Evidence Of Immune Activation Research Articles

Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study.

AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575-590).

Evidence for Immune Activation and Resistance to Glucocorticoids Following Childhood Maltreatment in Adolescents Without Psychopathology.

Early-life stress (ELS) increases the risk for psychopathology. Immune and endocrine changes have been reported in adults and are associated with maladaptation of stress-responsive systems. Here we investigated the effects of ELS on endocrine and immune pathways in adolescents without psychopathology. Thirty adolescents with a history of childhood maltreatment and 27 adolescents without ELS history were recruited. Blood and hair samples were obtained from all participants. Lymphocytes were isolated and stimulated in vitro. Flow cytometry was used to evaluate lymphocyte subsets, Th1/Th2/Th17 cytokines, mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB) signaling pathways, as well as lymphocyte sensitivity to dexamethasone. Brain-derived neurotrophic factor (BDNF) and hair cortisol were assessed with enzyme-linked immunosorbent assays (ELISAs). Adolescents with a history of ELS had increased percentages of T-cell activation markers (CD3+CD4+CD25+ and CD3+CD69+) and senescent T cells (CD8+CD28- and CD4+CD28-), as well as decreased percentages of NK (CD3-CD56+) and NK T cells (CD3+CD56+). Following stimulation, lymphocytes of ELS+ adolescents produced significantly more IL-2, IL-4, IFN-γ, and IL-17 and engaged more MAPK ERK and NF-κB signaling. ELS was associated with increased hair cortisol levels in parallel with increased lymphocyte resistance to dexamethasone and low plasma BDNF levels. These data provide the first indication of the presence of immune activation and pro-inflammatory profiles in healthy adolescents exposed to ELS, which could contribute to increased vulnerability of trauma-related psychopathology later in life. The underlying mechanisms of this impairment may include the enhanced activation of both MAPK and NF-κB signaling in parallel to partial resistance to glucocorticoids.

Enhanced susceptibility to alcohol-induced bacterial translocation, immune activation, and persistent inflammation in patients with alcoholic hepatitis: a prospective observational study

Abstract Up to 30% chronic heavy drinkers develop a spectrum of severe alcoholic liver diseases, including alcoholic hepatitis (AH). Alcohol-induced impairment of intestinal integrity and microbial translocation into the portal vein lead to immune activation and play a major role in the pathogenesis of AH. To better understand why AH develops only in some heavy drinkers and the effect of alcohol abstinence on immunity, we conducted a prospective study to compare plasma LPS levels and peripheral blood immunoprofiles between 68 AH patients and 65 heavy drinkers without liver disease (HDC) who were followed up to 12 months. Plasma samples were also obtained from 31 health donors (HD). Plasma LPS was detected in a higher portion of AH patients than HDC (80% vs 49%) at baseline, and in only 8% HD. However, LPS levels were not different between AH an HDC subjects with detectable LPS. Compared with HDC, AH patients had higher baseline plasma levels of sCD14, sCD163, sICAM-1, sVCAM-1, IL-22, TNF-α, IL-8, IP10, IL-4, IL-6, IL-9, IL-10, FGF2, IL-7, IL-15, and TGF-α, but lower levels of the anti-inflammatory chemokine MDC. AH patients also had more activated, yet dysfunctional monocytes, T cells, and B cells as they expressed higher levels of CD38 and CD69, but lower levels of HLA-DR, CD80, and CD86. In spite of having significant bacterial translocation, HDC showed little evidence of immune activation. With alcohol abstinence, levels of many dysregulated immune markers normalized in AH patients. However, TNF-α, IL-8, IL-10, sCD163, and sVCAM-1 levels remained higher. Conclusion AH patients were more susceptible to alcohol-induced bacterial translocation and immune activation. Alcohol abstinence reduced but did not fully reverse immunological abnormalities.

Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy

Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. By combining 5'LTR-to-3'LTR single-genome amplification and direct amplicon sequencing, we have identified the presence of "defective" proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection. Although these novel usHIV-RNA transcripts had exon structures that were different from those of the known spliced HIV-RNA variants, they maintained translationally competent ORFs, involving elements of gag, pol, env, rev, and nef to encode a series of novel HIV-1 chimeric proteins. These novel usHIV-RNAs were detected in five of five patients, including four of four patients with prolonged viral suppression of HIV-RNA levels <40 copies per milliliter for more than 6 y. Our findings suggest that the persistent defective proviruses of HIV-1 are not "silent," but rather may contribute to HIV-1 pathogenesis by stimulating host-defense pathways that target foreign nucleic acids and proteins.

MP72-15 GENE EXPRESSION IN THE BLOOD OF INTERSTITIAL CYSTITIS PATIENTS AND CONTROLS DISTINGUISHES PATHWAYS ASSOCIATED WITH INTERSTITIAL CYSTITIS AND PREDICTS CLINICAL RESPONSE TO CYCLOSPORINE THERAPY

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Interstitial Cystitis1 Apr 2016MP72-15 GENE EXPRESSION IN THE BLOOD OF INTERSTITIAL CYSTITIS PATIENTS AND CONTROLS DISTINGUISHES PATHWAYS ASSOCIATED WITH INTERSTITIAL CYSTITIS AND PREDICTS CLINICAL RESPONSE TO CYCLOSPORINE THERAPY Daniel Shoskes, Karen Keslar, Barbara Tucky, and Robert Fairchild Daniel ShoskesDaniel Shoskes More articles by this author , Karen KeslarKaren Keslar More articles by this author , Barbara TuckyBarbara Tucky More articles by this author , and Robert FairchildRobert Fairchild More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1628AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Interstitial cystitis (IC) is a heterogeneous condition with urinary and systemic symptoms. Clinically relevant phenotyping has been a challenge, but some patients, especially those with Hunner's Ulcers, have evidence for immune activation. We hypothesize that gene expression signatures can be used as a biomarker to phenotype patients with IC and predict response to specific therapies. METHODS As part of a clinical trial of oral cyclosporine A (CyA), blood was collected from 26 IC patients prior to treatment and after 3 months of CyA at 3 mg/kg/d as well as from 20 asymptomatic controls. A training set of 6 controls and 6 IC patients including those who did or did not respond to CyA was initially run. RNA was isolated from whole blood (Tempus tubes) and analyzed using Illumina HT-12 v4 BeadChip arrays. PANTHER pathway analysis and DAVID functional classification were used for annotation and grouping of differently expressed genes. RESULTS Using the criteria of fold-changes less than 0.5 or greater than 2 and p<.05, we found 155 unique genes that were differently expressed in the blood of IC patients vs controls representing 55 pathways including inflammation mediated by chemokines and cytokines, T cell activation, integrin signaling, angiogenesis, and apoptosis. Comparing patients who subsequently had significant clinical improvement with CyA therapy to those who didn't improve, there were 37 genes with at least two fold differential expression. Using DAVID functional annotation clustering, these genes represented responses in inflammation, wound healing, and innate immunity. Finally, following CyA therapy, interleukin signaling changed in all patients but other pathways that changed were distinct between responders and non-responders. In CyA responders, the altered gene expression pathways were related to matrix remodeling (plasminogen activating cascade) and pain modulation (cannabinoid and dopamine receptor signaling). CONCLUSIONS Gene expression signatures in whole blood distinguished between IC patients and controls as well as between patients who would subsequently improve with CyA therapy. Pathways altered following CyA therapy in the responders could serve as potential targets for new drug development. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e958 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Daniel Shoskes More articles by this author Karen Keslar More articles by this author Barbara Tucky More articles by this author Robert Fairchild More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract P3-07-31: Immune activation signatures identify a subset of ER+ breast cancers with increased pathologic complete response to neoadjuvant chemotherapy

Abstract Background: Proliferation is the strongest predictor of response to neoadjuvant chemotherapy in estrogen receptor-positive (ER+) breast cancer. Evidence of immune activation has also been associated with improved response to neoadjuvant chemotherapy in breast cancer. We hypothesized that immune signatures may be associated with response independent of proliferation in ER+ breast cancers. Approach: We compiled microarray expression data from breast cancer biopsies obtained prior to neoadjuvant chemotherapy on 465 ER-positive/HER2-negative patients by reported pathologic receptor status. We evaluated the association of 118 published gene expression signatures with response to neoadjuvant chemotherapy, based on study-defined pathologic complete response (pCR) versus residual disease (RD). Results: Overall, 42 of 118 signatures were significantly associated with response to neoadjuvant chemotherapy in ER+ breast cancer (FDR-corrected p&amp;lt;0.05, simple logistic regression). Of those signatures that achieved significance, 52% (22/42) of signatures were proliferation-associated based on correlation to the 11-gene PAM50 proliferation index (Pearson's R2&amp;gt;0.30, p&amp;lt;1e-10). Among signatures that were NOT proliferation-associated, 50% (10/20) were immune-related. Using unsupervised hierarchical clustering of all 118 signatures, these ten immune signatures formed a distinct cluster. Of the 10 signatures, nine were designed to reflect "immune activation" and were highly correlated with each other in ER+ tumors (R2&amp;gt;0.4, p&amp;lt;0.001). The mean of each of these nine signatures was significantly higher in patients with pCR versus RD (FDR-corrected p&amp;lt;0.05, t-test). Patients with higher "immune activation" signatures had increased likelihood of pCR within multiple subgroups of ER+ breast cancer, including luminal B and non-luminal PAM50 subgroups, as well as intermediate- and high-proliferation ER+ breast cancers. For luminal A or low-proliferation breast cancers, "immune activation" signatures were not significantly associated with response, though very few patients achieved pCR in these two subgroups. Conclusions: Gene expression signatures associated with "immune activation" identify a subset of ER+ breast cancers with higher rates of pCR to neoadjuvant chemotherapy. These "immune activation" signatures appear to be proliferation-independent and may provide additional predictive information to existing gene expression-based approaches for ER+ breast cancer. Citation Format: Stover DG, Waks AG, Erica ML, Brugge JS, Winer EP, Selfors LM. Immune activation signatures identify a subset of ER+ breast cancers with increased pathologic complete response to neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-31.

Abstract A38: Phase I study of combination immunotherapy with agonistic CD40 monoclonal antibody (mAb) CP-870,893 (αCD40) and anti-CTLA-4 antibody tremelimumab (treme) in patients with metastatic melanoma

Abstract Purpose: Combining therapeutic activation of immune cells and checkpoint inhibition may improve response rates and overall survival in patients with metastatic melanoma. CP-870,893 (αCD40) is an agonistic fully human IgG2 mAb targeting the immune stimulatory molecule CD40. Treme is a fully human IgG2 mAb targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a negative co-stimulatory molecule found on T cells. Methods: Patients with histologically confirmed metastatic melanoma, measurable disease by RECIST 1.0, and no history of autoimmune diseases or previous treatments targeting CD40 or CTLA-4 were enrolled on a single-arm open-label dose escalation phase 1 study. αCD40 and treme were dosed i.v. every 3 weeks and 12 weeks, respectively , for a potential total of 16 doses of αCD40 and 4 doses of treme. Dose escalation followed a 3 + 3 strategy with alternating increases of αCD40 (range 0.1-0.2 mg/kg) and treme (range 6-15 mg/kg) in each cohort. Patient outcomes were scored using the Common Terminology Criteria for Adverse Events v3.0. Flow cytometric analysis of baseline blood samples was compared to samples obtained at least 3 weeks after the last dose of αCD40 and treme. Results were compared by paired t test. Results: Toxicity: Twenty-four patients were enrolled and treated at 4 different dose levels. Two patients were replaced per protocol due to rapid, symptomatic progression of disease; these patients were not evaluated for response but were included in toxicity analysis. Patients had received a median of 1 (range 0-5) prior treatments for metastatic disease prior to enrollment. Dose-limiting toxicities (DLT), considered to be likely due to treatment, were colitis (n=1) and hypophysitis (n=1) at 0.2mg/kg αCD40 and 15mg/kg treme and uveitis (n=1) at 0.2mg/kg αCD40 and 10mg/kg treme. Cytokine release syndrome (CRS), grade 1-2, occurring within 24 hours of CP administration, was the most common treatment-related toxicity occurring in 19 (79.2%) patients and typically involving chills and fever. CRS symptoms were controlled with standard supportive care in the chemotherapy infusion suite and with instructed use of antipyretics and antihistamines at home. All episodes of CRS resolved within 24 hours of αCD40 administration. The estimated maximum tolerated dose was 0.2 mg/kg of αCD40 and 10 mg/kg of treme. Outcomes: Overall objective response rate was 27.3% (best response): two patients (9.1%) had complete responses to treatment and four (18.2%) patients had partial responses. The median follow-up was 22 months with a median progression free survival of 2.5 months (95% CI: 2.0–3.1 months) and a median overall survival (OS) of 26.1 months (95% CI: 13.1–39.1 months). Two patients remain disease free for more than 18 months after study completion without further medical treatment. Correlative studies: Flow cytometric analysis of peripheral blood lymphocytes revealed changes in CD8+ T cell phenotypes. Double positive granzyme B+ and Ki-67+ cells increased from 0.56 ± 0.17% (mean ± standard error) for all CD8+ T cells at baseline to 1.01 ± 0.23% post-treatment (p=0.03). CD8+ T cells expressing both programmed cell death 1 and eomesodermin were also higher after treatment, increasing from 7.7 ± 1.1% to 10.4 ±1.8% (p= 0.04) of all CD8+ T cells. Conclusion: Combination therapy with αCD40 and treme was well-tolerated in patients with metastatic melanoma, with rates of CRS and other toxicity similar to previously reported rates for αCD40 or treme treatments alone. Overall objective response rate was 27.3%, with median OS of 26.1 months including two patients still disease-free. This antitumor activity, and biomarker evidence of immune activation, provides a rationale for expanded study. Citation Format: David L. Bajor, Rosemarie Mick, Matthew J. Riese, Richman P. Lee, Xiaowei Xu, Drew A. Torigian, Erietta Stelekati, Martha Sweeney, Brendan J. Sullivan, Lynn M. Schuchter, Ravi Amaravadi, E John Wherry, Robert H. Vonderheide. Phase I study of combination immunotherapy with agonistic CD40 monoclonal antibody (mAb) CP-870,893 (αCD40) and anti-CTLA-4 antibody tremelimumab (treme) in patients with metastatic melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A38.

5-Aminosalicylate Is No Help in Diarrhea-Predominant IBS

In diarrhea-predominant irritable bowel syndrome (IBS-D), the colon is endoscopically and histologically normal, but there is some evidence of immune activation. To assess the potential efficacy of slow-release mesalamine in IBS-D, researchers randomized 136 patients to receive mesalamine (4 g per day) or placebo for 12 weeks in …

A gender factor in shaping T-cell immunity to melanoma.

A gender factor in shaping T-cell immunity to melanoma.

Evidence for immune activation in patients with residual hepatitis C virus RNA long after successful treatment with IFN and ribavirin.

Low-level hepatitis C virus (HCV) RNA may persist in PBMCs after successful treatment of chronic hepatitis C, but the consequences of this phenomenon are unclear. Forty-nine patients who achieved a sustained virological response (SVR) after pegylated IFN and ribavirin therapy were analysed 52-66 months after the SVR. HCV RNA was detected in PBMCs from 18 patients (47.4 %), and PBMCs in two patients stained positive for non-structural protein 3 (NS3). Quantification of various cytokine and chemokine transcripts in PBMCs revealed that levels of IL-6, IL-8, IL-12, TNF-α and macrophage inflammatory protein 1β were significantly higher in HCV-positive patients than in HCV-negative individuals. In conclusion, persistence of HCV RNA in PBMCs of patients with a SVR appears to be associated with immune activation.

HIV enteropathy and aging: gastrointestinal immunity, mucosal epithelial barrier, and microbial translocation.

Despite decreases in morbidity and mortality as a result of antiretroviral therapy, gastrointestinal dysfunction remains common in HIV infection. Treated patients are at risk for complications of 'premature' aging, such as cardiovascular disease, osteopenia, neurocognitive decline, malignancies, and frailty. This review summarizes recent observations in this field. Mucosal CD4 lymphocytes, especially Th17 cells, are depleted in acute HIV and simian immune deficiency virus (SIV) infections, although other cell types also are affected. Reconstitution during therapy often is incomplete, especially in mucosa. Mucosal barrier function is affected by both HIV infection and aging and includes paracellular transport via tight junctions and uptake through areas of apoptosis; other factors may affect systemic antigen exposure. The resultant microbial translocation is associated with systemic immune activation in HIV and SIV infections. There is evidence of immune activation and microbial translocation in the elderly. The immune phenotypes of immunosenescence in HIV infection and aging appear similar. There are several targets for intervention; blockage of residual mucosal virus replication, preventing antigen uptake, modulating the microbiome, improving T cell recovery, combining therapies aimed at mucosal integrity, augmenting mucosal immunity, and managing traditional risk factors for premature aging in the general population. Aging may interact with HIV enteropathy to enhance microbial translocation and immune activation.

Corrigendum: Evidence for immune activation in patients with residual hepatitis C virus RNA long after successful treatment with IFN and ribavirin.

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Indication of Immune Activation in Patients with Perceived Food Hypersensitivity

Majority of the patients with perceived food hypersensitivity have irritable bowel syndrome (IBS), and a significant proportion of IBS patients also attribute their gastrointestinal complaints to food items. Different factors such as disturbed intestinal fermentation, enteric dysmotility, post-infectious changes and altered microbial flora in the colon as well as psychological disturbances likely play a role in the pathophysiology and symptoms generation in patients with food hypersensitivity. In addition, a number of studies in these patient groups indicate that local, systemic and mucosal immune systems are activated. The question now is no longer intestinal immune activation, but how the immune system is activated in these patients. In the following review, the potential pathogenetic role of the immune system and evidence of immune activation are reported in patients with perceived food hypersensitivity.

Implications of Acquired Environmental Enteric Dysfunction for Growth and Stunting in Infants and Children Living in Low- and Middle-Income Countries

Changes in small bowel function early in infancy in developing countries are increasingly being demonstrated, probably accompanied by altered mucosal architecture in most individuals, including reduced enterocyte mass and evidence of immune activation and inflammation in the mucosa. These alterations appear to be the result of factors of uncertain nature in the environment, and may be a cause of growth faltering and stunting in young children. For these reasons, this constellation of findings is being referred to as environmental enteropathy, or as we propose herein, environmental enteric dysfunction. If the causes were known and effective interventions were available, strategies and policies to intervene at--or possibly before--birth could be developed and promoted in order to prevent subsequent malnutrition and recurrent infection, which are known to interact in a cyclical and synergistic manner in a downward clinical course often ending in death. Resources would be mobilized and applied differently, and the emphasis would change from treatment to prevention. In order to move in this highly desired direction, investments in research will be required to establish the criteria to assess environmental enteric dysfunction, determine its predictive value for growth faltering and stunting, identify the causes, and propose and test potential interventions. The concepts and tools are available. What is required is the decision to move forward along this pathway to better health for infants and children in low-income countries.

A New Murine Model for Gastrointestinal Anthrax Infection.

The scientific community has been restricted by the lack of a practical and informative animal model of gastrointestinal infection with vegetative Bacillus anthracis. We herein report the development of a murine model of gastrointestinal anthrax infection by gavage of vegetative Sterne strain of Bacillus anthracis into the complement-deficient A/J mouse strain. Mice infected in this manner developed lethal infections in a dose-dependent manner and died 30 h-5 d following gavage. Histological findings were consistent with penetration and growth of the bacilli within the intestinal villi, with subsequent dissemination into major organs including the spleen, liver, kidney and lung. Blood cultures confirmed anthrax bacteremia in all moribund animals, with approximately 1/3 showing co-infection with commensal enteric organisms. However, no evidence of immune activation was observed during infection. Time-course experiments revealed early compromise of the intestinal epithelium, characterized by villus blunting and ulceration in the ileum and jejunum. A decrease in body temperature was most predictive of near-term lethality. Antibiotic treatment of infected animals 24 h following high-dose bacterial gavage protected all animals, demonstrating the utility of this animal model in evaluating potential therapeutics.

Clinical and histological features of leprosy and human immunodeficiency virus co-infection in Brazil

Both leprosy and human immunodeficiency virus (HIV) are infectious diseases, and are an important global health problem. Patients with leprosy who are co-infected with HIV seem to be at higher risk of developing leprosy reactions. To examine the histological features of leprosy in patients with HIV and leprosy co-infection, particularly to determine whether the typical leprosy histopathology is present in skin biopsies, and to assess the histological features of leprosy reactions in co-infected patients. This was a matched cohort study with 11 co-infected patients and 31 HIV-negative patients with leprosy. A structured protocol for skin-biopsy evaluation was followed, focusing on inflammation of the skin and dermal nerves. Of the 11 HIV-positive patients, 7 (63%) had borderline tuberculoid (BT) leprosy and 5 (70%) of these 7 patients had developed a type 1 reaction. The lesions in these patients were immunologically active, with 100% of biopsies having evidence of compact granulomas, 90% evidence of oedema and 30% evidence of necrosis. In this study, patients co-infected with HIV and M.leprae had the typical histological lesions of leprosy. There was evidence of immune activation in patients who received combination antiretroviral therapy, and these patients had BT leprosy and leprosy-upgrading reactions.

Postinfectious Chronic Gut Dysfunction: From Bench to Bedside

The relationship between acute infectious gastroenteritis and the subsequent development of chronic gastrointestinal dysfunction has been established on the basis of clinical observations, prospective and epidemiological clinical studies, and from animal models. Clinically, two specific syndromes have been identified: postinfectious irritable bowel syndrome and postinfectious functional dyspepsia. These syndromes may develop in up to 30% of patients with gastroenteritis and both host and microbial risk factors have been identified. Initially, these conditions were considered to be short lived but recent epidemiological data indicate that they can persist for at least 8 years or more. Studies on animal models as well as in patients have identified changes in intestinal barrier and motor functions, as well as evidence of immune activation and low-grade inflammation. These findings prompt ongoing research into the role of anti-inflammatory medication treatment for these conditions. In addition, current research examines possible changes in the intestinal microbiota as a basis for the low-grade inflammation and symptom generation. The long-term consequences of these syndromes remain to be determined.

Biological effects and clinical significance of lenalidomide‐induced tumour flare reaction in patients with chronic lymphocytic leukaemia: in vivo evidence of immune activation and antitumour response

Lenalidomide has demonstrated impressive antileukaemic effects in patients with chronic lymphocytic leukaemia (CLL). The mechanism(s) by which it mediates these effects remain unclear. Clinically, CLL patients treated with lenalidomide demonstrate an acute inflammatory reaction, the tumour flare reaction that is suggestive of an immune activation phenomenon. Samples from CLL patients treated with lenalidomide were used to evaluate its effect on the tumour cell and components of its microenvironment (immune cellular and cytokine). Lenalidomide was unable to directly induce apoptosis in CLL cells in vitro, however it modulated costimulatory (CD80, CD83, CD86) surface molecules on CLL cells in vitro and in vivo. Concurrently, we demonstrated that NK cell proliferation was induced by lenalidomide treatment in patients and correlated with clinical response. Cytokine analysis showed increase in levels of TNF-α post-lenalidomide treatment, consistent with acute inflammatory reaction. Furthermore, the basal cytokine profile (high IL-8, MIG, IP-10 and IL-4 levels and low IL-5, MIP1a, MIP1b, IL12/p70) was predictive of clinical response to lenalidomide. Collectively, our correlative studies provide further evidence that the antileukaemic effect of lenalidomide in CLL is mediated not only through modulation of the leukaemic clone but also through elements of the tumour microenvironment.

Immune-mediated steroid-responsive epileptic spasms and epileptic encephalopathy associated with VGKC-complex antibodies

Autoantibodies that bind to voltage-gated potassium-channel complex proteins (VGKC-complex antibodies) occur frequently in adults with limbic encephalitis presenting with cognitive impairment and seizures. Recently, VGKC-complex antibodies have been described in a few children with limbic encephalitis, and children with unexplained encephalitis presenting with status epilepticus. We report a case of infantile-onset epileptic spasms and developmental delay compatible with epileptic encephalopathy. Our patient was a female infant, aged 4 months at presentation. She had evidence of immune activation in the central nervous system with elevated cerebrospinal fluid neopterin and mirrored oligoclonal bands, which prompted testing for autoantibodies. VGKC-complex antibodies were elevated (201 pmol/L, normal<100), but extended antibody testing, including leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2), was negative. The patient showed a partial response to steroid treatment, which was started late in the disease course. On review at 13 months of age, her development was consistent with an age of 5 to 6 months. These results suggest that VGKC-complex antibodies might represent a marker of immune therapy responsiveness in a subgroup of patients with infantile epileptic encephalopathy.

Strong viremia control in vaccinated macaques does not prevent gradual Th17 cell loss from central memory

It has been proposed that microbial translocation might play a role in chronic immune activation during HIV/SIV infection. Key roles in fighting bacterial and fungal infections have been attributed to Th17 and Tc17 cells. Th17 cells can be infected with HIV/SIV, however whether effective vaccination leads to their maintenance following viral challenge has not been addressed. Here we retrospectively investigated if a vaccine regimen that potently reduced viremia post-challenge preserved Th17 and Tc17 cells, thus adding benefit in the absence of sterilizing protection. Rhesus macaques were previously vaccinated with replication-competent Adenovirus recombinants expressing HIV tat and HIV env followed by Tat and gp140 protein boosting. Upon SHIV 89.6P challenge, the vaccines exhibited a significant 4 log reduction in chronic viremia compared to sham vaccinated controls which rapidly progressed to AIDS [39]. Plasma and cryopreserved PBMC samples were examined pre-challenge and during acute and chronic infection. Control macaques exhibited a rapid loss of CD4 + cells, including Th17 cells. Tc17 cells tended to decline over the course of infection although significance was not reached. Immune activation, assessed by Ki-67 expression, was associated with elevated chronic viremia of the controls. Significantly increased plasma IFN-γ levels were also observed. No increase in plasma LPS levels were observed suggesting a lack of microbial translocation. In contrast, vaccinated macaques had no evidence of immune activation within the chronic phase and preserved both CD4 + T-cells and Tc17 cells in PBMC. Nevertheless, they exhibited a gradual, significant loss of Th17 cells which concomitantly displayed significantly higher CCR6 expression over time. The gradual Th17 cell decline may reflect mucosal homing to inflammatory sites and/or slow depletion due to ongoing low levels of SHIV replication. Our results suggest that potent viremia reduction during chronic SHIV infection will delay but not prevent the loss of Th17 cells.