Administration Of IFN-alpha Research Articles

A-103 Combined immune-based strategies targeting viral persistence in ART-suppressed SIV-infected rhesus macaques

Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals, but does not eliminate an extremely durable reservoir of latently infected cells that is established early after infection. Understanding the phenotype and location of latently infected cells represents a critical challenge in designing a cure for HIV; furthermore, many HIV-infected individuals given ART exhibit residual inflammation, which may contribute to virus persistence. This presentation will discuss immune based strategies targeting HIV persistence developed over the past several years using the model of SIV infection in rhesus macaques. Recent work identified PD-1+ follicular helper CD4+ T-cells as an important cellular compartment for viral persistence. We have described that CTLA-4+PD-1-memory CD4+ T-cells, which share phenotypic markers with regulatory T-cells and localize outside the B-cell follicle of the lymph nodes, are significantly enriched in SIV-DNA; contain robust levels of replication-competent virus; and increase their contribution to the SIV reservoir with prolonged ART. Finally, we showed that Interleukin-21 and IFN-alpha administration in ART-treated, SIV-infected RMs reduces residual immune activation during ART and temporally delay viral rebound after ART treatment interruption. These recent advancements highlight the complexity and diversity of the mechanisms and T-cell populations that can contribute to the residual reservoirs of virally infected cells. Developing a range of different interventions to target individual components of viral reservoirs represent both a formidable challenge and an exciting opportunity for the years to come.

114. Inflammation induced changes in Anterior Cingulate Cortex Glutamate is associated with Depression and Fatigue

Behavioral symptoms including depression and fatigue are well-known consequences of activated peripheral immunity. Increased glutamate turnover in mood-regulating brain regions targeted by inflammatory mediators such as cytokines might mediate this relationship. We used single voxel proton magnetic resonance spectroscopy (MRS) to quantify glutamate concentrations in the anterior cingulate cortex (ACC) before and after four weeks of exposure to interferon (IFN)-alpha. IFN-alpha is an inflammatory cytokine used in the treatment of hepatitis C virus (HCV) infection that is known to cause depression and fatigue up to 50% of patients depending on the dose. Sixteen HCV patients underwent MRS scans, behavior ratings and immune marker assessments before and after 4 weeks of IFN-alpha treatment. Fourteen HCV control patients awaiting IFN-alpha therapy were studied in parallel. IFN-alpha administration was associated with significant increases in glutamate concentrations measured as glutamate/creatine (Glu/Cr) ratios in the ACC. Increases in the Glu/Cr ratio in the ACC was in turn correlated with increases in plasma soluble tumor necrosis factor 2 receptor (r = 0.54, p < 0.002), depression (r = 0.53, p < 0.003) and fatigue (r = 0.41, p < 0.03). The above findings are consistent with previously reported changes in ACC function among HCV patients following IFN-alpha treatment and among healthy volunteers administered immune stimuli including typhoid vaccination. These data suggest that altered glutamate metabolism as a result of impaired glial function may contribute to ACC changes following immune activation.

Interferon-alpha inhibits airway eosinophila and hyperresponsiveness in an animal asthma model

BackgroundAsthma is characterized by a chronic inflammatory process involving high numbers of inflammatory cells and mediators which have multiple inflammatory effects on the airway. Interferon (IFN)-alpha, which is used widely for treating chronic hepatitis C, is reported to have an effect on patients with Churg-Strauss syndrome. Therefore, it may also be suitable for patients with severe asthma.ObjectiveWe studied the effect of IFN-alpha on airway eosinophilia in a guinea pig model of asthma and the expression of adhesion molecules on human eosinophils and vascular endothelial cells.MethodsAfter antigen challenge, airway hyperresponsiveness and airway eosinophilia were measured in a guinea pig asthma model with or without airway IFN-alpha administration. Expression of adhesion molecules on eosinophils and cultured human umbilical vein endothelial cells (HUVECs) was also evaluated with or without IFN-alpha.ResultsIFN-alpha inhibited eosinophil recruitment into the tracheal wall and improved airway hyperresponsiveness in sensitized guinea pigs. IFN-alpha also significantly suppressed IL-1 beta-induced intercellular adhesion molecule-1 (ICAM-1) expression on HUVECs. However, IFN-alpha did not suppress platelet-activating factor-induced macrophage antigen-1 expression on human eosinophils. IFN-alpha significantly inhibited eosinophil adhesion to IL-1 beta-induced HUVECs and migration through IL-1 beta induced HUVECs.ConclusionThe findings suggest that the modulation of ICAM-1 in lung with pre-existing inflammation following treatment with IFN-alpha may be a novel and selective treatment for control of chronic airway inflammation and hyperresponsiveness associated with asthma.

178. Interferon-alpha-induced fatigue is associated with alterations in CNS glutamate metabolism as measured by magnetic resonance spectroscopy

Peripheral inflammatory states and their behavioral consequences including fatigue have been well-documented. One mechanism that may contribute to inflammation-induced behavioral changes is alterations in central nervous system (CNS) glutamate metabolism. To examine the role of CNS glutamate in inflammation-induced fatigue, proton magnetic resonance spectroscopy ( MRS ) was conducted in 12 patients with hepatitis C (HCV) before and after 4 weeks of treatment with interferon ( IFN )- alpha compared to 12 HCV patients awaiting IFN-alpha therapy. IFN-alpha is an inflammatory cytokine well-known to induce symptoms of fatigue in a high percentage of patients. Compared to controls, the glutamate /creatine ratio in the left basal ganglia significantly increased following 4 weeks of IFN-alpha administration ( p < 0.05). This increase in the glutamate /creatine ratio was in turn significantly correlated with increases in fatigue severity ( r = 0.435, p = 0.034). Increased glutamate concentrations in the left basal ganglia are consistent with previously reported alterations in basal ganglia function following IFN-alpha treatment in cancer patients and patients with HCV. The data are also consistent with changes in basal ganglia function in healthy volunteers administered immune stimuli including endotoxin or typhoid vaccination. These data suggest that altered glutamate metabolism possibly as a result of altered glial function may contribute to basal ganglia changes following acute and chronic immune activation.

Exogenous IFN-alpha Administration Reduces Influenza A Virus Replication in the Lower Respiratory Tract of Rhesus Macaques

To determine the role of innate immune responses in controlling influenza A virus replication, rhesus macaques (RM) were administered pegylated IFN-alpha prior to virus challenge. Systemic and mucosal pegylated IFN-alpha administration induced expression of the interferon-stimulated genes (ISG) MxA and OAS in the airways. RM treated with IFN-alpha 24 hours prior to influenza virus challenge had significantly lower peak vRNA levels in the trachea compared to untreated animals. In addition to blunting viral replication, IFN-alpha treatment minimized the weight loss and spike in body temperature after influenza infection of RM. These results confirm the importance of IFN-alpha induced innate immune responses in the rapid control of influenza A virus replication in primates.

Interferon α bei Patienten mit chronischer Hepatitis C

Interferon α (IFN-alpha) is widely used in the treatment of viral infections, including hepatitis C. Unfortunately depression is a common side effect of IFN-alpha therapy. The presence of depressive symptoms is important because they have an adverse effect on the course of the illness and reduce the quality of life and the treatment adherence. The current prospective study examines the effects of IFN-alpha on the development of depressive disorders, on cognitive functioning and on quality of life.A total of 25 patients with chronic hepatitis C infection were investigated. All patients were treated in the Department of Gastroenterology and Hepatology, University of Medicine of Graz, Austria. Psychometric observer rating and self-rating scales were administered 1 month and 3 months after the beginning of the antiviral treatment to evaluate depressive symptoms [Beck Depression Inventory (BDI); Hamilton Depression Scale]. The data on life satisfaction before therapy and health-related quality of life were obtained from the Fragebogen zur Lebenszufriedenheit (FLZ) and the SF-36 (Health Status Questionnaire). Cognitive function was based on the SKT (Syndrom Kurztest). All patients completed the Social Support Questionnaire (SSS), a multidimensional self-report measure of social support.Three months after the initial IFN-alpha administration in the whole sample significant impairments in health-related quality of life were found in the health-related domains "physical functioning", "role physical", "role emotional", "social functioning" and "vitality". The whole sample showed cognitive impairments. No changes in social support were recorded. Three months after the first INF-alpha administration, 48% (n=12) of the sample suffered from moderate clinical depression. In comparison to patients without pathological affective findings, patients with INF-alpha-induced clinical depression showed decreased life satisfaction before the initial antiviral therapy. Impairments in health-related quality of life (SF-36) were found in the sample with clinical depression in the health-related domains "general health", "social functioning", "role emotional", "vitality" and "mental health".Hepatitis C is associated with an increased prevalence of psychiatric disorders, particularly depression. INF-alpha patients having low levels of life satisfaction in the domains "self-concept" (skills, appearance, self-confidence, vitality …), "employment" and "physical health and constitution" seem to face a major risk of depression.

96. Chronic IFN-alpha administration reduces basal ganglia dopamine release in rhesus monkeys: Preliminary results from in vivo microdialysis and neuroimaging

96. Chronic IFN-alpha administration reduces basal ganglia dopamine release in rhesus monkeys: Preliminary results from in vivo microdialysis and neuroimaging

Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue

Cytokine-induced stimulation of p38 mitogen activated protein kinase (MAPK) has been shown to influence behaviorally-relevant pathophysiologic pathways including monoamine neurotransmission and neuroendocrine function and thus may contribute to behavioral changes that occur during chronic administration of the innate immune cytokine, interferon (IFN)-alpha. Accordingly, in the current study, phosphorylation (activation) of intracellular p38 MAPK in peripheral blood lymphocytes was analyzed by flow cytometry every 2h for 12h following the initial injection of IFN-alpha in eleven patients with chronic hepatitis C. Hourly assessments of plasma concentrations of adrenocorticotropic hormone, cortisol and interleukin-6 were also obtained. Symptoms of depression and fatigue were measured at baseline and after 4 and 12weeks of IFN-alpha treatment. Acute administration of IFN-alpha significantly increased the percentage of lymphocytes staining positive for intracellular phosphorylated p38 (p-p38). IFN-alpha-induced increases in p-p38 were significantly greater in patients that developed clinically significant depressive symptoms [Montgomery–Asberg Depression Rating Scale (MADRS) score⩾15] during the first 12weeks of IFN-alpha treatment. Increases in the percentage of p-p38-positive lymphocytes following the first IFN-alpha injection also highly correlated with depression severity at weeks 4 (r=0.85, p=0.001) and 12 (r=0.70, p=0.018). Similar relationships were observed for fatigue. Examination of relationships between p-p38 induction and factors previously reported to predict IFN-alpha-induced depressive symptoms revealed strong associations of p-p38 with baseline MADRS (r=0.82, p=0.002) and cortisol responses to the initial injection of IFN-alpha (r=0.91, p=0.000). Taken together, these findings indicate that sensitivity of p38 MAPK signaling pathways to immune stimulation is associated with depressive symptoms during chronic IFN-alpha treatment.

Interferon-lambda as a potential therapeutic agent in cancer treatment.

The discovery that type I interferon (IFN-alpha/beta) inhibited tumor cell growth was welcomed initially with great excitement as it rapidly became a U.S. Food and Drug Administration-approved drug to treat several forms of cancer. In time, this enthusiasm diminished as severe toxicity associated with IFN-alpha administration, resistance to the therapy, or less than optimal responses became evident in cancer patients, thus restricting its clinical use and reducing its potential as an anticancer drug. The recent discovery of a third type of IFN [IFN-lambda/interleukin (IL)-29/IL-28], which shares the same biological properties of type I IFNs, opens the door for evaluating the therapeutic potential of IFN-lambda as it uses a distinct receptor complex whose expression, unlike type I IFN receptors, is restricted to cells of specific lineage. It is unclear whether the mechanism by which type III IFNs restrict tumor cell proliferation is different or the same from the one utilized by type I IFN. Nevertheless, accumulating evidence as described in this review suggests that, in contrast to IFN-alpha therapy, IFN-lambda therapy could be less toxic and suitable for certain types of malignancies as not all cells are responsive to this cytokine.

Association between HCV amino acid substitutions and outcome of peginterferon and ribavirin combination therapy in HCV genotype 1b and high viral load

We prospectively compared the sensitivity to interferon (IFN) and the efficacy of antiviral combination therapy with peginterferon (PEG-IFN) and ribavirin for chronic hepatitis C virus (HCV) genotype 1b infection according to the amino acid sequences of the HCV core, E1, and NS5A regions reported to be associated with the outcome of antiviral therapy. A total of 107 patients with HCV genotype 1b were investigated. All patients received combination therapy with PEG-IFN alpha-2b and ribavirin. Amino acids 70 and 91 (core), 139 (E1), and 2209-2248 (NS5A) of HCV were analyzed by direct nucleotide sequencing. The reduction in HCV RNA concentration at 24 h after a single administration of conventional IFN-alpha and after the start of combination therapy was significantly less marked, and rates of complete early virologic response, end-of-treatment response, and sustained virologic response (SVR) were significantly lower (all P < 0.0001) in patients with glutamine at amino acid 70 (n = 29) than in those with arginine at that position (n = 70). We found no differences associated with the other amino acid positions. Amino acid 70 was an independent factor for the responses to the therapy in multivariate analysis. The identity of amino acid 70 of the HCV core region affected the sensitivity to IFN; patients with glutamine at amino acid 70 of HCV showed resistance to IFN. Consequently, it strongly affected the outcome of combination therapy with PEG-IFN and ribavirin in Japanese patients with HCV genotype 1b.

Successful treatment for metastases from renal cell carcinoma with alternation of interferon-alpha subtypes

Here we present a case in which alternation of interferon-alpha (IFN-alpha) treatments was effective in treating pulmonary metastases and lymph node metastases from renal cell carcinoma (RCC). A 56-year-old man underwent left radical nephrectomy under the diagnosis of left RCC. The histological diagnosis was clear cell carcinoma G2, IFN-alpha, pT1b. He subsequently underwent two operations for right pulmonary metastasis and right hilar lymph node metastasis. Postoperatively he was treated with intramuscular administration of natural IFN-alpha (Sumiferon) which prevented definite recurrence for 1 year. However, multiple pulmonary metastases and left hilar lymph node metastasis occurred 11 months after discontinuation of Sumiferon. Therefore, treatment with another natural IFN-alpha (OIF) was started. Although OIF was continued for 7 months, pulmonary metastases and left hilar lymph node metastasis continued to progress. Therefore, treatment was changed to Sumiferon, after which the pulmonary metastases and left hilar lymph node metastasis decreased in size. The metastases showed no progression for 16 months after switching from OIF to Sumiferon.

Membranous Nephropathy Associated with Chronic Hepatitis B Occurring in a Short Period After Acute Hepatitis B Virus Infection

We herein present a case of membranous nephropathy associated with chronic hepatitis B following acute hepatitis B virus (HBV) infection. A 22-year-old man was admitted to our hospital for evaluation of proteinuria, pitting edema on both legs, and increased body weight in December 2002. At the age of 18, he had suffered from acute hepatitis A and syphilis, and was found to be negative for hepatitis B surface antigen (HBsAg). Furthermore, he suffered from acute hepatitis B (AH-B) at the age of 21; he was found to be positive for HBsAg and anti-IgM antibody to core antigen (IgM HBcAb). However, he discontinued outpatient treatment before confirmation of HBsAg clearance or the appearance of antibody to HBsAg (HBsAb). At the present admission, HBsAg, antibody to hepatitis B e antigen (HBeAg), and HBcAb were positive, while IgM HBcAb was negative. His genotype of HBV was type A (HBV/A). Histopathological findings of the renal biopsy specimen confirmed glomerulonephritis and glomerular deposition of HBsAg. Thus, he was diagnosed as having nephrotic syndrome caused by membranous nephropathy (MN) associated with chronic hepatitis B (CH-B) following AH-B. Although interferon-alpha (IFN-alpha) administration was started for the treatment and temporary improvement of proteinuria was observed, remission of MN was not achieved.

Interferon-α induced severe thrombocytopenia: A case report and review of the literature

We report a case of severe thrombocytopenia following pegylated interferon-alpha 2a (Peg-IFN-alpha 2a) treatment of hepatitis C virus infection and summarize the clinical characteristics of 16 cases of IFN-alpha induced severe thrombocytopenia and its immune-mediated mechanism. Discontinuation of IFN-alpha and early administration of immunosuppressants are the effective therapy for IFN-alpha induced severe thrombocytopenia.

Sterile alpha motif containing domain 9 is involved in death signaling of malignant glioma treated with inactivated Sendai virus particle (HVJ‐E) or type I interferon

Malignant glioma is one of the most aggressive cancers. For the development of effective therapeutic strategies against such malignant diseases, elucidation of molecular targets is necessary. We found that inactivated Sendai virus particle (HVJ-E) induced extensive cell death in the human glioblastoma cell line U251MG. Intradermal U251MG tumors were more effectively suppressed by HVJ-E than interferon (IFN)-beta. From microarray analysis of gene expression in U251MG cells treated with HVJ-E, we focused on the up-regulation of sterile alpha motif containing domain 9 (SAMD9) gene. The expression of the SAMD9 gene was induced by administration of recombinant human IFN-alpha, -beta or -gamma. The up-regulation of the SAMD9 gene by HVJ-E treatment was abrogated by IFN receptor blocking antibody or JAK inhibitor treatment. When SAMD9 expression was knocked down by RNA interference, apoptotic cell death induced by HVJ-E was blocked in U251MG cells. Suppression of SAMD9 using SAMD9 siRNA also inhibited IFN-beta-induced death in U251MG cells with a small, but significant, difference to control groups. However, overexpression of the SAMD9 gene failed to induce significant cell death in U251MG cells. Thus, SAMD9 could be a key molecule to control cancer cell death by HVJ-E or IFN-beta treatment.

CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: relationship to CNS immune responses and depression

Cytokine-induced activation of indoleamine 2,3 dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-alpha. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during IFN-alpha treatment has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after ~12 weeks of either treatment with IFN-alpha (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. IFN-alpha significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-alpha had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-alpha, soluble tumor necrosis factor-alpha receptor 2 (sTNFR2) and monocyte chemoattractant protein (MCP)-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-alpha activated IDO in concert with central cytokine responses, resulting in increased brain KYN, QUIN, KA, and ultimately depressive symptoms.

Type‐I interferon receptor expression: Its circadian rhythm and downregulation after interferon‐α administration in peripheral blood cells from renal cancer patients

To investigate the regulation of interferon-alpha (IFN-alpha) receptor expression in metastatic renal cell carcinoma (RCC) after IFN-alpha administration. Blood sampling was carried out in eight patients with metastatic RCC and six healthy volunteers. Flow-cytometric analysis using a monoclonal antibody against the active subunit of the type-I IFN-alpha receptor (IFNAR2) was carried out to examine the circadian rhythm of IFNAR2 expression in peripheral blood mononuclear cells (PBMC) as well as its downregulation after IFN-alpha administration. According to its circadian rhythm IFNAR2 in PBMC had a peak expression at night. Once IFN-alpha is administered, IFNAR2 levels in PBMC showed downregulation within 48 h and recovered within another 48 h. Our findings might support the establishment of an optimal schedule for IFN-alpha administration.

The antitumor and immunoadjuvant effects of IFN-alpha in combination with recombinant poxvirus vaccines.

IFN-alpha is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines. The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-alpha with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen. The phenotypic and functional effects of IFN-alpha were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-alpha administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-alpha and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice. We identified a dose and schedule of IFN-alpha that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8(+)) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-alpha distal to the site of vaccination. The combination of IFN-alpha and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA(+) adenocarcinomas. In mice with pancreatic tumors, IFN-alpha slowed tumor growth, induced CTL activity, and increased CD8(+) tumor-infiltrating lymphocytes. These data suggest that IFN-alpha can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas.

Interferon-α counteracts the angiogenic switch and reduces tumor cell proliferation in a spontaneous model of prostatic cancer

Interferon (IFN)-alpha is a cytokine with marked therapeutic activity in transplantable tumor models, that is in part due to angiogenesis inhibition. Aim of this study was to investigate the effects of IFN-alpha during the early phases of tumor development in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. To provide sustained IFN-alpha production, TRAMP mice were injected intraperitoneally with lentiviral vectors. IFN-alpha administration resulted in rapid and protracted upregulation of IFN-alpha-regulated genes associated with antiangiogenic and antiproliferative functions in the prostate of TRAMP mice, including guanylate-binding protein 1 (GBP-1), IFI204 and CXCL10-11. These transcriptional changes were accompanied by effects on the tumor vasculature, including significant reduction of intraductal microvessel density and increased pericyte coverage, and marked reduction of tumor cell proliferation, without induction of tumor necrosis. Intriguingly, GBP-1 and myxovirus resistance A, two IFN-regulated proteins, were found expressed in approximately 40% of human prostate cancer samples analyzed, suggesting expression of endogenous IFN-alpha. Overall, these findings demonstrate that IFN-alpha is able to counteract the angiogenic switch and impairs tumor cell proliferation in preinvasive lesions. Since the angiogenic switch also marks progression of human prostatic cancer, these results highlight the potential of angiogenesis inhibitors for the development of chemoprevention strategies in high-risk individuals.

Interferon‐α enhances CD317 expression and the antitumor activity of anti‐CD317 monoclonal antibody in renal cell carcinoma xenograft models

A murine (mAHM) and a humanized (AHM) monoclonal antibody against CD317 (also called tetherin, BST2, or HM1.24 antigen), expressed preferentially in neoplastic B cells such as multiple myeloma, exhibited antitumor effects as a result of antibody-dependent cellular cytotoxicity (ADCC). The putative interferon (IFN) response elements IRF-1/2 and ISGF3 are present in the promoter of the CD317 gene, and IFN has been used for the treatment of not only myeloproliferative diseases but also solid tumors such as renal cell carcinoma (RCC) and melanoma. Therefore, we examined the effects of IFN on the expression of CD317 and on the antitumor activity of AHM and mAHM in RCC and melanoma. Flow cytometry and in vitro ADCC assays with human or mouse effector cells demonstrated that IFN-alpha markedly increased the amount of cell surface CD317 and augmented the ADCC activity of mAHM and AHM in RCC cells and to a lesser extent in melanoma cells. Administration of IFN-alpha to mice bearing RCC xenografts also increased the expression of CD317 in tumor cells. When coadministered with IFN-alpha, mAHM exhibited more profound antitumor activity in both IFN-alpha-sensitive and -insensitive RCC xenograft models. Thus, AHM in combination with IFN-alpha may be an effective therapy for the treatment of RCC.

Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha: Relationship to Monoamines and Depression

Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established. Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after approximately 12 weeks of either no treatment (n = 12) or treatment with pegylated IFN-alpha 2b (n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA (r(2) = -.25, p < .05). These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.