogeneic T cells. After overnight culture with granulocyte macro-phage-colony-stimulating factor (GMCSF) and CD40L, both subsets up-regulated surface costimulatory molecules, and CD11c+ pre-DCs became potent allostimulators. Freshly isolated CD123++ pre-DCs showed typical plasmacytoid morphology and, when cultured with IL-3 and CD40L for 72 hours, developed mature DC morphology. Following stimulation with CD40L, CD11c+ pre-DCs secreted increased levels of IL-12p40. Importantly, herpes simplex virus-stimulated CD123++ pre-DCs, but not CD11c+ pre-DCs, secreted interferon-alpha (IFN-alpha). Corresponding DC subsets were identified by flow analysis and immunohistochemistry in lymph nodes wherein both populations were increased 2- to 3-fold by Flt3L administration. CD123+ pre-DCs produced IFN-alpha in response to in vivo viral infection. Thus, rhesus monkeys exhibit 2 distinct DC precursor populations that closely resemble those of humans. Both are mobilized into blood and lymphoid tissue by Flt3L, offering potential for their further characterization and possible therapeutic application.

Animals↗
PubMed2003

Pharmacologic, biologic, and genetic engineering approaches to potentiation of donor-derived dendritic cell tolerogenicity.

There are various approaches to the enhancement of dendritic cell (DC) tolerogenicity for the promotion of cell or organ allograft survival. Both pharmacologic and biologic agents, including several commonly used immunosuppressive drugs, and specific anti-inflammatory cytokines inhibit DC maturation, whereas co-stimulation-blocking agents can also promote the induction of antigen-specific T-cell unresponsiveness by DC. Delivery of genes encoding molecules that subvert T-cell responses by various mechanisms, and targeting of DC migration by selective manipulation of chemokine and chemokine receptor expression, represent additional promising strategies. In this short review, the authors consider those approaches that have been used to promote the tolerogenicity of donor-derived DC in experimental models. Whereas most work to date has focused on myeloid DC, manipulation of other DC subsets may also offer potential for improving the outcome of transplantation and enhancing tolerance induction.

Animals↗
PubMed2002

Manipulation of dendritic cells as an approach to improved outcomes in transplantation.

At the time of organ transplantation, a variety of non-parenchymal cells are transplanted simultaneously with the allograft. Recognition of the importance of these cells as potential immunostimulatory cells lead to the concept of 'passenger leukocytes' as the principal instigators of rejection. Passenger leukocytes include interstitial dendritic cells (DCs) and blood-derived monocytes/macrophages. As investigators have discovered the significance of DCs in influencing graft outcome, so have they begun to determine the best ways to influence DCs themselves. This review discusses the role of DCs in transplantation and then focuses on three different approaches for manipulating DCs to improve allograft survival: (1) targeting of chemokines involved in DC migration, (2) pharmacological arrest of DC maturation, and (3) genetic engineering of DCs.

Animals↗
PubMed2002

Strategies for preclinical evaluation of dendritic cell subsets for promotion of transplant tolerance in the nonhuman primate.

A role for dendritic cells (DC) as critical regulators of immune reactivity has become increasingly recognized. There is evidence in rodent models that donor-derived DC, particularly in the immature state, can prolong organ allograft survival and even induce donor-specific tolerance. To allow the potential tolerogenic properties of these cells to be evaluated more fully with a view to clinical testing, it is necessary to identify DC subsets in nonhuman primates. We have identified the putative rhesus monkey equivalents of circulating human DC subset precursors as lineage(-), HLA-DR(+), CD123(lo),CD11c(hi)(pDC1) and lineage(-), HLA-DR(+), CD123(hi),CD11c(lo)(pDC2). Testing of these DC populations both in vitro and in vivo, as well as in transplant models in combination with conventional or experimental immunosuppressive reagents, will aid the development of novel strategies for the promotion of allo-antigen specific tolerance in transplantation.

Animals↗
PubMed2002

Transient bone marrow edema in renal transplantation: a distinct post-transplantation syndrome with a characteristic MRI appearance.

We describe four patients who developed severe knee pain within 3 months of renal transplantation. Plain radiographs were normal and inflammatory markers (CRP, ESR) were all within normal ranges. Magnetic resonance imaging (MRI) showed a distinctive pattern in all four cases of bone marrow signal changes, extending from the epiphyseal region into the metaphyseal region in two cases. The appearances were different from those of avascular necrosis (AVN) and reflex sympathetic dystrophy and showed no progression to develop AVN during the follow-up period of 36 months. In all cases the pain resolved over a period of 3 months without specific therapy. Follow-up MRI scans were obtained in all patients after the pain had subsided, which revealed resolution of the MRI changes. We suggest that MRI be the investigation in such patients and that bone marrow edema changes will regress without the need to withdraw cyclosporin.

Adult↗