Immunoprivileged Site Research Articles

Regulatory T cells limit age-associated retinal inflammation and neurodegeneration

BackgroundAgeing is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown.MethodsRegulatory T cells were selectively depleted in both young (2–4 months) and aged (18–23 months) FoxP3-DTR mice. We evaluated neuroretinal degeneration, gliosis, subretinal space phagocyte infiltration, and retinal pigmented epithelium morphology through immunofluorescence analysis. Subsequently, aged Treg depleted animals underwent adoptive transfer of both young and aged regulatory T cells from wild-type mice, and the resulting impact on neurodegeneration was assessed. Statistical analyses employed included the U-Mann Whitney test, and for comparisons involving more than two groups, 1-way ANOVA analysis followed by Bonferroni’s post hoc test.ResultsOur study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes.ConclusionOur findings demonstrate an essential role for regulatory T cells in maintaining age retinal homeostasis and preventing age-related neurodegeneration. This previously undescribed role of regulatory T cells in limiting retinal inflammation, RPE/choroid epithelium damage and subsequently photoreceptor loss with age, opens novel avenues to explore regulatory T cell neuroprotective and anti-inflammatory properties as potential therapeutic approaches for age-related retinal diseases.

DENDRITIC CELLS IN GLIOBLASTOMA TREATMENT: A MODERN VIEW OF THE PROBLEM AND OWN EXPERIENCE.

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults. The improvement of the efficacy of GBM treatment is an urgent problem encouraging the development of novel therapeutic strategies, in particular, immunotherapeutic modalities. With more understanding of the intimate interrelationships between the immune system and the mechanisms involved in cancer origin and progression, the skepticism related to the relevance of the immunotherapeutic approaches in the treatment of brain tumors is gradually decreasing. The review discloses the modern concepts on the association between CNS and the immune system. For a long time, CNS was considered as the immunoprivileged site that prevents the effects of immunotherapy in the treatment of brain tumors. Nowadays, these views are reconsidered, which opens the way to the use of immunotherapeutic approaches in GBM treatment. The results of the recent clinical trials on immunotherapy as a supplement to the conventional GBM treatment are considered. Vaccines based on the dendritic cell (DC) technology are regarded as the most promising for this purpose. The preliminary results of the Ukrainian clinical study are also presented and discussed. The results of the international clinical trials as well as our own experience give evidence of the relevance for using DC vaccines in the complex treatment of GBM, which is supported by the increased survival of patients and the safety of vaccine application. It is of high importance that GBM patients with the most unfavorable prognosis can benefit from DC vaccines as a component of the complex treatment. The prospects for immunotherapy in neurooncology are discussed.

Retention of Human iPSC-Derived or Primary Cells Following Xenotransplantation into Rat Immune-Privileged Sites.

In regenerative medicine, experimental animal models are commonly used to study potential effects of human cells as therapeutic candidates. Although some studies describe certain cells, such as mesenchymal stromal cells (MSC) or human primary cells, as hypoimmunogenic and therefore unable to trigger strong inflammatory host responses, other studies report antibody formation and immune rejection following xenotransplantation. Accordingly, the goal of our study was to test the cellular retention and survival of human-induced pluripotent stem cell (iPSCs)-derived MSCs (iMSCs) and primary nucleus pulposus cells (NPCs) following their xenotransplantation into immune-privileged knee joints (14 days) and intervertebral discs (IVD; 7 days) of immunocompromised Nude and immunocompetent Sprague Dawley (SD) rats. At the end of both experiments, we could demonstrate that both rat types revealed comparably low levels of systemic IL-6 and IgM inflammation markers, as assessed via ELISA. Furthermore, the number of recovered cells was with no significant difference between both rat types. Conclusively, our results show that xenogeneic injection of human iMSC and NPC into immunoprivileged knee and IVD sites did not lead to an elevated inflammatory response in immunocompetent rats when compared to immunocompromised rats. Hence, immunocompetent rats represent suitable animals for xenotransplantation studies targeting immunoprivileged sites.

Moving to the Outskirts: Interplay Between Regulatory T Cells and Peripheral Tissues.

Regulatory T cells (Tregs) restrain excessive immune responses and dampen inflammation. In addition to this classical immune suppressive role, Tregs in non-lymphoid tissues also promote tissue homeostasis, regeneration and repair. In this review, we outline our current understanding of how Tregs migrate to peripheral tissues and the factors required for their maintenance at these sites. We discuss the tissue-specific adaptations of Tregs at barrier and immuno-privileged sites and the mechanisms that regulate their function within these organs. Furthermore, we outline what is known about the interactions of Tregs with non-immune cells in the different peripheral tissues at steady state and upon challenge or tissue damage. A thorough understanding of the tissue-specific adaptations and functions of Tregs will potentially pave the way for therapeutic approaches targeting their regenerative role.

HLA-G/sHLA-G and HLA-G-Bearing Extracellular Vesicles in Cancers: Potential Role as Biomarkers.

As a non-classic major histocompatibility complex (MHC) class I molecule, human leukocyte antigen G (HLA-G) is expressed in fetal-maternal interface and immunoprivileged site only in healthy condition, and in pathological conditions such as cancer, it can be de novo expressed. It is now widely accepted that HLA-G is a key molecule in the process of immune escape of cancer cells, which is ubiquitously expressed in the tumor environment. This raises the possibility that it may play an adverse role in tumor immunity. The expression level of HLA-G has been demonstrated to be highly correlated with clinical parameters in many tumors, and its potential significance in the diagnosis and prognosis of cancer has been postulated. However, because HLA-G itself has up to seven different subtypes, and for some subtypes, detected antibodies are few or absent, it is hard to evaluate the actual expression of HLA-G in tumors. In the present work, we described (a) the structure and three main forms of HLA-G, (b) summarized the mechanism of HLA-G in the immune escape of tumor cells, (c) discussed the potential role of HLA-G as a tumor marker, and reviewed (d) the methods for detecting and quantifying HLA-G.

The FasLane to ocular pathology-metalloproteinase cleavage of membrane-bound FasL determines FasL function.

Fas ligand (FasL) is best known for its ability to induce cell death in a wide range of Fas-expressing targets and to limit inflammation in immunoprivileged sites such as the eye. In addition, the ability of FasL to induce a much more extensive list of outcomes is being increasingly explored and accepted. These outcomes include the induction of proinflammatory cytokine production, T cell activation, and cell motility. However, the distinct and opposing functions of membrane-associated FasL (mFasL) and the C-terminal soluble FasL fragment (sFasL) released by metalloproteinase cleavage is less well documented and understood. Both mFasL and sFasL can form trimers that engage the trimeric Fas receptor, but only mFasL can form a multimeric complex in lipid rafts to trigger apoptosis and inflammation. By contrast, a number of reports have now documented the anti-apoptotic and anti-inflammatory activity of sFasL, pointing to a critical regulatory function of the soluble molecule. The immunomodulatory activity of FasL is particularly evident in ocular pathology where elimination of the metalloproteinase cleavage site and the ensuing increased expression of mFasL can severely exacerbate the extent of inflammation and cell death. By contrast, both homeostatic and increased expression of sFasL can limit inflammation and cell death. The mechanism(s) responsible for the protective activity of sFasL are discussed but remain controversial. Nevertheless, it will be important to consider therapeutic applications of sFasL for the treatment of ocular diseases such as glaucoma.

Adequate Placental Sampling for the Diagnosis and Characterization of Placental Infection by Zika Virus.

The detection of Zika virus (ZIKV) in immunoprivileged anatomical sites, potential sites for viral persistence, may guide the confirmation of undefined cases of ZIKV infection and also bring to light unknown pathways of viral transmission. Thus, this study aimed to characterize ZIKV infection in stratified, standardized placental samples in women with exanthematic febrile manifestations during pregnancy and compare findings to the standard investigation protocol of official health agencies. To this end, a case series of placental findings within a prospective cohort study was conducted over a period of 24 months. Serum/urine were obtained at the time of clinical case identification. Placental sampling was performed following standard investigation protocol (samples of 1.0 cm sent to a reference laboratory) and in a systematic way at various regions, such as chorionic plate, chorionic villi, basal plate, amniotic membrane, and umbilical cord, for subsequent ZIKV identification and quantification. Clinical information was obtained and histological preparation with hematoxylin–eosin staining for morphological evaluation was performed. This case series included 17 placentas systematically collected. Of these, 14 were positive by qRT-PCR for ZIKV, 5 in the umbilical cord, 7 in the amniotic membrane, 7 in the chorionic plate, 13 in the chorionic villi, and 7 in the basal plate, whereas none were reported by the reference laboratory. The most common morphological and anatomopathological findings were increased stromal cellularity, villitis, calcification, maternal vascular malperfusion, placental hypoplasia, and maternal–fetal hemorrhage (intervillous thrombi). Seven women presented positive testing for ZIKV in serological and/or molecular tests during gestation in urine. While viral quantification in urine ranged from 101 to 103 FFU eq/ml, that in different placental regions ranged from 103 to 108 FFU eq/g. Thus, ZIKV can infect different regions of the placenta and umbilical cord of pregnant women, showing that the systematic collection and adequate storage of the placenta is fundamental for the detection of ZIKV in this organ. The detection of ZIKV in the placenta after several months of initial symptoms suggests that this tissue may be a site for viral persistence during pregnancy.

Evaluation of Novel Antibodies to Centrin-1 for Radioimmunotherapy of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the US with a very low survival rate. Unlike other solid malignancies, a biopsy of the pancreas is very invasive and recommend only with a mass suspected to be PDAC. Centrin1 (CETN1), a cancer/testis antigens (CATs), has been showed a 25-fold upregulation in 50% of the tumors from pancreatic cancer patients. Since testes are an immunoprivileged site, CETN1 could be a perfect target of radioimmunotherapy as the side effects of the treatment would be minimal. In this study, we developed novel antibodies (69-11 and 76-6) that are highly specific to CETN1, compared to its compensatory protein CENT2, which is widely expressed in all eukaryotic cells. 69-11 and 76-6 are either labeled with 213Bi, an alpha emitter, or with 177Lu, a beta emitter, for the treatment study. The radiolabeled antibodies were administered to PDAC xenografts-bearing nude mice. The localization of the radiolabeled antibodies in the tumors and normal organs was determined with micro SPECT/CT imaging. The tumors were monitored for 50 days. The toxicity assessment included weekly blood chemistry and kidney and liver functions assessment when PDAC-bearing mice were sacrificed at the end of the study. Labeling with 213Bi converted CETN1-specific antibodies into a very effective radioimmunotherapy reagent with tumor growth significantly (P=0.01) slowed down by either 100 or 200 μCi single injection. Importantly, the effect of the antibodies on the tumors was CETN1-specific, as 200 μCi control IgG had no effect on the tumor growth. In spite of impressive localization in the tumor demonstrated during the imaging experiments, 177Lu-labeled antibody was not very effective in slowing down tumor growth with no difference from 177Lu-IgG control (P=0.06) and was several folds less effective than 213Bi-labeled antibody. Both 213Bi and 177Lu groups showed only transient hematologic toxicity and absence of liver and kidney toxicity attesting to the very high safety margin of targeting CETN1 with radioimmunotherapy. In conclusion, the novel antibodies have the ability to detect CETN1 in vivo and in vitro, are highly efficacious and safe for treatment of PDAC, and warrant further work on developing them into clinical agents for diagnosis and therapy of PDAC.

Local release of rapamycin by microparticles delays islet rejection within the anterior chamber of the eye

The anterior chamber of the eye (ACE) has emerged as a promising clinical islet transplantation site because of its multiple advantages over the conventional intra-hepatic portal site. This includes reduced surgical invasiveness and increased islet graft survival rate. It also allows for enhanced accessibility and monitoring of the islets. Although the ACE is initially an immuno-privileged site, this privilege is disrupted once the islet grafts are re-vascularized. Given that the ACE is a confined space, achieving graft immune tolerance through local immunosuppressive drug delivery is therefore feasible. Here, we show that islet rejection in the ACE of mice can be significantly suppressed through local delivery of rapamycin by carefully designed sustained-release microparticles. In this 30-day study, allogeneic islet grafts with blank microparticles were completely rejected 18 days post-transplantation into mice. Importantly, allogeneic islet grafts co-injected with rapamycin releasing microparticles into a different eye of the same recipient were preserved much longer, with some grafts surviving for more than 30 days. Hence, islet allograft survival was enhanced by a localized and prolonged delivery of an immunosuppressive drug. We envisage that this procedure will relieve diabetic transplant recipients from harsh systemic immune suppression, while achieving improved glycemic control and reduced insulin dependence.

Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas.

While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma‐associated microglia/macrophages (GAMs), on patients’ clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I–IV). Furthermore, we analyzed a cohort of 241 IDH1R132H‐non‐mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high‐grade astrocytomas by CD11b‐based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT‐PCR and bioinformatic analyses. A higher amount of CD68‐, CD163‐ and CD206‐positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro‐inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti‐inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2‐like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H‐non‐mutant GBMs.

Time for a "Plan B" in Peritoneal Metastatic Disease.

Peritoneal involvement in cancer is the harbinger of a particularly unfavorable prognosis. The peritoneal cavity microenvironment is skewed toward immunoregulatory conditions promoted by macrophage populations and innate-like B-1 B cells, which provide immune privilege to malignant cell foci. In this issue of Cancer Research, Haro and colleagues demonstrate that triggering innate IgM-mediated B-1a immune responses via pathogen- or danger-associated molecular pattern recognition exerts antitumor effects on peritoneal metastases by inducing classical complement cascade activation. Exploitation of innate B-1 humoral responses and noncellular immunity is a promising strategy to counter the "castling" of metastatic tumor cells in the peritoneal immunoprivileged site.See related article by Haro et al., p. 159.

Understanding central nervous system efficacy of antimicrobials.

The requirements for antimicrobial treatment to reach the central nervous system (CNS) are of maximal importance, for two major reasons: (i) the brain is an immuno-privileged site, with virtually no leukocytes in the brain parenchyma or cerebrospinal fluid (CSF) at baseline; (ii) the blood–brain barrier (BBB) drastically reduces the diffusion of antimicrobials into the CNS [1]. Treatment of CNS infections has been a major area of research since the discovery of the first antimicrobials. Treatment regimens recommended for encephalitis [2, 3], meningitis [4], and brain abscess [5], have to comply with the pharmacokinetic (PK), and pharmacodynamic (PD) characteristics of available antibacterial, antiviral, antifungal, and antiparasitic agents [6]. Due to the numerous constraints created by the BBB, therapeutic options are quite limited, so that current practices for treatment of CNS infections are remarkably similar worldwide, with much less heterogeneity than for other major infectious diseases (e.g. pneumonia, abdominal, or skin and skin structure infections). This paper summarizes the main parameters that must be taken into account to ensure efficacy of antimicrobial agents in the CNS, with an emphasis on antibacterial drugs.

Vaccine Strategies in Gliomas

To discuss the current state of glioma vaccine development and highlight the challenges associated with clinical implementation of these approaches. Vaccination strategies against gliomas have matured considerably during the past years, although proof-of efficacy from controlled clinical trials is still lacking. Advances in antigen discovery, including the definition of neoepitopes including epidermal growth factor receptor variant III (EGFRvIII), isocitrate dehydrogenase (IDH)1R132H and Histone (H)3.3K27M, using multi-omic approaches and computational algorithms allow targeting single antigens, but also implementing truly personalized approaches. In addition, new concepts of vaccine manufacturing including RNA and DNA vaccines improve immunogenicity and applicability in personalized settings. As an increasing amount of clinical data defy the concept of the central nervous system (CNS) as a strictly immunoprivileged site, novel vaccine approaches enter the clinic including critical efforts to identify biomarkers of response and resistance and strategies to overcome the immunosuppressive glioma microenvironment.

Microencapsulation of Parathyroid Cells for the Treatment of Hypoparathyroidism.

Cell encapsulation is an alternative to avoid rejection of grafted tissue, thus bringing an interesting alternative in cell therapy. It is particularly relevant in ailments where only the implant of small quantities of tissues is warranted. In such circumstances, the use of immunosuppressive therapy in patients implanted with tissues from donors is debatable, yet unavoidable at present in order to prevent rejection and/or sensitization of the host to the tissue, in turn jeopardizing the success of successive implants. Hence, a new line of thought, which aims to provide an immunoprivileged site for the grafted tissue, while at the same time insure its nutrition, as well as its survival and continued function, appears as a most attractive possibility. To achieve these goals, cells or tissues harvested for transplant could be encapsulated in biologically compatible matrices. Among the matrices currently in existence, sodium alginate is the most widely used polymer for tissue encapsulation.In the present chapter, we present a technique used to encapsulate parathyroid tissue, for use as cell transplant therapy in patients with secondary hypoparathyroidism. With this procedure, implanted tissue survives and remains functional for up to 18 months.

Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8+ Cells In Vivo.

HIV- and SIV-specific CD8+ T cells are typically largely excluded from lymphoid B cell follicles, where virus-producing cells are most highly concentrated, suggesting that B cell follicles are somewhat of an immunoprivileged site where virus-specific CD8+ T cells are not able to clear all follicular HIV- and SIV-producing cells. To gain insights into follicular CD8+ T cell function, we characterized follicular virus-specific CD8+ T cells in situ by using an SIV-infected rhesus macaque model of HIV. We found that subsets of follicular SIV-specific CD8+ T cells are able to migrate throughout the follicle, are likely inhibited by Foxp3+ cells, and are likely exhausted but that, nonetheless, subsets are likely functional, as they express markers consistent with effector function and show signs of suppressing viral replication in vivo These findings support HIV cure strategies that increase the frequency of functional follicular virus-specific CD8+ T cells.

The roles of TAM receptor tyrosine kinases in the mammalian testis and immunoprivileged sites.

Three members of a receptor tyrosine kinase family, including Tyro3, Axl, and Mer, are collectively called as TAM receptors. TAM receptors have two common ligands, namely, growth arrest specific gene 6 (Gas6) and protein S (ProS). The TAM-Gas6/ProS system is essential for phagocytic removal of apoptotic cells, and plays critical roles in regulating immune response. Genetic studies have shown that TAM receptors are essential regulators of the tissue homeostasis in immunoprivileged sites, including the testis, retina and brain. The mechanisms by which the TAM-Gas6/ProS system regulates the tissue homeostasis in immunoprivileged sites are emerging. The roles of the TAM-Gas6/ProS system in regulating the immune privilege were intensively investigated in the mouse testis, and several studies were performed in the eye and brain. This review summarizes our current understanding of TAM signaling in the testis and other immunoprivileged tissues, as well as highlights topics that are worthy of further investigation.

Development of RGD-modified nanoparticles with epigallocatechin gallate (EGCG) loading as ophthalmic nanomedicine to inhibit corneal neovascularization development

Development of RGD-modified nanoparticles with epigallocatechin gallate (EGCG) loading as ophthalmic nanomedicine to inhibit corneal neovascularization development

Acute Myeloid Leukemia Relapse Presenting as Complete Monocular Vision Loss due to Optic Nerve Involvement.

Acute myeloid leukemia (AML) involvement of the central nervous system is relatively rare, and detection of leptomeningeal disease typically occurs only after a patient presents with neurological symptoms. The case herein describes a 48-year-old man with relapsed/refractory AML of the mixed lineage leukemia rearrangement subtype, who presents with monocular vision loss due to leukemic eye infiltration. MRI revealed right optic nerve sheath enhancement and restricted diffusion concerning for nerve ischemia and infarct from hypercellularity. Cerebrospinal fluid (CSF) analysis showed a total WBC count of 81/mcl with 96% AML blasts. The onset and progression of visual loss were in concordance with rise in peripheral blood blast count. A low threshold for diagnosis of CSF involvement should be maintained in patients with hyperleukocytosis and high-risk cytogenetics so that prompt treatment with whole brain radiation and intrathecal chemotherapy can be delivered. This case suggests that the eye, as an immunoprivileged site, may serve as a sanctuary from which leukemic cells can resurge and contribute to relapsed disease in patients with high-risk cytogenetics.

Abstract A019: Prognostic significance of natural killer ligand expression in acute myeloid leukemia

Abstract Immune evasion is a hallmark of persistence and progression of many haematological and non-haematological tumors. Progression of acute myeloid leukaemia (AML) post allogeneic stem cell transplant is often associated with evidence of immune escape and relapse in immuno-privileged sites. Natural killer (NK) cells play a key role in the control of malignancy and have been implicated in the success of haplo-identical allogeneic transplantation for AML. It is not known whether expression of NK cell-activating ligands on AML blasts may allow for improved immunological surveillance in the absence of allogeneic transplant following remission induction and therefore predict a lower rate of relapse in these high-risk patients. A pilot study of 19 AML patients undertaken by our group and others identified that patients with intermediate/high blast expression of activating NK ligands MIC A and B, CD155 and ULBP1,2,5 and 6 correlated with favourable cytogenetics and a lower incidence of leukaemia-specific mortality, compared to those with low to nil expression. We further assessed the impact of NK ligand (CD112 and CD155, HLA-A/B/C, PD-L1 and PD-L2, MIC A and B, ULBP1,2,5 and 6) expression on prognosis in AML on a larger cohort. Bone marrow aspirates from 63 newly diagnosed patients who received intensive cytarabine based remission induction chemotherapy were evaluated by 14 colour flow cytometry on a BD LSR Fortessa for expression of 4 activating and 6 inhibitory ligands. Blasts were identified by size, granularity and expression of CD45 according to diagnostic flow cytometry gating procedures. The number and net phenotype (inhibitory vs activating) of ligand expression was compared with both overall survival (OS) and relapse free survival (RFS). The median age of the cohort was 53.7 years, with a median bone marrow blast count of 71% at diagnosis. 73% of patients had intermediate risk cytogenetics (as defined by the MRC classification), 19% were poor risk, with only 8% having a favourable cytogenetic profile. Median survival was 19.3 months and correlated closely with cytogenetic risk group. MIC A and B, ULBP1,2,5 and 6, all recognized by the NK cell activating receptor NKG2D, were found to be the most prevalent on AML blasts, with 50% of patients expressing one or more of these ligands. However the intensity and combinatorial expression of these markers varied extensively between patients. Interim survival analysis showed a trend towards increased OS in patients having a net activating ligand phenotype compared to those with a balanced or an inhibitory phenotype. This difference was more pronounced in the subset of patients with intermediate risk cytogenetics. Further subgroup and single ligand analyses are underway. As well as highlighting the essential role that NK cells play in modulating the anti-tumour immune response, this preliminary data also suggests that expression of NK cell ligands on the surface of AML blasts at diagnosis may correlate with overall survival and become a promising biomarker for patient outcome in AML. Citation Format: Rachel Koldej, Jane Ripley, Christopher Chan, Mark Smyth, Paul Neeson, David Ritchie, Travis Perera. Prognostic significance of natural killer ligand expression in acute myeloid leukemia. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A019.

Ixodes tick saliva suppresses the keratinocyte cytokine response to TLR2/TLR3 ligands during early exposure to Lyme borreliosis.

Ixodes hard tick induces skin injury by its sophisticated biting process. Its saliva plays a key role to enable an efficient blood meal that lasts for several days. We hypothesized that this feeding process may also be exploited by pathogens to facilitate their transmission, especially in the context of arthropod-borne diseases. To test this, we used Lyme borreliosis as a model. This bacterial infection is caused by Borrelia burgdorferi sensu lato transmitted by Ixodes. We co-incubated Borrelia with human keratinocytes in the presence of poly (I: C), a dsRNA TLR3 agonist generated by skin injury. This induced a strong cytokine response from human primary keratinocytes that was much greater than that induced by Borrelia alone. OspC, a TLR2/1 agonist and a major surface lipoprotein of Borrelia also amplified the process. Interestingly, tick saliva inhibited cytokine responses by keratinocytes to these TLR agonists. We propose that Borrelia uses the immunoprivileged site produced by tick saliva to facilitate its transmission.