William J Jordan’s research while affiliated with King's College London and other places

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Publications (11)


Altered expression and endocytic function of CD205 in human dendritic cells, and detection of a CD205-DCL-1 fusion protein upon dendritic cell maturation
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April 2007

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201 Reads

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67 Citations

Immunology

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William J Jordan

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CD205 (DEC-205) is a member of the macrophage mannose receptor family of C-type lectins. These molecules are known to mediate a wide variety of biological functions including the capture and internalization of ligands for subsequent processing and presentation by dendritic cells. Although its ligands await identification, the endocytic properties of CD205 make it an ideal target for those wishing to design vaccines and targeted immunotherapies. We present a detailed analysis of CD205 expression, distribution and endocytosis in human monocyte-derived dendritic cells undergoing lipopolysaccharide-induced maturation. Unlike other members of the macrophage mannose receptor family, CD205 was up-regulated upon dendritic cell maturation. This increase was a result of de novo synthesis as well as a redistribution of molecules from endocytic compartments to the cell surface. Furthermore, the endocytic capacity of CD205 was abrogated and small amounts of the recently identified CD205-DCL-1 fusion protein were detected in mature DC. Our results suggest that CD205 has two distinct functions -- one as an endocytic receptor on immature dendritic cells and a second as a non-endocytic molecule on mature dendritic cells -- and further highlight its potential as an immuno-modulatory target for vaccine and immunotherapy development.


Interferon‐α2a is sufficient for promoting dendritic cell immunogenicity

January 2006

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63 Reads

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32 Citations

Clinical & Experimental Immunology

Type I interferons (IFNs) are widely used therapeutically. IFN-alpha2a in particular is used as an antiviral agent, but its immunomodulatory properties are poorly understood. Dendritic cells (DCs) are the only antigen-presenting cells able to prime naive T cells and therefore play a crucial role in initiating the adaptive phase of the immune response. We studied the effects of IFN-alpha2a on DC maturation and its role in determining Th1/Th2 equilibrium. We found that IFN-alpha2a induced phenotypic maturation of DCs and increased their allostimulatory capacity. When dendritic cells were stimulated simultaneously by CD40 ligation and IFN-alpha2a, the production of interleukin (IL)-10 and IL-12 was increased. In contrast, lipopolysaccharide (LPS) stimulation in the presence of IFN-alpha2a mainly induced IL-10 release. The production of IFN-gamma and IL-5 by the responder naive T cells was also amplified in response to IFN-alpha2a-treated DCs. Furthermore, IL-12 production by IFN-alpha2a-treated DCs was enhanced further in the presence of anti-IL-10 antibody. Different results were obtained when DCs were treated simultaneously with IFN-alpha2a and other maturation factors, in particular LPS, and then stimulated by CD40 ligation 36 h later. Under these circumstances, IFN-alpha2a did not modify the DC phenotype, and the production of IL-10/IL-12 and IFN-gamma/IL-5 by DCs and by DC-stimulated naive T cells, respectively, was inhibited compared to the effects on DCs treated with maturation factors alone. Altogether, this work suggests that IFN-alpha2a in isolation is sufficient to promote DC activation, however, other concomitant events, such as exposure to LPS during a bacterial infection, can inhibit its effects. These results clarify some of the in vivo findings obtained with IFN-alpha2a and have direct implications for the design of IFN-alpha-based vaccines for immunotherapy.


Figure 1. Organ/tissue trafficking and distribution of Treg cells. Distinct chemokine receptors and integrin molecules implicated in Treg-cell organ/tissue trafficking and compartmentalization are presented. Bone marrow–derived CXCL12 mediates Treg-cell bone marrow trafficking. Environmental CCL22 mediates Treg-cell trafficking into human ovarian cancer and mouse cardiac grafts. The lymphoid homing molecules CCR7 and CD62L may facilitate lymphoid homing of Treg cells. Certain CC chemokines and integrins may mediate Treg-cell trafficking into inflammatory tissues/organs.  
Creation of tolerogenic human dendritic cells via intracellular CTLA4: A novel strategy with potential in clinical immunosuppression
  • Article
  • Full-text available

December 2005

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144 Reads

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63 Citations

Blood

Activation of T lymphocytes requires the recognition of peptide-major histocompatibility complexes (MHCs) and costimulatory signals provided by antigen-presenting cells (APCs). It has been shown that T-cell activation without costimulation can lead to anergy. In this study, we developed a novel strategy to inhibit expression of B7 molecules (CD80/86) by transfecting APCs with a gene construct encoding a modified cytotoxic T lymphocyte antigen 4 (CTLA4) molecule (CTLA4-KDEL) that is targeted to the endoplasmic reticulum (ER). APCs expressing this construct failed to express CD80/86 on their surface, were unable to stimulate allogeneic and peptide-specific T-cell responses, and induced antigen-specific anergy of the responding T cells. Cells expressing CTLA4-KDEL do not up-regulate the indoleamine 2, 3-dioxygenase enzyme, unlike cells treated with soluble CTLA4-immunoglobin (Ig). This gene-based strategy to knock out surface receptors is an attractive alternative to using immature dendritic cells for preventing transplant rejection and treating of autoimmune diseases.

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Toll-like receptor mRNA expression patterns in human dendritic cells and monocytes

June 2005

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1,011 Reads

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90 Citations

Molecular Immunology

The innate immune system recognises a wide spectrum of pathogens without a need for prior exposure. The main cells responsible are monocytes, macrophages, dendritic cells (DC) and neutrophils phagocytose microbial pathogens triggering a cytokine network resulting in the development of inflammatory and specific immune responses. Findings in the Toll-like receptor (TLR) family, initially discovered in Drosophila, further elucidated these processes. Toll-like receptors induce activation of an innate immune response and at present ten TLRs have been identified, named TLRs 1-10. In addition to the ignition of the innate immune response, evidence implicates the TLR family in a spectrum of systemic disorders following bacterial infections including sepsis and multiple organ failure, and can be detrimental, leading to tissue injury. In this project, our main goal was to investigate the effects of a TLR4 ligand, lipolysaccharide (LPS) in human DC and monocytes. Our hypothesis is that different professional APCs, express different mRNA TLR transcripts. Our findings indicate that TLR expression patterns change in relation to the pathogen involved and in the case of DC, and the maturation stage the latter are upon challenging. Our results and interpretation showed significant alteration of transcript expression patterns upon LPS challenge in all cell subsets, with DC subsets expressing different TLR mRNA patterns as they go through different maturation stages.


IL-13 production by donor T cells is prognostic of acute graft-versus-host disease following unrelated donor stem cell transplantation

January 2004

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75 Reads

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47 Citations

Blood

Despite the success of human leukocyte antigen (HLA) typing in allogeneic stem cell transplantation (SCT) it is rare to find an unrelated donor that is perfectly matched, making identification of "permissive" mismatches of paramount importance. Here, we describe novel associations between donor T-cell cytokine production during donor-antipatient mixed lymphocyte reactions (MLRs) and acute graft-versus-host disease (aGVHD). The data reveal positive correlations between both Th1-type and Th2-type cytokine production and GVHD and the assay established could potentially represent a useful tool for identification of permissible unrelated SCT donors. Associations between interleukin 13 (IL-13) levels and aGVHD were by far the strongest predictor of a GVHD (P =.0002). All patients suffering severe (grade III) aGVHD following SCT had donors who produced very high pretransplantation IL-13 responses, while those developing little or no aGVHD (grades 0-I) produced no IL-13 at all. IL-13 levels were independent of all other cytokines measured as well as cytotoxic T-lymphocyte precursor (CTLp) frequencies. The cytokines IL-5, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) also predicted development of aGVHD (P <.05 for all 3), appearing to be coproduced in the assay and correlating with estimated CTLp frequencies. The data challenge the notion that aGVHD is purely a Th1-type cytokine-driven response, high-lighting a novel and highly significant link between the Th2-type cytokine IL-13 and aGVHD.



Cross-species costimulation: Relative contributions of CD80, CD86, and CD40

July 2003

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20 Reads

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30 Citations

Transplantation

The response of human CD4+ T cells against porcine cells is of comparable magnitude to that induced by human leukocyte antigen-mismatched allogeneic cells. This reflects productive interactions between key costimulatory molecules across the species barrier. Inhibition of these molecular interactions will be crucial in overcoming CD4+ T-cell-mediated rejection of xenografts. We have performed a detailed investigation to determine the expression profiles and relative contributions of the three key costimulatory molecules in the porcine-human xenogeneic response. Whereas only porcine CD86 is constitutively expressed on resting endothelial cells, both CD40 and CD80 are rapidly expressed after activation. All three costimulatory molecules are expressed by professional antigen-presenting cells. We have isolated full-length cDNA clones for human and porcine CD80, CD86, and CD40. Human fibroblast cell lines (M1) coexpressing DR1 were transfected with these cDNAs and used in mixed lymphocyte reactions and flow cytometric studies in vitro. These data provide the first characterization of the expression profile and functional role of porcine CD80. Functional assays demonstrate that pCD40, pCD80, and pCD86 are independently capable of costimulating human CD4+ T cells, albeit with differing kinetics. Proliferative responses were of comparable magnitude to those obtained when costimulation was provided by human CD40, CD80, and CD86. These data have implications for therapy targeting the direct pathway of xenorecognition; costimulatory molecule blockade must be directed against both the B7/CD28 and CD40/CD40L pathways.


CD40 can cotimulate human memory T cells and favors IL-10 secretion

May 2003

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14 Reads

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16 Citations

European Journal of Immunology

Optimal proliferation of T cells, although initiated via ligation of the CD3/TCR complex, requires additional costimulatory signals. While the most well-defined in vitro pathway of costimulation is via the B7 family of molecules, a large body of data clearly demonstrates an in vivo role for the CD40/CD154 pathway in transplantation, autoimmunity and allergy. We have examined the role of CD40 as an independent costimulatory molecule by generating a panel of transfected human fibroblasts expressing DR1 with either CD80, CD86 or CD40. Functional assays using allogeneic CD4(+) T cells as responders demonstrated that CD40 was capable of costimulating CD4(+) T cell proliferation particularly in the CD45RO subset. Costimulation by CD40 induced much higher levels of IL-10 than were induced by B7-expressing cells. On day 3 the dominant costimulation was provided by CD40, while by day 5 this was overshadowed by CD80 and CD86. Nonetheless, the provision of costimulation by CD40 was enough to expand an alloreactive T cell line. These results were confirmed in experiments using primary cultures of CD40(+)CD80/CD86(-) renal tubular epithelial cells as the stimulator population. Thus, CD40 is capable of functioning independently (in the absence of B7) as a costimulatory molecule both in terms of proliferation and cytokine release. The data have interesting implications concerning the consequences of antigen presentation by tissue parenchymal cells.


Optimal analysis of composite cytokine responses during alloreactivity

March 2002

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17 Reads

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35 Citations

Journal of Immunological Methods

The one-way mixed lymphocyte reaction (MLR) is a useful model of the graft-vs.-host (GvH) response that occurs following bone-marrow transplantation (BMT). Previous studies of the MLR have shown high levels of type-1 cytokine production, such as IL-1, IL-6, IFN-gamma and TNF-alpha, but low or undetectable levels of type-2 cytokines, such as IL-4 and IL-10. Here, through establishing optimal conditions for the examination of levels and kinetics of a more definitive panel of type-1/type-2 cytokines (IL-4, IL-5, IL-10 and IL-13, IFN-gamma, TNF-alpha and the soluble IL-4 receptor) we show that, contrary to previously published data, the human alloresponse is truly heterogeneous, resulting in abundant type-2 as well as type-1 cytokine secretion. The kinetics of cytokine levels in the MLR show surprising complexity, suggesting a well-defined regulation as the alloresponse develops over time. Furthermore, each MLR responder:stimulator combination tested produces a composite cytokine profile that is intrinsic to that particular pairing. These combination-specific cytokine responses are reproducible when tested on multiple occasions over time. These data reveal a potential clinical application for the cytokine MLR in selecting donors for BMT with the least inflammatory cytokine profile. Additional analysis of this system reveals that the bulk of cytokine measured is both allospecific and T-cell-derived, with comparatively low levels produced through an autologous mechanism. Interestingly, although most of the cytokine detected is produced by CD45RO+ 'mature/activated' T cells, CD45RA+ 'naive' T cells are responsible for transient early production of IL-4. This novel finding suggests that naive T cells themselves could regulate type-1/type-2 developmental fate through an autocrine IL-4 mechanism.


"Accomodated" pig endothelial cells promote nitric oxide-dependent Th-2 cytokine responses from human T cells

December 2001

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13 Reads

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8 Citations

Transplantation

Cardiac and renal allo- and xenografts can become naturally resistant to vascular rejection. Understanding this process of "accommodation" would enhance our understanding of vascular inflammatory responses and have implications for immune manipulation and tolerance induction. A feature of these grafts is infiltration by leukocytes secreting a Th-2 pattern of cytokines. HLA-DR-1-transfected, immortalized porcine endothelial cells (IPEC) were incubated with polyclonal human immunoglobulin G (IgG) for 6 days before incubation with purified human CD4+ T cells. IgG-incubated IPEC stimulated a normal proliferative response from alloreactive T cells. However, interferon (IFN)-gamma levels were significantly reduced, whereas interleukin (IL)-5 and IL-10 were maintained at levels equivalent to those stimulated by control IPEC. Cognate interaction between T cells and IPEC was not required for this effect, because IgG-incubated, MHC-class II-negative IPEC caused reduced IFN-gamma secretion during a response to human Epstein-Barr virus-transformed B cells. Experiments with the nitric oxide (NO) donor, (z)-1-2-[2-Aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), and the NO synthase inhibitor, NG-monomethyl-L-arginine.monoacetate (L-NMMA), showed that NO released by the IgG-incubated IPEC was actively involved in the development of this phenotype. These data suggest a novel, IgG-mediated, NO-dependent mechanism by which endothelial cells (EC) influence T cell responsiveness and that the Th-2 cytokine skewing seen in "accommodated" grafts may be a secondary phenomenon, resulting from the T-EC interactions.


Citations (10)


... The other signal is delivered by the binding of costimulatory molecules to their ligands (2,6,7). It is well known that signaling solely through the interaction of TCR with MHC-peptide complex results in anergy (9). Costimulatory molecules, playing a key role in the modulation of T cell responses, are becoming promising candidates for immunotherapy (10). ...

Reference:

Increased Neutralizing Antibody Production and Interferon-γ Secretion in Response to Porcine Reproductive and Respiratory Syndrome Virus Immunization in Genetically Modified Pigs
Prevention of co-stimulation molecule expression using intracellular CTLA4: a novel strategy for induction of T cell anergy
  • Citing Conference Paper
  • September 2003

Xenotransplantation

... This idea is supported by the strong correlation between graft survival and expression of protective genes in vascular ECs. In animal models, where long-term allograft survival was established, expression of anti-apoptotic molecules A20, haem oxygenase-1 (HO-1), Bcl-xL and Bcl-2 were observed in graft ECs [2][3][4][5]. Some of these molecules have a dual cytoprotective role, inasmuch as they inhibit cell death but also act as anti-inflammatory mediators. ...

"Accomodated" pig endothelial cells promote nitric oxide-dependent Th-2 cytokine responses from human T cells
  • Citing Article
  • December 2001

Transplantation

... At 6 and 24 h post-infection (hpi) cells were collected and RNA extracted as indicated below. These time-points are considered optimal for the afferent phase of immune-mediators and cytokines production (Jordan and Ritter, 2002). ...

Optimal analysis of composite cytokine responses during alloreactivity
  • Citing Article
  • March 2002

Journal of Immunological Methods

... Additionally, HBx-stimulated podocytes promoted the expression of CD40L of CD4 + T cells. It has been reported that CD40 is expressed in professional APCs and epithelial cells, and it can regulate the activation and proliferation of T cells [26,27]. Based on these results, we believe that HBx-stimulated podocytes can modulate the activation of CD4 + T cells, which may be associated with the activation of CD40-CD40L signaling. ...

CD40 can cotimulate human memory T cells and favors IL-10 secretion
  • Citing Article
  • May 2003

European Journal of Immunology

... In particular, CD40 and CD80/ CD86 on antigen-presenting cells must interact with CD154 (CD40 L) and CD28 or cytotoxic Tlymphocyte antigen-4 (CTLA-4) on T cells. Extensive studies conducted by Rogers et al. (2003) have shown that porcine CD40, CD80, and CD86 are independently capable of costimulating human CD4 þ cells efficiently, albeit via different kinetics. In particular, porcine endothelial cells constitutively express CD80/CD86 (Koshika et al. 2011) and SLA class I, and possibly class II molecules as well (Choo et al. 1997). ...

Cross-species costimulation: Relative contributions of CD80, CD86, and CD40
  • Citing Article
  • July 2003

Transplantation

... This triggers the production of proinflammatory cytokines and type I IFNs [36]. Although TLRs are expressed mostly on monocyte-macrophages and dendritic cells (DCs) [37], they are also expressed on astrocytes, microglia, oligodendrocytes, and neurons [38]. Prolonged inflammation can activate M1 proinflammatory microglia together with infiltrating macrophages [39], which exacerbates inflammation, increases neuronal toxicity and may promote protein aggregation. ...

Toll-like receptor mRNA expression patterns in human dendritic cells and monocytes

Molecular Immunology

... Interestingly, immature DCs have been used to promote anergic T-cell development in the settings of transplantation and automimmunity [57]. Similarly, DCs lacking the expression of costimulatory molecules have even engineered for immunosuppression purposes [58]. Ex vivo MoDC pulsing using homologous TNBC cell membranes provides the possibility of applying a wide spectrum of potential antigens that may not be reached in vivo and could bypass issues of tumor antigen loss. ...

Creation of tolerogenic human dendritic cells via intracellular CTLA4: A novel strategy with potential in clinical immunosuppression

Blood

... Observations from previous studies have shown controversial findings requiring further investigation [17,18]. It is important to note that these low levels of IL-12 production by the impaired DCs of HCV patients, has been shown to be increased after successful Pegylated IFN-α plus Ribavirin (PEG-IFNα/RBV) treatment, which promotes the predominance of Th1 cells, making the possibility of viral elimination higher [19,20]. ...

Interferon‐α2a is sufficient for promoting dendritic cell immunogenicity
  • Citing Article
  • January 2006

Clinical & Experimental Immunology

... Interestingly, mature chicken MoDCs displayed a distinct upregulation of DEC205 expression pattern when compared to MRC1LB. This increase in DEC205 expression was previously reported at both protein and mRNA levels in mature human MoDCs, and it was postulated that DEC205 has a non-endocytic function in mature dendritic cells (22,53,54). Despite downregulation of endocytosis, the upregulation of DEC205 may also suggest that mature chicken MoDCs retain some capacity for antigen uptake, as previously observed in mouse BmDCs (55). ...

Altered expression and endocytic function of CD205 in human dendritic cells, and detection of a CD205-DCL-1 fusion protein upon dendritic cell maturation
  • Citing Article
  • April 2007

Immunology

... There was also upregulation of cytokines or chemokines, such as IL-13, Colony-stimulating factor (CSF)-1, and C-X-C motif chemokine ligand 5 (CXCL5), which may have mixed roles in GVHD pathogenesis. [32][33][34][35][36] Some molecules, such as IL-19, have not been specifically studied in GVHD but are associated with autoimmune diseases such as psoriasis 37 ( Figure 4C; supplemental Table 1). Much of our current knowledge on the immune stimulation by mitochondria comes from studying specific mitochondrial byproducts (mitochondrial DAMPs) in isolation. ...

IL-13 production by donor T cells is prognostic of acute graft-versus-host disease following unrelated donor stem cell transplantation
  • Citing Article
  • January 2004

Blood