ORCID Profile
0000-0002-6513-6406
Current Organisations
University of Queensland
,
University of Western Australia
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Immunology | Animal Physiology - Cell | Transplantation Immunology | Tumor Immunology | Cell Physiology | Physiology | Autoimmunity | Allergy |
ANZSRC Socio-Economic Objective (SEO)
Diabetes | Preventive Medicine | Immune system and allergy | Expanding Knowledge in the Biological Sciences | Cancer and related disorders | Immune System and Allergy
Related Links
Publications
Maintenance of peripheral tolerance to islet antigens
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.JAUT.2016.05.009
Abstract: Reestablishment of immune tolerance to the insulin-producing beta cells is the desired goal for type 1 diabetes (T1D) treatment and prevention. Immune tolerance to multiple islet antigens is defective in in iduals with T1D, but the mechanisms involved are multifaceted and may involve loss of thymic and peripheral tolerance. In this review we discuss our current understanding of the varied mechanisms by which peripheral tolerance to islet antigens is maintained in healthy in iduals where genetic protection from T1D is present and how this fails in those with genetic susceptibility to disease. Novel findings in regards to expression of neo-islet antigens, non-classical regulatory cell subsets and the impact of specific genetic variants on tolerance induction are discussed.
The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-2017
DOI: 10.1158/1078-0432.CCR-16-1576
Abstract: Purpose: To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival. Experimental Design: We performed high-throughput unbiased TCRβ sequencing on a population-based cohort of 92 patients with DLBCL treated with conventional (i.e., non-checkpoint blockade) frontline “R-CHOP” therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString. The primary endpoints were 4-year overall survival (OS) and progression-free survival (PFS). Results: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (P & 0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS rate of 60.0% [95% confidence interval (CI), 31.7%–79.6%], compared with 79.8% in patients with a low dominant clone (95% CI, 66.7%–88.5% P = 0.005). A highly dominant clone also predicted inferior 4-year PFS rate of 46.6% (95% CI, 22.5%–76.6%) versus 72.6% (95% CI, 58.8%–82.4%, P = 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV+ DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell ersity was associated with significantly elevated PD-1, PD-L1, and PD-L2 immune checkpoint molecules. Conclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy. Clin Cancer Res 23(7) 1820–8. ©2016 AACR.
Autoimmune diabetes is suppressed by transfer of proinsulin-encoding Gr-1+ myeloid progenitor cells that differentiate in vivo into resting dendritic cells
Publisher: American Diabetes Association
Date: 02-2005
DOI: 10.2337/DIABETES.54.2.434
Abstract: The nature of the T-cell response to antigen is governed by the activation state of the antigen-presenting dendritic cell (DC). Immature or resting DCs have been shown to induce T-cell responses that may protect against the development of autoimmune disease. Effectively harnessing this “tolerogenic” effect of resting DCs requires that it be disease-specific and that activation of DCs by manipulation ex vivo is avoided. We reasoned that this could be achieved by transferring in vivo partially differentiated myeloid progenitor cells encoding a disease-specific autoantigen. With the aim of preventing autoimmune diabetes, we transferred myeloid progenitor cells encoding proinsulin into NOD mice. Bone marrow (BM) was cultured in granulocyte macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-β1, a cytokine combination that expands myeloid cells but inhibits terminal DC differentiation, to yield Gr-1+/CD11b+/CD11c− myeloid progenitor cells and a minor population of CD11c+/CD11b+/CD86lo immature DCs. After transfer, Gr-1+ myeloid cells acquired the characteristics of resting DCs (CD11c+/MHC classIIint/CD86lo/CD40lo). Gr-1+ myeloid cells generated from transgenic NOD mice that expressed proinsulin controlled by a major histocompatibility complex (MHC) class II promoter, but not from wild-type NOD mice, transferred into 4-week-old female NOD mice significantly suppressed diabetes development. The transfer of DC progenitors encoding a disease-specific autoantigen is, therefore, an effective immunotherapeutic strategy that could be applied to humans.
IL-1 beta Produced in Response to Islet Autoantigen Presentation Differentiates T-helper-17 Cells at the Expense of Regulatory T cells: Implications for the Timing of Tolerizing Immunotherapy
Publisher: Elsevier BV
Date: 2010
Interleukin-1β Produced in Response to Islet Autoantigen Presentation Differentiates T-Helper 17 Cells at the Expense of Regulatory T-Cells
Publisher: American Diabetes Association
Date: 27-10-2010
DOI: 10.2337/DB10-0104
Abstract: The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelBlo DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1β is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelBlo DCs in the prediabetic period. We injected RelBlo DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T effectors to Treg in vitro. Tolerizing RelBlo DCs significantly inhibited diabetes progression when administered to 4-week-old but not 14-week-old mice. IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelBlo DCs exacerbated the IL-1–dependent decline in Treg function and promoted Th17 conversion. IL-1β, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1β/IL-17 checkpoint signals the need for other strategies.
Steady‐state dendritic cells continuously inactivate T cells that escape thymic negative selection
Publisher: Wiley
Date: 07-07-2009
DOI: 10.1038/ICB.2009.46
Abstract: Induction of peripheral tolerance by steady-state peripheral dendritic cells (DCs) presenting self antigen may be important in preventing autoimmune diseases mediated by self-reactive T cells that escape thymic deletion. However, the relative contribution of thymic and peripheral tolerance to the inactivation of self-specific repertoires is yet to be clearly defined. Here we tested the relative contribution of thymic and peripheral tolerance induction, using mice (11c.OVA) in which ovalbumin (OVA) expression is genetically targeted to DCs in conjunction with mice (Vbeta5 TCR transgenic), where a polyclonal repertoire of OVA-specific T cells of erse affinity is present. The expression of OVA in thymic DC reduced the frequency of OVA(257-264)-specific mature CD8 single-positive thymocytes although some functional OVA-specific CD8(+) T cells escaped negative selection and were detectable in the periphery. After adult thymectomy, OVA(257-264)-reactive T cells declined in the periphery indicating that the repertoire of OVA(257-264)-specific T cells that escaped negative selection and egressed to the periphery, were susceptible to inactivation by steady-state peripheral DC. Thus, in the face of inefficient negative selection, peripheral tolerance induction to cognate antigen by resting DC is a crucial requirement for the inactivation of a self-specific repertoire.
Antigen-Specific Suppression of Inflammatory Arthritis Using Liposomes
Publisher: The American Association of Immunologists
Date: 15-03-2009
Abstract: Existing therapies for rheumatoid arthritis and other autoimmune diseases are not Ag specific, which increases the likelihood of systemic toxicity. We show that egg phosphatidylcholine liposomes loaded with Ag (OVA or methylated BSA) and a lipophilic NF-κB inhibitor (curcumin, quercetin, or Bay11-7082) suppress preexisting immune responses in an Ag-specific manner. We injected loaded liposomes into mice primed with Ag or into mice suffering from Ag-induced inflammatory arthritis. The liposomes targeted APCs in situ, suppressing the cells’ responsiveness to NF-κB and inducing Ag-specific FoxP3+ regulatory T cells. This regulatory mechanism suppressed effector T cell responses and the clinical signs of full-blown Ag-induced arthritis. Thus, liposomes encapsulate Ags and NF-κB inhibitors stably and efficiently and could be readily adapted to deliver Ags and inhibitors for Ag-specific suppression of other autoimmune and allergic diseases.
The periphery is the dominant site of B-cell deletion in a polyclonal repertoire
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2020
DOI: 10.1101/2020.03.10.985192
Abstract: The concerted actions of multiple tolerance checkpoints limit the possibility of immune attack against self-antigens. For B cells, purging of autoreactivity from the developing repertoire has been almost exclusively studied using B-cell receptor transgenic models. Analyses have generally agreed that central and peripheral tolerance occurs in the form of deletion, receptor editing and anergy. However, when and where these processes occur in a normal polyclonal repertoire devoid of B-cell receptor engineering remain unclear. Here, employing sensitive tools that alleviate the need for B-cell receptor engineering, we track the development of self-reactive B cells and challenge whether deletion plays a meaningful role in B-cell tolerance. We find self-reactive B cells can mature unperturbed by ubiquitous self-antigen expression but, even in the presence of T-cell help, are robustly anergic in the periphery. These studies query the prominence attributed to central and peripheral deletion by most BCR transgenic studies and suggest that other mechanisms predominantly govern B cell tolerance.
MHC Class II Expression Is Regulated in Dendritic Cells Independently of Invariant Chain Degradation
Publisher: Elsevier BV
Date: 06-2001
DOI: 10.1016/S1074-7613(01)00148-0
Abstract: We have investigated the mechanisms that control MHC class II (MHC II) expression in immature and activated dendritic cells (DC) grown from spleen and bone marrow precursors. Degradation of the MHC II chaperone invariant chain (Ii), acquisition of peptide cargo by MHC II, and delivery of MHC II-peptide complexes to the cell surface proceeded similarly in both immature and activated DC. However, immature DC reendocytosed and then degraded the MHC II-peptide complexes much faster than the activated DC. MHC II expression in DC is therefore not controlled by the activity of the protease(s) that degrade Ii, but by the rate of endocytosis of peptide-loaded MHC II. Late after activation, DC downregulated MHC II synthesis both in vitro and in vivo.
Blockade of PD-1/PD-L1 promotes adoptive T-Cell immunotherapy in a tolerogenic environment
Publisher: Public Library of Science (PLoS)
Date: 05-03-2015
Comparative analysis of dendritic cell density and total number in commonly transplanted organs: Morphometric estimation in normal mice
Publisher: Elsevier BV
Date: 03-2000
DOI: 10.1016/S0966-3274(00)00010-1
Abstract: Dendritic cells (DC) are considered to be the major cell type responsible for induction of primary immune responses. While they have been shown to play a critical role in eliciting allosensitization via the direct pathway, there is evidence that maturational and/or activational heterogeneity between DC in different donor organs may be crucial to allograft outcome. Despite such an important perceived role for DC, no accurate estimates of their number in commonly transplanted organs have been reported. Therefore, leukocytes and DC were visualized and enumerated in cryostat sections of normal mouse (C57BL/10, B10.BR, C3H) liver, heart, kidney and pancreas by immunohistochemistry (CD45 and MHC class II staining, respectively). Total immunopositive cell number and MHC class II+ cell density (C57BL/10 mice only) were estimated using established morphometric techniques--the fractionator and disector principles, respectively. Liver contained considerably more leukocytes (approximately 5-20 x 10(6)) and DC (approximately 1-3 x 10(6)) than the other organs examined (pancreas: approximately 0.6 x 10(6) and approximately 0.35 x 10(6) heart: approximately 0.8 x 10(6) and approximately 0.4 x 10(6) kidney approximately 1.2 x 10(6) and 0.65 x 10(6), respectively). In liver, DC comprised a lower proportion of all leukocytes (approximately 15-25%) than in the other parenchymal organs examined (approximately 40-60%). Comparatively, DC density in C57BL/10 mice was heart > kidney > pancreas >> liver (approximately 6.6 x 10(6), 5 x 10(6), 4.5 x 10(6) and 1.1 x 10(6) cells/cm3, respectively). When compared to previously published data on allograft survival, the results indicate that the absolute number of MHC class II+ DC present in a donor organ is a poor predictor of graft outcome. Survival of solid organ allografts is more closely related to the density of the donor DC network within the graft.
Simple, rapid and inexpensive typing of common HLA class I alleles for immunological studies.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.JIM.2018.12.002
Abstract: Current HLA-typing methods are typically designed to provide exquisitely-detailed identification of multiple HLA-alleles to satisfy the requirements for organ and bone marrow transplantation or genetic studies. Many human immunological studies, on the other hand, focus around only a small number of HLA alleles that are abundant or of relevance to specific diseases. Consequently, for such studies, many HLA typing approaches are not cost-effective and are potentially complicated, slow and not easily performed in-house. Work-flow would be streamlined by a simple, inexpensive and rapid typing method able to be performed in-house. We outline a straightforward approach that provides appropriate data for much immunological research. In a predominantly Caucasian population, flow cytometry using anti-HLA-A2, -B8 and -B7 antibodies consistently and accurately screened for s les carrying the highly-abundant HLA class I alleles HLA-A*02:01, -B*08:01 and -B*07:02 that form the focus of immunological studies. Next, we describe a straightforward and simple strategy for design and use of allele-specific PCR primers to identify, at high-resolution, alleles of interest. When combined with a simple gDNA extraction technique this provides reliable, simple and inexpensive in-house HLA typing demonstrated here for highly-abundant HLA class I alleles.
Resident tissue macrophages within the normal rat iris lack immunosuppressive activity and are effective antigen-presenting cells
Publisher: Swets & Zeitlinger Publishers
Date: 09-2000
Fms-like tyrosine kinase 3 ligand administration overcomes a genetically determined dendritic cell deficiency in NOD mice and protects against diabetes development
Publisher: Oxford University Press (OUP)
Date: 31-01-2005
Abstract: A dendritic cell (DC) imbalance with a marked deficiency in CD4- 8+ DC occurs in non-obese diabetic (NOD) mice, a model of human autoimmune diabetes mellitus. Using a NOD congenic mouse strain, we find that this CD4- 8+ DC deficiency is associated with a gene segment on chromosome 4, which also encompasses non-MHC diabetes susceptibility loci. Treatment of NOD mice with fms-like tyrosine kinase 3 ligand (FL) enhances the level of CD4- 8+ DC, temporarily reversing the DC subtype imbalance. At the same time, fms-like tyrosine kinase 3 ligand treatment blocks early stages of the diabetogenic process and with appropriately timed administration can completely prevent diabetes development. This points to a possible clinical use of FL to prevent autoimmune disease.
Immunobiology of liver dendritic cells
Publisher: Wiley
Date: 02-2002
DOI: 10.1046/J.0818-9641.2001.01058.X
Abstract: Dendritic cells (DC) are rare, bone marrow-derived antigen-presenting cells that play a critical role in the induction and regulation of immune reactivity. In this article, we review the identification and characterization of liver DC, their ontogenic development, in vivo mobilization and population dynamics. In addition, we discuss the functions of DC isolated from liver tissue or celiac lymph, or propagated in vitro from liver-resident haemopoietic stem rogenitor cells. Evidence concerning the role of DC in viral hepatitis, liver tumours, autoimmune liver diseases, granulomatous inflammation and the outcome of liver transplantation is also discussed.
Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells
Publisher: American Diabetes Association
Date: 17-06-2022
DOI: 10.2337/DB22-0177
Abstract: Type 1 diabetes is an autoimmune disease with no cure, where clinical translation of promising therapeutics has been h ered by the reproducibility crisis. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent research centers. Treatment with sRAGE increased regulatory T cells (Tregs) within the islets, pancreatic lymph nodes, and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE with use of knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration, and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T-cell ision, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy and reproducibility at multiple research centers and in human T cells.
Clinically-Relevant Rapamycin Treatment Regimens Enhance CD8+ Effector Memory T Cell Function In The Skin and Allow their Infiltration into Cutaneous Squamous Cell Carcinoma
Publisher: Informa UK Limited
Date: 30-07-2018
Peripheral Tolerance Checkpoints Imposed by Ubiquitous Antigen Expression Limit Antigen-Specific B Cell Responses under Strongly Immunogenic Conditions
Publisher: The American Association of Immunologists
Date: 09-2020
Abstract: A series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy in iduals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically relevant B cell responses without the use of an engineered BCR. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. In this study, we use a strong adjuvant to provide bystander innate and adaptive signals that promote B cell responsiveness in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although self-reactive B cells are recruited into the germinal center, their development does not proceed, possibly because of rapid counterselection. Consequently, differentiation of plasma cells is blunted, and Ab responses are transient and devoid of affinity maturation. We propose this approach, and these tools can be more widely applied to track Ag-specific B cell responses to more disease-relevant Ags, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell–mediated autoimmunity.
Transfer of antigen-encoding bone marrow under immune-preserving conditions deletes mature antigen-specific B cells in recipients and inhibits antigen-specific antibody production
Publisher: Cold Spring Harbor Laboratory
Date: 21-12-2019
DOI: 10.1101/2019.12.20.885343
Abstract: Pathological activation and collaboration of T and B cells underlies pathogenic autoantibody responses. Existing treatments for autoimmune disease cause non-specific immunosuppression and induction of antigen-specific tolerance remains an elusive goal. Many immunotherapies aim to manipulate the T-cell component of T-B interplay but few directly target B cells. One possible means to specifically target B cells is the transfer of gene-engineered BM that, once engrafted, gives rise to widespread specific and tolerogenic antigen expression within the hematopoietic system. Gene-engineered bone marrow encoding ubiquitous ovalbumin expression was transferred after low-dose (300cGy) immune-preserving irradiation. B-cell responsiveness was monitored by analyzing ovalbumin-specific antibody production after immunization with ovalbumin/complete Freund’s adjuvant. Ovalbumin-specific B cells and their response to immunization were analyzed using multi-tetramer staining. When antigen-encoding bone marrow was transferred under immune-preserving conditions, cognate antigen-specific B cells were purged from the recipient’s pre-existing B cell repertoire as well as the repertoire that arose after bone marrow transfer. OVA-specific B-cell deletion was apparent within the established host B-cell repertoire as well as that developing after gene-engineered bone marrow transfer. OVA-specific antibody production was substantially inhibited by transfer of OVA-encoding BM and activation of OVA-specific B cells, germinal centre formation and subsequent OVA-specific plasmablast differentiation were all inhibited. Low levels of gene-engineered bone marrow chimerism were sufficient to limit antigen-specific antibody production. These data show that antigen-specific B cells within an established B-cell repertoire are susceptible to de novo tolerance induction and this can be achieved by transfer of gene-engineered bone marrow. This adds further dimensions to the utility of antigen-encoding bone marrow transfer as an immunotherapeutic tool.
CD4+/CD8+ double-positive T cells: more than just a developmental stage?
Publisher: Oxford University Press (OUP)
Date: 30-10-2014
Abstract: CD4+/CD8+ DP thymocytes are a well-described T cell developmental stage within the thymus. However, once differentiated, the CD4+ lineage or the CD8+ lineage is generally considered to be fixed. Nevertheless, mature CD4+/CD8+ DP T cells have been described in the blood and peripheral lymphoid tissues of numerous species, as well as in numerous disease settings, including cancer. The expression of CD4 and CD8 is regulated by a very strict transcriptional program involving the transcription factors Runx3 and ThPOK. Initially thought to be mutually exclusive within CD4+ and CD8+ T cells, CD4+/CD8+ T cell populations, outside of the thymus, have recently been described to express concurrently ThPOK and Runx3. Considerable heterogeneity exists within the CD4+/CD8+ DP T cell pool, and the function of CD4+/CD8+ T cell populations remains controversial, with conflicting reports describing cytotoxic or suppressive roles for these cells. In this review, we describe how transcriptional regulation, lineage of origin, heterogeneity of CD4 and CD8 expression, age, species, and specific disease settings influence the functionality of this rarely studied T cell population.
Impaired T-cell function in B-cell lymphoma: A direct consequence of events at the immunological synapse?
Publisher: Frontiers Media SA
Date: 02-06-2015
Low‐generation asymmetric dendrimers exhibit minimal toxicity and effectively complex DNA
Publisher: Wiley
Date: 24-02-2011
DOI: 10.1002/PSC.1347
Abstract: Conventional dendrimers are spherical symmetrically branched polymers ending with active surface functional groups. Polyamidoamine (PAMAM) dendrimers have been widely studied as gene delivery vectors and have proven effective at delivering DNA to cells in vitro. However, higher-generation (G4-G8) PAMAM dendrimers exhibit toxicity due to their high cationic charge density and this has limited their application in vitro and in vivo. Another limitation arises when attempts are made to functionalize spherical dendrimers as targeting moieties cannot be site-specifically attached. Therefore, we propose that lower-generation asymmetric dendrimers, which are likely devoid of toxicity and to which site-specific attachment of targeting ligands can be achieved, would be a viable alternative to currently available dendrimers. We synthesized and characterized a series of peptide-based asymmetric dendrimers and compared their toxicity profile and ability to condense DNA to spherical PAMAM G1 dendrimers. We show that asymmetric dendrimers are minimally toxic and condense DNA into stable toroids which have been reported necessary for efficient cell transfection. This paves the way for these systems to be conjugated with targeting ligands for gene delivery in vitro and in vivo.
Re-educating immunity in respiratory allergies: the potential for hematopoietic stem cell-mediated gene therapy
Publisher: Springer Science and Business Media LLC
Date: 17-11-2018
CD4+CD8β+ double-positive T cells in skin-draining lymph nodes respond to inflammatory signals from the skin
Publisher: Oxford University Press (OUP)
Date: 21-06-2017
Abstract: CD4+CD8+ double-positive (DP), mature, peripheral T cells are readily detectable in a variety of species and tissues. Despite a common association with autoimmune and malignant skin disorders, however, little is understood about their role or function. Herein, we show that DP T cells are readily detectable in the blood, spleen, and peripheral lymph nodes of naïve C57BL/6 mice. DP T cells were also present in Jα18−/− and CD1d−/− mice, indicating that these cells are not NK-T cells. After skin administration of CASAC adjuvant, but not Quil A adjuvant, both total DP T cells and skin-infiltrating DP T cells increased in number. We explored the possibility that DP T cells could represent aggregates between CD4+ and CD8+ single-positive T cells and found strong evidence that a large proportion of apparent DP T cells were indeed aggregates. However, the existence of true CD4+CD8+ DP T cells was confirmed by Amnis ImageStream (Millipore Sigma, Billerica, MA, USA) imaging. Multiple rounds of FACS sorting separated true DP cells from aggregates and indicated that conventional analyses may lead to ∼10-fold overestimation of DP T cell numbers. The high degree of aggregate contamination and overestimation of DP abundance using conventional analysis techniques may explain discrepancies reported in the literature for DP T cell origin, phenotype, and function.
Choroidal mast cell dynamics during experimental autoimmune uveoretinitis in rat strains of differing susceptibility.
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/09273949409057797
Abstract: Choroidal mast cells have been implicated in the pathogenesis of experimental autoimmune uveoretinitis (EAU). The aim of the present study was to examine the dynamics of choroidal mast cells during the course of EAU in rat strains of varying susceptibility. Histochemical staining showed choroidal mast cell degranulation in Lewis rats, a highly susceptible strain, commenced nine days post-immunisation, and peaked at day 11, at which time the percentage of degranulated choroidal mast cells (32. 5± 4%) was significantly higher than controls (15. 3 ± 3% p <0.05). At day 14, mean choroidal mast cell density was significantly reduced (from 23. 6 ± 1/mm(2) tot 16. 2 ± 2/mm(2) p<0.05) and early signs of choroidal mast cell regeneration were evident. Immunisation of PVG/C (moderate susceptibility) and Brown Norway (very low susceptibility) rats produced a similar pattern of morphological changes. Onset of clinical signs in Lewis rats, which possess approximately 1100 to 1800 choroidal mast cells per eye, occurred one day following commencement of choroidal mast cell degranulation but prior to the peak of degranulation. However, in PVG/C and Brown Norway rats, which possess only approximately 70 and 110 choroidal mast cells per eye respectively, onset of disease was not temporally linked to commencement of degranulation. Production of antigen-specific IgE during the course of EAU was extremely low in all three strains. These results indicate that choroidal mast cells may be important in the pathogenesis of EAU in Lewis rats but not in PVG/C or Brown Norway rats and that non-IgE mediated degranulation may play a role in disease induction.
Regulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation
Publisher: The American Association of Immunologists
Date: 05-2015
Abstract: Inducible BALT (iBALT) can lify pulmonary or systemic inflammatory responses to the benefit or detriment of the host. We took advantage of the age-dependent formation of iBALT to interrogate the underlying mechanisms that give rise to this ectopic, tertiary lymphoid organ. In this study, we show that the reduced propensity for weanling as compared with neonatal mice to form iBALT in response to acute LPS exposure is associated with greater regulatory T cell expansion in the mediastinal lymph nodes. Ab- or transgene-mediated depletion of regulatory T cells in weanling mice upregulated the expression of IL-17A and CXCL9 in the lungs, induced a tissue neutrophilia, and increased the frequency of iBALT to that observed in neonatal mice. Remarkably, neutrophil depletion in neonatal mice decreased the expression of the B cell active cytokines, a proliferation-inducing ligand and IL-21, and attenuated LPS-induced iBALT formation. Taken together, our data implicate a role for neutrophils in lymphoid neogenesis. Neutrophilic inflammation is a common feature of many autoimmune diseases in which iBALT are present and pathogenic, and hence the targeting of neutrophils or their byproducts may serve to ameliorate detrimental lymphoid neogenesis in a variety of disease contexts.
DONOR PRETREATMENT WITH Flt-3 LIGAND AUGMENTS ANTIDONOR CYTOTOXIC T LYMPHOCYTE, NATURAL KILLER, AND LYMPHOKINE-ACTIVATED KILLER CELL ACTIVITIES WITHIN LIVER ALLOGRAFTS AND ALTERS THE PATTERN OF INTRAG
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1998
DOI: 10.1097/00007890-199806270-00009
Abstract: Liver allografts are accepted across major histocompatibility complex (MHC) barriers in mice and induce donor-specific tolerance without requirement for immunosuppressive therapy. There is evidence that passenger leukocytes may play a key role in tolerance induction. Flt-3 ligand (FL) is a recently cloned hematopoietic cytokine that strikingly augments functional dendritic cells (DCs) within lymphoid and nonlymphoid tissue. The expression of costimulatory molecules and MHC class II antigen on DCs isolated from livers of FL-treated B10 (H2b) mice (10 microg/day 10 days) was examined by flow cytometric analysis, and their allostimulatory activity assessed in primary mixed leukocyte cultures. B10 livers from FL-treated donors were transplanted orthotopically into naive C3H (H2k) recipients. Donor cells (MHC class II+) in recipient spleens were identified by immunohistochemistry. Antidonor cytotoxic T lymphocyte activity, and both natural killer and lymphokine-activated killer cell activities of graft nonparenchymal cells and host splenocytes were determined using isotope release assays. Apoptotic activity within liver grafts was determined by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling. DCs isolated from livers of FL-treated donor mice exhibited increased cell surface expression of CD40, CD80, CD86, and IAb, and augmented T cell allostimulatory activity compared with controls. Within 24 hr of organ transplantation, the numbers of donor IAb+ cells within recipient spleens was augmented substantially compared with normal liver recipients. Livers from FL-treated donors were rejected acutely (median survival time, 5 days), whereas control B10 liver allografts survived >100 days. Nonparenchymal cells from rejecting grafts 4 days after transplantation exhibited increased antidonor cytotoxic T lymphocyte, natural killer, and lymphokine-activated killer cell activities compared with cells from spontaneously accepted grafts. This augmented cytotoxic reactivity was associated with histologic evidence of injury to bile duct epithelium and vascular endothelium that was not readily evident in controls. Thus, although normal livers provide allostimulatory signals sufficient to elicit an antidonor immune response, regulatory mechanisms that may include apoptosis of graft-infiltrating T cells, and that are overcome by augmenting the number of functional donor DCs, may account for inherent liver tolerogenicity.
Ultrastructural pathology of experimental autoimmune uveitis in the rat
Publisher: Informa UK Limited
Date: 1993
DOI: 10.3109/08916939308993315
Abstract: Experimental autoimmune uveoretinitis (EAU) has been extensively studied as a model for human posterior uveitis, however, few ultrastructural studies of EAU in the rat have been reported. In the present report we document a systematic time-course study of the posterior segment changes in the Lewis rat. The disease varied somewhat in severity in animals sacrificed at identical times after immunisation. In the prodromal stage of the disease, usually around day 14, early pathological changes included mild peripapillary vasculitis and low grade mononuclear and neutrophilic infiltration of the subretinal space with phagocytosis of the rod outer segments. The features of the severe or active diseases were most evident on day 21 and included mixed cellular infiltrate of the vitreous, subretinal serohaemorrhagic exudate, focal retinal detachment and necrosis. Outer retinal destruction was often most severe adjacent areas of retinal vasculitis. Focal monocytic subpigment epithelial microgranulomas, reminiscent of Dalen-Fuch's nodules in humans, were also identified. By day 28 and 49 active inflammation had subsided and large segments of the outer retina were completely destroyed. The retinal pigment epithelium (RPE) also showed signs of activation in the vicinity of focal retinochoroidal mononuclear infiltrates including multilayering, proliferation and increased phagocytosis. Finally, neovascularisation of the RPE by non-fenestrated capillaries derived from the retinal vasculature was evident in the late stages of the disease.
Short-course rapamycin treatment enables engraftment of immunogenic gene-engineered bone marrow under low-dose irradiation to permit long-term immunological tolerance
Publisher: Figshare
Date: 2017
Most lymphoid organ dendritic cell types are phenotypically and functionally immature
Publisher: American Society of Hematology
Date: 15-09-2003
DOI: 10.1182/BLOOD-2003-02-0513
Abstract: Dendritic cells (DCs) have been thought to follow a life history, typified by Langerhans cells (LCs), with 2 major developmental stages: an immature stage that captures antigens in the periphery and a mature stage that presents those antigens in the lymphoid organs. However, a systematic assessment of the maturity of lymphoid organ DCs has been lacking. We have analyzed the maturity of the DC types found in the steady state in the spleen, lymph nodes (LNs), and thymus. The DCs that migrate into the iliac, mesenteric, mediastinal, or subcutaneous LNs from peripheral tissues were mature and therefore could not process and present newly encountered antigens. However, all the other DC types were phenotypically and functionally immature: they expressed low levels of surface major histocompatibility complex class II (MHC II) and CD86, accumulated MHC II in their endosomes, and could present newly encountered antigens. These immature DCs could be induced to mature by culture in vitro or by inoculation of inflammatory stimuli in vivo. Therefore, the lymphoid organs contain a large cohort of immature DCs, most likely for the maintenance of peripheral tolerance, which can respond to infections reaching those organs and mature in situ.
c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells
Publisher: Rockefeller University Press
Date: 07-12-2009
DOI: 10.1084/JEM.20091411
Abstract: During thymopoiesis, a unique program of gene expression promotes the development of CD4 regulatory T (T reg) cells. Although Foxp3 maintains a pattern of gene expression necessary for T reg cell function, other transcription factors are emerging as important determinants of T reg cell development. We show that the NF-κB transcription factor c-Rel is highly expressed in thymic T reg cells and that in c-rel−/− mice, thymic T reg cell numbers are markedly reduced as a result of a T cell–intrinsic defect that is manifest during thymocyte development. Although c-Rel is not essential for TGF-β conversion of peripheral CD4+CD25− T cells into CD4+Foxp3+ cells, it is required for optimal homeostatic expansion of peripheral T reg cells. Despite a lower number of peripheral T reg cells in c-rel−/− mice, the residual peripheral c-rel−/− T reg cells express normal levels of Foxp3, display a pattern of cell surface markers and gene expression similar to those of wild-type T reg cells, and effectively suppress effector T cell function in culture and in vivo. Collectively, our results indicate that c-Rel is important for both the thymic development and peripheral homeostatic proliferation of T reg cells.
Proinsulin is encoded by an RNA splice variant in human blood myeloid cells
Publisher: Proceedings of the National Academy of Sciences
Date: 31-10-2006
Abstract: Genes for peripheral tissue-restricted self-antigens are expressed in thymic and hematopoietic cells. In thymic medullary epithelial cells, self-antigen expression imposes selection on developing autoreactive T cells and regulates susceptibility to autoimmune disease in mouse models. Less is known about the role of self-antigen expression by hematopoietic cells. Here we demonstrate that one of the endocrine self-antigens expressed by human blood myeloid cells, proinsulin, is encoded by an RNA splice variant. The surface expression of immunoreactive proinsulin was significantly decreased after transfection of monocytes with small interfering RNA to proinsulin. Furthermore, analogous to proinsulin transcripts in the thymus, the abundance of the proinsulin RNA splice variant in blood cells corresponded with the length of the variable number of tandem repeats 5′ of the proinsulin gene, known to be associated with type 1 diabetes susceptibility. Self-antigen expression by peripheral myeloid cells extends the umbrella of “immunological self” and, by analogy with the thymus, may be implicated in peripheral immune tolerance.
Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific b-cell responses under strongly immunogenic conditions
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2020
DOI: 10.1101/2020.03.10.985127
Abstract: A series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached, however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy in iduals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically-relevant B-cell responses, without the use of an engineered B-cell receptor. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. Here we use a strong adjuvant to provide bystander innate and adaptive signals that promote B-cell responsiveness, in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although autoreactive B cells are recruited into the germinal centre, their development does not proceed, possibly through rapid counter-selection. Consequently, differentiation of plasma cells is blunted, and autoantibody responses are transient and devoid of affinity maturation. We propose this approach and these tools can be more widely applied to track antigen-specific B cell responses to more disease relevant antigens, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell-mediated autoimmunity.
Dendritic cells and tolerance induction
Publisher: Oxford University Press (OUP)
Date: 09-1996
DOI: 10.1046/J.1365-2249.1996.D01-779.X
Abstract: Dendritic cells (DC) are widely accepted as the most potent antigen-presenting cells (APC), and considerable interest has been generated in their potential for the immunological therapy of cancer and infectious disease. Recently, however, a broader understanding of the phenotypic ersity and functional heterogeneity of DC has been acquired. Thus, in addition to having a role in central tolerance, DC are now regarded as potential modulators of peripheral immune responses. Harnessing this potential may offer a new approach to the immunosuppressive therapy of allograft rejection or autoimmunity. Here, the concept of ‘tolerogenic’ DC is placed in the context of rapidly accumulating new evidence of the erse properties of these important APC.
The Protease Inhibitor Cystatin C Is Differentially Expressed among Dendritic Cell Populations, but Does Not Control Antigen Presentation
Publisher: The American Association of Immunologists
Date: 15-11-2003
DOI: 10.4049/JIMMUNOL.171.10.5003
Abstract: Dendritic cells (DC) undergo complex developmental changes during maturation. The MHC class II (MHC II) molecules of immature DC accumulate in intracellular compartments, but are expressed at high levels on the plasma membrane upon DC maturation. It has been proposed that the cysteine protease inhibitor cystatin C (CyC) plays a pivotal role in the control of this process by regulating the activity of cathepsin S, a protease involved in removal of the MHC II chaperone Ii, and hence in the formation of MHC II-peptide complexes. We show that CyC is differentially expressed by mouse DC populations. CD8+ DC, but not CD4+ or CD4−CD8− DC, synthesize CyC, which accumulates in MHC II+L + compartments. However, Ii processing and MHC II peptide loading proceeded similarly in all three DC populations. We then analyzed MHC II localization and Ag presentation in CD8+ DC, bone marrow-derived DC, and spleen-derived DC lines, from CyC-deficient mice. The absence of CyC did not affect the expression, the subcellular distribution, or the formation of peptide-loaded MHC II complexes in any of these DC types, nor the efficiency of presentation of exogenous Ags. Therefore, CyC is neither necessary nor sufficient to control MHC II expression and Ag presentation in DC. Our results also show that CyC expression can differ markedly between closely related cell types, suggesting the existence of hitherto unrecognized mechanisms of control of CyC expression.
Asymmetric Peptide Dendrimers are Effective Linkers for Antibody-Mediated Delivery of Diverse Payloads to B Cells in Vitro and in Vivo
Publisher: Springer Science and Business Media LLC
Date: 22-05-2014
DOI: 10.1007/S11095-014-1408-1
Abstract: Safe, targeted delivery of therapeutics remains a focus of drug/gene delivery, the aim being to achieve optimal efficacy while minimising off-target delivery. Dendrimers have a vast array of potential applications and have great potential as gene and drug delivery tools. We previously reported the development of peptide dendrimers that effectively complexed DNA and that have distinct advantages over conventional spherical dendrimers. Here, to expand the application of peptide-based low generation dendrimers we tested their capacity to be transformed into linkers for antibody-based targeting of erse payloads. Peptide-based low-generation asymmetric dendrimers were generated and conjugated to partially-reduced antibodies specific for B cell surface antigens or an irrelevant antigen. Preservation of antigen binding by the antibodies and targeting of the conjugated dendrimers carrying a small molecule (biotin) or plasmid DNA payloads was tested. Peptide-based low generation dendrimers were efficiently and site-specifically conjugated to antibodies with retention of antigen-binding capacity. Altering the branching termini of dendrimers facilitated delivery of erse payloads in vitro and in vivo. We propose that safe, non-toxic peptide dendrimers, which are readily synthesised and modifiable for a variety of applications, form the basis of a new family of biocompatible "linkers" with substantial potential for targeted delivery applications.
Short-course rapamycin treatment enables engraftment of immunogenic gene-engineered bone marrow under low-dose irradiation to permit long-term immunological tolerance
Publisher: Springer Science and Business Media LLC
Date: 09-03-2017
Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8 + T‐cell priming to tolerance in autoimmune‐prone NOD mice
Publisher: Wiley
Date: 18-07-2017
Abstract: Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic β cells. Therapies need to incorporate strategies to overcome the genetic defects that impair induction or maintenance of peripheral T-cell tolerance and contribute to disease development. We tested whether the enforced expression of an islet autoantigen in antigen-presenting cells (APC) counteracted peripheral T-cell tolerance defects in autoimmune-prone NOD mice. We observed that insulin-specific CD8
Tetramer-based identification of naïve antigen-specific B cells within a polyclonal repertoire
Publisher: Wiley
Date: 17-04-2018
Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function
Publisher: The American Association of Immunologists
Date: 27-12-2010
Abstract: Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8+ T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8+ T cells is slow, allowing transiently expanded memory CD8+ T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a erse range of APCs, that CD8+ memory T cells can be rapidly inactivated by MHC class II+ hematopoietic APCs through a mechanism that involves a rapid and sustained downregulation of TCR, in which the effector response of CD8+ memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8+ T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases.
Impact of Flt-3 ligand on donor-derived antigen presenting cells and alloimmune reactivity in heart graft recipients given adjuvant donor bone marrow
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0966-3274(98)80012-9
Abstract: The influence of the haematopoietic growth factor Flt-3 ligand (FL) on the incidence and function of donor major histocompatibility complex (MHC) class II+ cells in the lymphoid tissues of noncytoablated recipients of heart allografts and donor bone marrow (BM) cells was investigated. C3H (H2k) mice received a nonvascularized B10 (H2b) heart allograft in the dorsal ear pinna, followed by an i.v. infusion of 50 x 10(6) donor BM cells. They were given FL (10 microg/day i.p., x7 days), tacrolimus (2mg/kg/day i.p., x13 days) or both agents immediately following heart transplantation (HTx) and were killed 10 or 21 days later. Their BM cells were propagated in vitro in granulocyte macrophage colony stimulating factor (GM-CSF) and IL-4 for 5 days to promote the growth of dendritic cells (DC). Donor DC were identified by immunocytochemical staining. Spleens were harvested, and donor (IAb+) cells enumerated by immunohistochemical analysis. Donor MHC class II DNA was detected in spleens and cultured BM-derived cells by reverse transcriptase-polymerase chain reaction (RT-PCR). A striking increase in donor MHC class II+ cells was noted in both the spleen and BM of the BM + tacrolimus-treated group compared to either the BM alone, or BM + FL-treated groups. Addition of FL treatment to BM + tacrolimus led to a further increase in donor cells in spleen (three-fold at 10 days, and two-fold at 21 days). The increase in donor cells at 10 days was almost 140-fold compared to that with donor BM alone. PCR analysis at this time revealed enhanced donor DNA in the BM + FL + tacrolimus group compared to that in the BM + tacrolimus group. FL treatment augmented mixed leucocyte reactions (MLR) and cytotoxic T lymphocyte (CTL) activity of host spleen cells against donor alloantigens. These effects were reversed by tacrolimus administration. Histopathology of heart grafts from tacrolimus-treated animals at 10 and 21 days showed absence or substantial reduction in cellular infiltration, and the preservation of viable myocardium. By contrast, in untreated mice, or animals given BM or BM + FL alone, there was marked cellular infiltration, and features of accelerated rejection. Donor-derived DC could be propagated in vitro from the BM of heart transplant recipients given donor BM, especially from mice that also received tacrolimus +/- FL. At day 21, donor-derived cells could only be propagated from the BM + FL + tacrolimus-treated group. These findings show that numbers of donor antigen presenting cells (APC) or their progenitors can be markedly increased in conventionally immunosuppressed organ allograft recipients given donor BM + a potent haematopoietic and DC-growth promoting cytokine. Although withdrawal of systemic immunosuppression appears to allow exhibition of the potential allostimulatory activity of these donor APC leading to rejection, the model provides a useful basis for further evaluation of the persistence and manipulation of donor haematopoietic cells and in particular, donor-derived APC, on the outcome of organ transplantation.
Erratum
Publisher: Proceedings of the National Academy of Sciences
Date: 03-02-2009
A combination of local inflammation and central memory T cells potentiates immunotherapy in the skin
Publisher: The American Association of Immunologists
Date: 15-12-2012
Abstract: Adoptive T cell therapy uses the specificity of the adaptive immune system to target cancer and virally infected cells. Yet the mechanism and means by which to enhance T cell function are incompletely described, especially in the skin. In this study, we use a murine model of immunotherapy to optimize cell-mediated immunity in the skin. We show that in vitro–derived central but not effector memory-like T cells bring about rapid regression of skin-expressing cognate Ag as a transgene in keratinocytes. Local inflammation induced by the TLR7 receptor agonist imiquimod subtly yet reproducibly decreases time to skin graft rejection elicited by central but not effector memory T cells in an immunodeficient mouse model. Local CCL4, a chemokine liberated by TLR7 agonism, similarly enhances central memory T cell function. In this model, IL-2 facilitates the development in vivo of effector function from central memory but not effector memory T cells. In a model of T cell tolerogenesis, we further show that adoptively transferred central but not effector memory T cells can give rise to successful cutaneous immunity, which is dependent on a local inflammatory cue in the target tissue at the time of adoptive T cell transfer. Thus, adoptive T cell therapy efficacy can be enhanced if CD8+ T cells with a central memory T cell phenotype are transferred, and IL-2 is present with contemporaneous local inflammation.
The T-cell receptor repertoire influences the tumor microenvironment and is associated with survival in aggressive B-cell lymphoma
Publisher: No publisher found
Date: 2017
DOI: 10.21417/B7C301
Cognate CD4+ Help Elicited by Resting Dendritic Cells Does Not Impair the Induction of Peripheral Tolerance in CD8+ T Cells
Publisher: The American Association of Immunologists
Date: 15-02-2007
DOI: 10.4049/JIMMUNOL.178.4.2094
Abstract: Peripheral tolerance is required to prevent autoimmune tissue destruction by self-reactive T cells that escape negative selection in the thymus. One mechanism of peripheral tolerance in CD8+ T cells is their activation by resting dendritic cells (DC). In contrast, DC can be “licensed” by CD4+ T cells to induce cytotoxic function in CD8+ T cells. The question that then arises, whether CD4+ T cell help could impair peripheral tolerance induction in self-reactive CD8+ T cells, has not been addressed. In this study we show that CD4+ T cell activation by resting DC results in helper function that transiently promotes the expansion and differentiation of cognate CD8+ T cells. However, both the CD4+ and CD8+ T cell populations ultimately undergo partial deletion and acquire Ag unresponsiveness, disabling their ability to destroy OVA-expressing pancreatic β cells and cause diabetes. Thus, effective peripheral tolerance can be induced by resting DC in the presence of CD4+ and CD8+ T cells with specificity for the same Ag.
Trafficking of APC from liver allografts of Flt3L-treated donors: Augmentation of potent allostimulatory cells in recipient lymphoid tissue is associated with a switch from tolerance to rejection
Publisher: Elsevier BV
Date: 03-1999
DOI: 10.1016/S0966-3274(99)80019-7
Abstract: Livers transplanted across major histocompatibility complex (MHC) barriers in mice are normally accepted without recipient immune suppression, and induce a state of functional tolerance. However, markedly increasing functional dendritic cells (DC) in the 'passenger leucocyte' population by donor pretreatment with the hematopoietic growth factor Flt3-ligand (Flt3L 10 microg/day for 10 days) results in acute allograft rejection. In this study, molecular, immunohistochemical and flow cytometric analysis of donor cell traffick into recipient lymphoid tissue 24 h after liver transplantation (C57BL/10 [H2b]-->C3H [H2k]) was performed. In addition, the capacity of donor-derived cells in these tissues to stimulate host T cell proliferation was examined. Reverse transcriptase polymerase chain reaction analysis revealed increases in donor genomic DNA in both thymi and spleens of mice given livers from Flt3L-treated donors compared to controls. Donor MHC class II+ (IAb+) cells in spleens were strikingly elevated (10-fold) in the former group. Two-colour flow cytometry revealed a similar increase in donor-derived H-2Kb+/I-Ab+ cells, and in the incidence of donor leucocytes expressing CD40, CD80, and CD86. CD11c+ DC comprised approximately 40% of the I-Ab+ cells in spleens of mice given livers from Flt3L-treated donors. These changes were associated with the presence, in spleens, of potent allostimulatory activity for naive recipient strain T cells, that was not observed in normal liver recipients. Elicitation of allograft rejection, associated with enhanced trafficking of stimulatory donor antigen-presenting cells (APC), in particular DC, suggests that normal liver graft survival and tolerance induction may be linked to failure/counter-regulation of APC-driven stimulation of effective anti-donor T cell responses.
KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.
Publisher: Elsevier BV
Date: 04-2018
The effect of interleukin-22 treatment on autoimmune diabetes in the NOD mouse.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2017
Distribution and characterisation of rat choroidal mast cells
Publisher: BMJ
Date: 03-1994
DOI: 10.1136/BJO.78.3.211
Abstract: Despite the implication that choroidal mast cells are involved in the onset of experimental autoimmune uveoretinitis (EAU), a widely used animal model of uveoretinitis, little is known of these cells. In the present study the distribution, total number, regional density, and phenotype of choroidal mast cells were examined in Lewis, Wistar Furth, PVG/c, and brown Norway rats. Choroidal mast cells were predominantly associated with arteries and arterioles of more than 30 microns diameter which lie in the outer (sclerad) choroid. The density of mast cells was greatest in the posterior choroid with density diminishing anteriorly. The choroid of male Lewis rats contained significantly greater number of mast cells than that of females (p < 0.01). Histochemical (Alcian blue/safranin) and immunohistochemical (anti-rat mast cell protease I and II monoclonal antibodies) studies revealed choroidal mast cells were of the connective tissue type. However, granule proteinase content appeared less than that of well characterised connective tissue mast cell populations such as those in mesentery and skin. Lewis rats exhibited the highest density of choroidal mast cells (23.6 (SD 1.2)/mm2), Wistar Furth approximately half that of Lewis (13.5 (0.7)/mm2) while PVG/c and brown Norway rats had very low densities (3.06(0.3) 1.95(0.2/mm2 respectively). These studies provide valuable choroidal mast cell data for rats which may have implications for our understanding of experimental models of intraocular inflammation and clinical uveitis.
Cell-based therapies for ocular inflammation
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.PRETEYERES.2013.02.002
Abstract: Since the plasticity and the potential for re-programming cells has become widely accepted, there has been great interest in cell-based therapies. These are being applied to a range of diseases, not least ocular diseases, where it is assumed that there is a reduced risk of immune rejection although this may be more perceived than real. There are two broad classes of cell-based therapies: those aimed at restoring structure and function of specific tissues and cells and those directed towards restoring immunological homeostasis by controlling the damaging effects of inflammatory disease. Stem cells of all types represent the first group and prototypically have been used with the aim of regenerating failing cells. In contrast, immune cells have been suggested as potential modulators of inflammation. However, there is functional overlap in these two applications, with some types of stem cells, such as mesenchymal stem cells, demonstrating a potent immunomodulatory effect. This review summarises recent information on cell based therapies for ocular disease, with special emphasis on ocular inflammatory disease, and explores current uses, potential and limitations.
APC‐targeted proinsulin expression inactivates insulin‐specific memory CD8+T cells in NOD mice
Publisher: Wiley
Date: 11-07-2017
DOI: 10.1038/ICB.2017.48
Abstract: Type 1 diabetes (T1D) results from T-cell-mediated autoimmune destruction of pancreatic β cells. Effector T-cell responses emerge early in disease development and expand as disease progresses. Following β-cell destruction, a long-lived T-cell memory is generated that represents a barrier to islet transplantation and other cellular insulin-replacement therapies. Development of effective immunotherapies that control or ablate β-cell destructive effector and memory T-cell responses has the potential to prevent disease progression and recurrence. Targeting antigen expression to antigen-presenting cells inactivates cognate CD8
Donor bone marrow potentiates the effect of tacrolimus on nonvascularized heart allograft survival
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-1998
DOI: 10.1097/00007890-199802270-00005
Abstract: The influence of donor hematopoietic cell microchimerism on organ allograft survival has been studied largely in vascularized transplant models. Here, we examine the impact of donor bone marrow (BM) cells administered intravenously together with transient systemic tacrolimus therapy on microchimerism, the survival of nonvascularized cardiac allografts, and growth of donor antigen-presenting cells [dendritic cells (DCs)] from recipient BM. Adult male C3H (H2k) mice received heterotopic heart transplants from B10 (H2b) donors in the dorsal ear pinna. They were given no further treatment, or either a short course of tacrolimus (FK506 2 mg/kg i.p. from day 0 to day 13), unmodified donor BM cells (50x10(6) i.v. on day 0) or both treatments. Grafts were examined daily for contractile activity. Anti-donor cytotoxic T lymphocyte responses were determined in recipients' spleens. Microchimerism (IAb+ cells) was demonstrated by immunocytochemical staining of spleens, and of cells expanded from recipient BM using cytokines and culture conditions that promote the growth of DCs. Tacrolimus alone significantly prolonged median heart graft survival time from 10 to 22 days (P<0.001). BM alone failed to prolong graft survival. By contrast, tacrolimus + donor BM resulted in a mean survival time of 42 days (P<0.01 compared with tacrolimus treatment alone). This marked increase in heart allograft survival was associated with reduced anti-donor cytotoxic T lymphocyte responses attributable to a nonspecific effect of tacrolimus. In addition, however, a link was observed between the beneficial effect of donor BM and comparatively large numbers of donor major histocompatibility complex class II (IAb+)-positive cells in recipients' spleens, and in cultures of granulocyte-macrophage colony-stimulating factor + interleukin-4-stimulated DCs from recipients' BM. No donor-derived cells were propagated from heart graft recipients given either tacrolimus or donor BM alone. This nonvascularized organ transplant model demonstrates the positive effect on allograft survival of donor BM given at the time of transplant to transiently immunosuppressed recipients. The findings also reveal links between hematopoietic cell chimerism, the presence of donor DC progenitors in recipient BM, and organ allograft survival.
Reduced interleukin‐2 responsiveness impairs the ability of T reg cells to compete for IL‐2 in nonobese diabetic mice
Publisher: Wiley
Date: 09-02-2016
DOI: 10.1038/ICB.2016.7
Abstract: Enhancement of regulatory T cell (Treg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of Treg cell homeostasis and function. We investigated how IL-2 pathway defects impact Treg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD Treg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, Treg cell frequency was preserved through expansion of CD25(low), effector phenotype Treg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD Treg cells. In vivo, treatment with IL-2-anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD Treg cells in the spleen and blood, but had reduced efficacy on lymph node Treg cells. In contrast, NOD CD8(+) and CD4(+) effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD Treg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2.
Origin and steady-state turnover of major histocompatibility complex Class II-positive dendritic cells and resident-tissue macrophages in the iris of the rat eye
Publisher: Elsevier BV
Date: 08-1996
DOI: 10.1016/0165-5728(96)00070-7
Abstract: Recent studies have identified distinct but co-existing networks of resident tissue macrophages and MHC class II-positive DC present in tissues bordering the anterior chamber of the eye, a site classically regarded as 'immune-privileged'. As the DC network, present at approximately 500 cells/mm2, accounts for virtually all MHC class II immunostaining in these tissues and possesses potent capacity to stimulate primary allogenic responses in vitro, it is proposed that these cells may play an important role in immune surveillance of the anterior chamber. Tissue macrophage and DC population kinetics in the iris were examined by using X-irradiation exposure to interrupt the steady-state renewal of these cells by haematopoietically derived precursors. MHC class II-positive iris DC exhibited a half-life of approximately 3 days, a rapid turnover rate which closely resembled that of DC present in mucosal epithelia. In contrast, the resident tissue macrophage population displayed a considerably slower turnover (half-life of 10-12 days) comparable to that of epidermal Langerhans cells in the present study. Bone marrow transplantation studies confirmed the haematopoietic origin of the iris DC population. The present study provides the first estimates of the steady-state population kinetics of antigen-presenting cell populations in the iris and has important implications for understanding the role of these cells in immunological homeostasis of the anterior chamber.
Steady-state antigen-expressing dendritic cells terminate CD4+ memory T-cell responses
Publisher: Wiley
Date: 25-06-2010
Abstract: CD4(+) T cells are important effectors of inflammation and tissue destruction in many diseases of immune dysregulation. As memory T cells develop early during the preclinical stages of autoimmune and inflammatory diseases, immunotherapeutic approaches to treatment of these diseases, once established, must include the means to terminate memory T-cell responses. Traditionally, it has been considered that, due to their terminally differentiated nature, memory T cells are resistant to tolerance induction, although emerging evidence indicates that some immunotherapeutic approaches can terminate memory T-cell responses. Here, we demonstrate that CD4(+) memory T-cell responses can be terminated when cognate antigen is transgenically expressed in steady-state DC. Transfer of in-vitro-generated CD4(+) memory T cells establishes, in nontransgenic recipients, a stable and readily recalled memory response to cognate antigen. In contrast, upon transfer to mice expressing cognate antigen targeted to DC, memory CD4(+) T cells undergo a phase of limited proliferation followed by substantial deletion, and recall responses are effectively silenced. This finding is important in understanding how to effectively apply immunotherapy to ongoing T-cell-mediated autoimmune and inflammatory diseases.
Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection
Publisher: American Diabetes Association
Date: 09-03-2016
DOI: 10.2337/DB15-1418
Abstract: Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by “conventional” therapies, memory T cell–mediated attack is a substantial challenge in islet transplantation, and this will extend to application of personalized approaches using stem cell–derived replacement β-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement β-cells. Here, we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions, inactivates established memory CD8+ T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8+ memory T cell–mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell–mediated gene therapy effectively terminates antigen-specific memory T-cell responses, and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and, importantly, the clinical application of personalized β-cell replacement therapies using patient-derived stem cells.
Immunogenic, but Not Steady-State, Antigen Presentation Permits Regulatory T-Cells To Control CD8+ T-Cell Effector Differentiation by IL-2 Modulation
Publisher: Public Library of Science (PLoS)
Date: 13-01-2014
Persistence of recipient lymphocytes in NOD mice after irradiation and bone marrow transplantation
Publisher: Elsevier BV
Date: 03-2004
Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity
Publisher: Springer Science and Business Media LLC
Date: 15-01-2006
DOI: 10.1038/NI1300
Abstract: The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.
Temporal regulation of natural killer T cell interferon gamma responses by β-catenin-dependent and-independent wnt signaling
Publisher: Frontiers Media SA
Date: 16-03-2018
Induction of antigen-specific tolerance through hematopoietic stem cell-mediated gene therapy: The future for therapy of autoimmune disease?
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.AUTREV.2011.08.012
Abstract: Based on the principle that immune ablation followed by HSC-mediated recovery purges disease-causing leukocytes to interrupt autoimmune disease progression, hematopoietic stem cell transplantation (HSCT) has been increasingly used as a treatment for severe autoimmune diseases. Despite clinically-relevant outcomes, HSCT is associated with serious iatrogenic risks and is suitable only for the most serious and intractable diseases. A further limitation of autologous HSCT is that relapse rates can be high, suggesting disease-causing leukocytes are incompletely purged or the environmental and genetic determinants that drive disease remain active. Incorporation of antigen-specific tolerance approaches that synergise with autologous HSCT could reduce or prevent relapse. Further, by reducing the requirement for highly toxic immune-ablation and instead relying on antigen-specific tolerance, the clinical utility of HSCT could be significantly ersified. Substantial progress has been made exploring HSCT-mediated induction of antigen-specific tolerance in animal models but studies have focussed on primarily on prevention of autoimmune diseases. However, as diagnosis of autoimmune disease is often not made until autoimmune disease is well developed and populations of autoantigen-specific pathogenic effector and memory T cells have become well established, immunotherapies must be developed to address effector and memory T-cell responses which have traditionally been considered the key impediment to immunotherapy. Here, focusing on T-cell mediated autoimmune diseases we review progress made in antigen-specific immunotherapy using HSCT-mediated approaches, induction of tolerance in effector and memory T cells and the challenges for progression and clinical application of antigen-specific 'tolerogenic' HSCT therapy.
Increased generation of dendritic cells from myeloid progenitors in autoimmune-prone nonobese diabetic mice
Publisher: The American Association of Immunologists
Date: 15-05-2002
DOI: 10.4049/JIMMUNOL.168.10.5032
Abstract: Aberrant dendritic cell (DC) development and function may contribute to autoimmune disease susceptibility. To address this hypothesis at the level of myeloid lineage-derived DC we compared the development of DC from bone marrow progenitors in vitro and DC populations in vivo in autoimmune diabetes-prone nonobese diabetic (NOD) mice, recombinant congenic nonobese diabetes-resistant (NOR) mice, and unrelated BALB/c and C57BL/6 (BL/6) mice. In GM-CSF/IL-4-supplemented bone marrow cultures, DC developed in significantly greater numbers from NOD than from NOR, BALB/c, and BL/6 mice. Likewise, DC developed in greater numbers from sorted (lineage−IL-7Rα−SCA-1−c-kit+) NOD myeloid progenitors in either GM-CSF/IL-4 or GM-CSF/stem cell factor (SCF)/TNF-α. [3H]TdR incorporation indicated that the increased generation of NOD DC was due to higher levels of myeloid progenitor proliferation. Generation of DC with the early-acting hematopoietic growth factor, flt3 ligand, revealed that while the increased DC-generative capacity of myeloid-committed progenitors was restricted to NOD cells, early lineage-uncommitted progenitors from both NOD and NOR had increased DC-generative capacity relative to BALB/c and BL/6. Consistent with these findings, NOD and NOR mice had increased numbers of DC in blood and thymus and NOD had an increased proportion of the putative myeloid DC (CD11c+CD11b+) subset within spleen. These findings demonstrate that diabetes-prone NOD mice exhibit a myeloid lineage-specific increase in DC generative capacity relative to diabetes-resistant recombinant congenic NOR mice. We propose that an imbalance favoring development of DC from myeloid-committed progenitors predisposes to autoimmune disease in NOD mice.
Dendritic cells in the thymus contribute to T-regulatory cell induction
Publisher: Proceedings of the National Academy of Sciences
Date: 16-12-2008
Abstract: Central tolerance is established through negative selection of self-reactive thymocytes and the induction of T-regulatory cells (T R s). The role of thymic dendritic cells (TDCs) in these processes has not been clearly determined. In this study, we demonstrate that in vivo , TDCs not only play a role in negative selection but in the induction of T R s. TDCs include two conventional dendritic cell (DC) subtypes, CD8 lo Sirpα hi/+ (CD8 lo Sirpα + ) and CD8 hi Sirpα lo/− (CD8 lo Sirpα − ), which have different origins. We found that the CD8 hi Sirpα + DCs represent a conventional DC subset that originates from the blood and migrates into the thymus. Moreover, we show that the CD8 lo Sirpα + DCs demonstrate a superior capacity to induce T R s in vitro . Finally, using a thymic transplantation system, we demonstrate that the DCs in the periphery can migrate into the thymus, where they efficiently induce T R generation and negative selection.
γ T cells augment rejection of skin grafts by enhancing cross-priming of CD8 T cells to skin-derived antigen
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1038/JID.2012.16
Hepatic dendritic cells: Immunobiology and role in liver transplantation
Publisher: Oxford University Press (OUP)
Date: 08-1999
DOI: 10.1002/JLB.66.2.322
Abstract: Traditional investigations of hepatic dendritic cells (DC) have focused on immunohistochemical studies of these cells within normal and pathological liver tissue. The recent availability of reagents for the improved characterization of DC, together with cytokine-based methods for the expansion of liver DC both in vivo and in vitro have begun to provide new insight into the immunobiology of these important antigen-presenting cells. Hepatic DC probably play a key role in the host response to blood-borne pathogens, and in the pathogenesis of infectious and autoimmune liver diseases. They appear to be important in determining the balance between liver transplant tolerance and rejection. Their possible role in oral and portal venous tolerance remains to be defined. In this article, we focus on emerging aspects of hepatic DC immunobiology, with particular reference to liver transplantation. J. Leukoc. Biol. 66: 322–330 1999.
Harnessing urbanisation for human wellbeing and planetary health
Publisher: Elsevier BV
Date: 03-0003
HPV16 E7 expression in skin induces TSLP secretion, type 2 ILC infiltration and atopic dermatitis‐like lesions
Publisher: Wiley
Date: 20-01-2015
DOI: 10.1038/ICB.2014.123
Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses
Publisher: American Society of Hematology
Date: 15-02-2008
DOI: 10.1182/BLOOD-2007-07-103200
Abstract: Antigen stimulation of naive T cells in conjunction with strong costimulatory signals elicits the generation of effector and memory populations. Such terminal differentiation transforms naive T cells capable of differentiating along several terminal pathways in response to pertinent environmental cues into cells that have lost developmental plasticity and exhibit heightened responsiveness. Because these cells exhibit little or no need for the strong costimulatory signals required for full activation of naive T cells, it is generally considered memory and effector T cells are released from the capacity to be inactivated. Here, we show that steady-state dendritic cells constitutively presenting an endogenously expressed antigen inactivate fully differentiated memory and effector CD8+ T cells in vivo through deletion and inactivation. These findings indicate that fully differentiated effector and memory T cells exhibit a previously unappreciated level of plasticity and provide insight into how memory and effector T-cell populations may be regulated.
Altering the balance between immune activation versus regulation in the skin to promote CD8 T-cell activity within epithelial cancers
Publisher: American Association for Cancer Research (AACR)
Date: 15-07-2016
DOI: 10.1158/1538-7445.AM2016-3999
Abstract: The Human Papilloma Virus (HPV) 16 is a high-risk HPV known to be a causative agent in numerous cancers including cervical cancer. While prophylactic vaccines exist to combat the spread of HPV16, successful therapeutic vaccines to combat established HPV16-associcated disease remain elusive. The expression, in a mouse model (“E7”), of the HPV16 E7 gene in keratinocytes under the control of the K14 promoter, leads to a local immune suppressive environment, as evidenced by the lack of graft rejection when E7 skin grafts are placed on WT recipient mice. Furthermore, well healed (& days) E7 skin grafts are not rejected when mice are immunised with E7 peptide in combination with Quil A- or CASAC-based adjuvants. This is despite a substantial increase in E7 peptide/H-2Db pentamer staining in the blood, and marked killing of E7-peptide expressing TC-1 cells when injected i.v., confirming that CD8 T-cells respond to vaccination and differentiate into CTL capable of killing E7-expressing target cells. We hypothesised that the removal of regulatory T-cells (T-reg) might lead to E7 graft rejection in immunised mice. The co-administration of an anti-CD4-depeting antibody at the time of immunisation led to rejection of ∼50% of grafts. To confirm a role for T-reg, E7-grafted T-reg-deficient Rag1-/- mice received purified donor CD8 T-cells from E7-vaccinated WT mice. FACS staining of Rag1-/- lymph nodes 30 days post CD8+ T-cell transfer confirmed the absence of classical CD4+FoxP3+ Treg, however the E7 grafts did not reject. As in the WT mice however, rejection could be induced through the co-administration of an anti-CD4 antibody. The data suggest that the removal of a CD4+, non T-reg cell, leads to CD8+ T-cell activity in the skin as evidenced by E7 skin graft destruction. Citation Format: Jennifer A. Bridge, Nana H. Overgaard, Raymond J. Steptoe, Ian H. Frazer, James W. Wells. Altering the balance between immune activation versus regulation in the skin to promote CD8 T-cell activity within epithelial cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research 2016 Apr 16-20 New Orleans, LA. Philadelphia (PA): AACR Cancer Res 2016 (14 Suppl):Abstract nr 3999.
In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV-driven tumours
Publisher: Wiley
Date: 12-11-2014
DOI: 10.1038/ICB.2013.75
Abstract: Small interfering RNAs (siRNAs) to inhibit oncogene expression and also to activate innate immune responses via Toll-like receptor (TLR) recognition have been shown to be beneficial as anti-cancer therapy in certain cancer models. In this study, we investigated the effects of local versus systemic delivery of such immune-stimulating Dicer-substrate siRNAs (IS-DsiRNAs) on a human papillomavirus (HPV)-driven tumour model. Localized siRNA delivery using intratumour injection of siRNA was able to increase siRNA delivery to the tumour compared with intravenous (IV) delivery and potently activated innate immune responses. However, IV injection remained the more effective delivery route for reducing tumour growth. Although IS-DsiRNAs activated innate immune cells and required interferon-α (IFNα) for full effect on tumour growth, we found that potent silencing siRNA acting independently of IFNα were overall more effective at inhibiting TC-1 tumour growth. Other published work utilising IS-siRNAs have been carried out on tumour models with low levels of major histocompatibility complex (MHC)-class 1, a target of natural killer cells that are potently activated by IS-siRNA. As TC-1 cells used in our study express high levels of MHC-class I, the addition of the immunostimulatory motifs may not be as beneficial in this particular tumour model. Our data suggest that selection of siRNA profile and delivery method based on tumour environment is crucial to developing siRNA-based therapies.
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