Nat Rev Immunol Research Articles

Cyclophosphamide and prednisone induction followed by cyclophosphamide mobilization effectively decreases the incidence of engraftment syndrome in patients with POEMS syndrome who undergo stem cell transplantation

High-dose chemotherapy with autologous stem cell transplantation (ASCT) can achieve excellent clinical responses in patients with POEMS syndrome (Jimenez Zepeda et al., Blood 2010;116:2403; Gertz et al., Am J Hematol 2005;79:319-328; Gherardi et al., Ann Neurol 1994;35:501-505; Gattinoni et al., Nat Rev Immunol 2006;6:383-393; Salem et al., J Immunol 2009;182:2030-2040; Salem et al., Cancer Immunol Immunother 2010;59:341-353; Salem et al., Cell Immunol 2010;261:134-143). However, High-dose melphalan with ASCT should be considered carefully due to its treatment-related morbidity (Vuckovic et al., Blood 2003;101:2314-2317), especially in patients with poor performance status owing to polyneuropathy and multiorgan involvement, such as cardiac, respiratory, and renal failure. Significant increases in the concentration of circulating macrophage colony-stimulating factor, erythropoietin, IL-6, and TNF-α, reach near maximal values at approximately day +12, predating neutrophil engraftment, and clinically manifest with fever, rash and edema (Dispenzieri et al., Eur J Haematol 2008;80:397-406). Depending on the definition used, approximately 50% of patients satisfied criteria for engraftment syndrome (ES) (Vuckovic et al., Blood 2003;101:2314-2317). ES occurs in 27-47% of patients who undergo ASCT; mortality rate is reported from 8% to 18% (Gattinoni et al., Nat Rev Immunol 2006;6:383-393; Vuckovic et al., Blood 2003;101:2314-2317). We have therefore reviewed our experience with ASCT in patients with POEMS syndrome who were treated with cyclophosphamide and prednisone as induction therapy followed by cyclophosphamide mobilization with an emphasis on treatment-related morbidity and frequency of ES. Our study confirms that ASCT is a feasible and efficacious treatment for patients with POEMS syndrome. In addition, the use of CP followed by cyclophosphamide mobilization decreases the incidence of PES leading to less morbidity and mortality rates.

Bupropion and Panic Disorder: Case Report and Review of the Literature

Bupropion and Panic Disorder: Case Report and Review of the Literature

The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases

Intestinal inflammation arises from abnormal host-microbe interactions. The perturbations of homeostatic coexistence involve host genetic factors, barrier function, innate and adaptive immunity, as well as qualitative and quantitative changes in the composition of the microbiota. Dysbiosis toward selected micro-organisms and decreased complexity of commensal bacteria have been observed in patients with Crohn's disease and ulcerative colitis, but it is not clear whether the dysbiosis contributes to development of inflammatory bowel disease or is instead a consequence of the disease. Pathogens with virulence factors that allow them to breach the intestinal barrier and induce chronic inflammation might mediate the pathogenesis of these diseases. To identify new therapeutic approaches for inflammatory bowel disease, it is important to identify host susceptibility factors involved in the control of microbial infection, characterize potential pathogens, and eliminate them or block the expression of their virulence factors.

Inducible SUMO modification of TANK alleviates its repression of TLR7 signalling

Adaptor proteins allow temporal and spatial coordination of signalling. In this study, we show SUMOylation of the adaptor protein TANK and its interacting kinase TANK-binding kinase 1 (TBK1). Modification of TANK by the small ubiquitin-related modifier (SUMO) at the evolutionarily conserved Lys 282 is triggered by the kinase activities of IκB kinase ɛ (IKKɛ) and TBK1. Stimulation of TLR7 leads to inducible SUMOylation of TANK, which in turn weakens the interaction with IKKɛ and thus relieves the negative function of TANK on signal propagation. Reconstitution experiments show that an absence of TANK SUMOylation impairs inducible expression of distinct TLR7-dependent target genes, providing a molecular mechanism that allows the control of TANK function.

A crucial role for host APCs in the induction of donor CD4+CD25+ regulatory T cell-mediated suppression of experimental graft-versus-host disease.

Allogeneic bone marrow transplantation is an effective treatment for a number of malignant and nonmalignant diseases (Applebaum. 2001. Nature. 411: 385-389 and Copelan. 2006. N Engl J Med. 354: 1813-1826). However, the application of this therapeutic modality has been impeded by a number of confounding side effects, the most frequent and severe of which is the development of graft-versus-host disease (GVHD) (Copelan. 2006. N Engl J Med. 354: 1813-1826 and Blazar and Murphy. 2005. Philos Trans R Soc Lond B Biol Sci. 360: 1747-1767). Alloreactive donor T cells are critical for causing GVHD (Fowler. 2006. Crit Rev Oncol Hematol. 57: 225-244 and Ferrara and Reddy. 2006. Semin Hematol. 43: 3-10), whereas recent data demonstrated a significant role for the naturally occurring thymic-derived donor CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) (Bluestone and Abbas. 2003. Nat Rev Immunol. 3: 253-257 and Shevach. 2006. Immunity. 25: 195-201) in suppressing experimental GVHD after bone marrow transplantation (Blazar and Taylor. 2005. Biol Blood Marrow Transpl. 11: 46-49 and Joffe and van Meerwijk. 2006. Semin Immunol. 18: 128-135) . Host APCs are required for induction of GVHD by the conventional donor T cells. However, it is not known whether they are also obligatory for donor Treg-mediated suppression of GVHD. Using multiple clinically relevant MHC-matched and -mismatched murine models of GVHD, we investigated the role of host APCs in the suppression of GVHD by donor Tregs. We found that alloantigen expression by the host APCs is necessary and sufficient for induction of GVHD protection by donor Tregs. This requirement was independent of their effect on the maintenance of Treg numbers and the production of IL-10 or IDO by the host APCs.

Tregs and Human Atherothrombotic Diseases

Immunology has recently penetrated the field of atherothrombosis. A number of human and experimental studies have documented that both cellular and molecular immune effectors are involved at various stages of the pathological process.1 This has directed our attention toward the use of immunomodulatory strategies in atherothrombosis; these strategies are commonly used for the treatment of other chronic inflammatory diseases. Notably, the administration of immunosuppressive drugs is the most common approach for treating immune-mediated diseases. However, the long-term administration of non–antigen-specific agents that cannot distinguish between beneficial and destructive immune responses is a major drawback of this strategy. See accompanying articles on pages 1825 and 1832 Interesting alternatives consist of strategies aimed at potentiating the physiological regulatory mechanisms, if defective. In the field of atherothrombosis research, experimental studies have clearly shown that a defect in regulatory CD4+ T cells (Tregs) favors atherogenesis.2 Based on their potent immunosuppressive activity, the expansion of the Treg compartment by cell transfer or the administration of stimulating molecules can be envisaged as a new therapeutic strategy. These findings have provided a strong incentive to perform clinical studies with the aim of assessing whether a defective Treg compartment is associated with the progression of atherosclerotic disease and the occurrence of atherothrombotic manifestations in humans. Three clinical studies,3–5 in a limited number of patients with coronary artery disease, first reported that patients with acute coronary syndromes have fewer and/or inefficient Tregs in their blood. In the present issue of Arteriosclerosis, Thrombosis, and Vascular Biology , a larger clinical study6 reports interesting challenges to these findings; a second study7 explores the role of Tregs in stenotic and dilative pathological remodeling …

Abstract SY03-01: The desirable death of the cancer cell: Immunogenic cell death for optimal chemotherapy

Abstract SY03-01: The desirable death of the cancer cell: Immunogenic cell death for optimal chemotherapy

Interleukin-10 Anergized Donor T Cell Infusion Improves Immune Reconstitution without Severe Graft-Versus-Host-Disease After Haploidentical Hematopoietic Stem Cell Transplantation.

Abstract 45Background: Adoptive transfer of regulatory T cells is a potentially attractive alternative to conventional immunosuppressive therapy in allogeneic hematopoietic stem cell transplantation (HSCT) (Roncarolo MG., Nat Rev Immunol 2007). Among CD4+ T cells, the subset known as Type 1 regulatory T (Tr1) cells are induced in an antigen specific manner by interleukin-10 (IL-10) and suppress via production of high levels of IL-10 (Groux H., Nature 1997). The aim of this phase I/II study was to establish the safety and efficacy of a new cellular therapy with Tr1 cells in a non-randomized study.Patients and Methods: A cellular therapy protocol for the adoptive transfer of IL-10 induced alloantigen specific donor-derived Tr1 cells in patients transplanted with CD34+ selected cells from haploidentical donor, has been applied to patients with high risk hematopoietic malignancies (www.risetfp6.org). Donor T cells, anergized ex vivo toward host alloantigens, presented by monocytes (original protocol) or tolerogenic dendritic cells (modified protocol) as host antigen presenting cells, in the presence of IL-10, are infused post-transplant into the host (IL-10 DLI). The infusion is made in the absence of immunosuppression for graft-versus-host-disease (GVHD) prophylaxis, with the ultimate goal to provide immune reconstitution without severe GVHD. The infused donor T cells, at the dose of 105 CD3+ cells/kg or 3 × 105 CD3+ cells/kg, are anergic towards host-HLA antigens and contain precursors of host-specific Tr1 cells but, at the same time, comprise memory T cells able to respond to nominal and viral antigens.Results: Eighteen patients have been enrolled, sixteen received CD34+ selected cells from haploidentical donor after myeloablative conditioning. Twelve patients have been treated with IL-10 anergized cell therapy at day +30 post transplant, at the dose of 105 CD3+ cells/kg with the exception of two patients who received 3 × 105 CD3+ cells/kg. No severe immediate reactions post infusion were registered. Five patients died from infections by day +30 after Tregs cell infusion and two patients dropped out for graft rejection. Five patients achieved immune reconstitution at a median of 30,5 days (range 15–46 days) after IL-10 DLI, followed by progressive normalization of TCR repertoire, memory/naïve phenotype and T cell functions in vitro and in vivo. Acute GVHD grade III was observed in one patient who received 3 × 105 CD3+ cells/kg; GVHD grade II was observed in 4 patients who received 105 CD3+ cells/kg and were successfully immune reconstituted. The median follow-up of the IL-10 DLI treated patients is 980 days (range 291–1624); 4 patients are alive and disease free and they do not require immunosuppressive treatment.Conclusions: Cellular therapy with IL-10 anergized donor T cells has proven to be safe and feasible, and to sustain immune reconstitution associated with a reduced severity of GVHD and no occurrence of relapse. This trial represents the first step towards an extended use of Tr1 cells as adjuvant treatment in allogeneic HSCT. Disclosures:No relevant conflicts of interest to declare.

Promotion of cardiovascular disease by exposure to the air pollutant ozone

in the decades following the discovery of the chemical nature of environmental air pollutants and the biochemical reactions they could undergo, it was viewed that the primary tissue target of air pollution would be our lungs. This made sense, as the principal constituents of photochemical air

Evidence for Inflammatory Signaling in Idiopathic Pulmonary Artery Hypertension

Knowledge of molecular mechanisms underlying pulmonary arterial hypertension (PAH) continues to increase with the emerging theme that PAH is a heterogeneous disease involving multiple molecular abnormalities. Mutations in several genes have been identified in subsets of patients with PAH, and multiple signaling systems that influence vascular tone, function, and remodeling have been associated with PAH.1,2,3 In addition to mutations in BMPR2 , serotonin ( 5-HT ) and polymorphisms in its transporter ( SERT ) play a critical role in the pulmonary vascular smooth muscle hyperplasia and vascular remodeling found in PAH.4,5 Other genes and signals thought to contribute to the development of idiopathic pulmonary arterial hypertension (IPAH) include somatic mutations of BAX ,5 upregulation of Angiopoietin 1 ,6 transforming growth factor β1 polymorphisms,7 ALK1 mutation,8 SMAD8 mutation,9 and increased hyaluronic acid content associated with increased Hyaluronan Synthase 1 and decreased Hyaluronoglucosaminidase 1 gene expression.10 A recent observation also suggests that the noncanonical Wnt pathway is activated in IPAH.11 Article see p 2313 Several transient receptor potential canonical (TRPC) family …

Leukocyte Telomere Length, Hypertension, and Atherosclerosis

In this issue of Hypertension , Yang et al1 report that leukocyte telomere length (LTL) is shorter in hypertensive patients than in their normotensive peers. What’s more, after 5 years of follow-up, the authors observed that hypertensive patients with short LTL were more likely to develop atherosclerotic coronary artery disease, whereas normotensive persons with short LTL were more likely to become hypertensive. Several features of this study merit attention. First, the study was conducted in a Chinese cohort, whereas the information we have about the relationships between LTL and cardiovascular risks is primarily derived from white populations. Second, the size of the cohort (388 hypertensive and 379 normotensive persons) and the meticulous attention devoted to characterizing hypertension lend credibility to the findings. Third, the 5-year follow-up period provided the opportunity to explore the potential cardiovascular ramifications of having a short LTL. Thus, the findings of this work indicate that the association between LTL and risks for coronary artery atherosclerosis apply not only to white but also to Chinese populations. What is the biological meaning of the associations between LTL and aging-related diseases, principally atherosclerosis and its risk factors? The short answer is: we do not know. What we do know is that LTL is highly variable at birth and throughout life.2 We also know that age-dependent LTL shortening is much faster in early life than during adulthood,3 probably because of the rapid proliferation of hematopoietic stem cells (HSCs) during growth and development. In fact, LTL shortening throughout life largely mirrors telomere shortening in HSCs. In these cells, like in other somatic cells with rudimentary activity of telomerase (the reverse transcriptase that adds telomere repeats onto …

Gene-Modified CD8+ T Cells Undergo Functional Polarization to Effector and Central Memory Cells in Response to Antigen Exposure.

Adoptive transfer (AT) of autologous T cells genetically-redirected against tumor antigens has considerable potential as cancer immunotherapy [Kershaw, Nat Rev Immunol. 2005]. However, the in vivo persistence of AT T cells is critical for tumor control and requires the development (in vitro or in vivo) of a memory T cell subset. We investigated the generation of memory T cell subsets in a novel chimeric T cell receptor-expressing T cell product prior to, and after exposure to cognate antigen. Gene-modified T cells (LeY-T) express a chimeric receptor comprising a single chain variable fragment (scFv) specific for Lewis Y (LeY) antigen coupled to the intracellular signaling domains of CD3 zeta and CD28, capable of inducing T cell effector granule release and target killing [Westwood PNAS 2005]. To produce LeY-T cells, PBMC from healthy donors (n=20) or multiple myeloma patients (n=2) were cultured with anti-OKT3 (30ng/ml) and IL-2 (600IU/ml) for three days, followed by two rounds of transduction with retroviral supernatant. Subsequently, T cells were expanded in high dose IL-2 (600IU/ml) from day 5 onwards. T cells were harvested for this study on culture days 10–12, CD8+ and CD4+ T cells expressed the chimeric protein (50–60)%. LeY CD8+ T cell subsets were assessed as naïve (N), central memory (CM), effector memory (EM) or effector (E) based on three features:-phenotype (CD45RA, CCR7, CD28, CD27 and perforin);homeostatic cytokine (IL-15/IL-7) proliferation;response to Lewis antigen contact including cell proliferation and cytokine secretion.We repeatedly observed that CD8+ LeY-T cells analyzed directly from the initial expansion culture demonstrate an effector memory (EM) phenotype (CD45RA−/CCR7−/CD28+/perforinhi and variable CD27 expression) (Figure 1A). Furthermore in vitro expanded LeY CD8 T cells express IL- 15R beta (CD122) and the common gamma chain (CD132), they proliferate in response to IL-15 (86% cell division, division index 1.82), but less with IL-7 (30% cell division, division index 0.56). Baseline expanded CD8+ LeY-T cells respond to the presence of LeY antigen by proliferating and secreting IFN-gamma (4–8% of CD8 T cells) but not IL-2. Importantly, no IFN-gamma secretion was seen in control T cells transduced with empty vector (Figure 1B, OVCAR cells). Furthermore, no IFN-gamma was secreted by the control or the CD8+ LeY-T cells in response to the Lewis antigen negative cell line (Figure 1C, HCT116 cells). To explore the memory component further, we examined the functional status of the CD8+ LeY-T cells seven and 30 days following a 48-hour exposure to LeY antigen (OVCAR cells), and compared this to CD8+ LeY-T cell functional status at baseline. Thus, direct from transduction, expansion culture LeY CD8+ T cells were largely EM phenotype (95%) a small population of cells (1–5)% had a CM phenotype (CD45RA−/CCR7+/CD28+/perforinlo). In contrast, seven days after Lewis antigen contact the EM cells had decreased to (76–88)% and CM increased to (10–21)%; this distribution was retained up to day 30 post-antigen exposure. In addition, seven days after Lewis antigen exposure, CD8+ LeY-T cells retain the capacity to proliferate in response to Lewis antigen and to secrete IFN-gamma, at no stage do these cells secrete IL-2. In conclusion, the CD8+ LeY-T cells produced by in vitro transduction and expansion culture have an EM functional status direct from in vitro culture indicating that they are an appropriate starting population for in vivo adoptive transfer. After exposure to LeY expressed on tumor cell lines in vitro, CD8+ LeY T cells show further polarization to either EM or CM cells. These results suggest that the LeY-chimeric T cells have the potential to form long-term memory populations in vivo after adoptive transfer. [Display omitted]

Ulcerative Colitis and Crohn's Disease Genetics: More Similar Than We Thought?

Ulcerative Colitis and Crohn's Disease Genetics: More Similar Than We Thought?

Plasmablastic lymphoma: One or more entities?

American Journal of HematologyVolume 83, Issue 10 p. 763-764 CommentaryFree Access Plasmablastic lymphoma: One or more entities?† Antonino Carbone, Corresponding Author Antonino Carbone [email protected] Department of Pathology, National Cancer Institute of Milan, Milan, ItalyDepartment of Pathology, Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, ItalySearch for more papers by this authorAnnunziata Gloghini, Annunziata Gloghini Department of Pathology, National Cancer Institute of Milan, Milan, ItalySearch for more papers by this author Antonino Carbone, Corresponding Author Antonino Carbone [email protected] Department of Pathology, National Cancer Institute of Milan, Milan, ItalyDepartment of Pathology, Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, ItalySearch for more papers by this authorAnnunziata Gloghini, Annunziata Gloghini Department of Pathology, National Cancer Institute of Milan, Milan, ItalySearch for more papers by this author First published: 22 July 2008 https://doi.org/10.1002/ajh.21259Citations: 29 † Conflict of Interest: Nothing to report. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 ES Jaffe, NL Harris, H Stein, JW Vardiman, Editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001. 2 Delecluse HJ,Anagnostopoulos I,Dallenbach F, et al. Plasmablastic lymphomas of the oral cavity: A new entity associated with the human immunodeficiency virus infection. Blood 1997; 89: 1413– 1420. 3 Castillo J,Pantanowithz L,Dezube BJ. HIV-associated plasmablastic lymphoma: A literature review of 112 cases. Am J Hematol, in press. 4 Nador RG,Cesarman E,Chadburn A, et al. Primary effusion lymphoma: A distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 1996; 88: 645– 656. 5 Dupin N,Diss TL,Kellam P, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 2000; 95: 1406– 1412. 6 Deloose ST,Smit LA,Pals FT, et al. High incidence of Kaposi sarcoma-associated herpesvirus infection in HIV-related solid immunoblastic/plasmablastic diffuse large B-cell lymphoma. Leukemia 2005; 19: 851– 855. 7 Carbone A,Gloghini A,Vaccher E, et al. KSHV/HHV-8 associated lymph node based lymphomas in HIV seronegative subjects: Report of two cases with anaplastic large cell morphology and plasmablastic immunophenotypes. J Clin Pathol 2005; 58: 1039– 1045. 8 Klein U,Gloghini A. Gaidano G, et al. Gene expression profile analysis of AIDS related primary effusion lymphoma (PEL) suggest a plasmablastic derivation and identifies PEL-specific transcripts. Blood 2003; 101: 4115– 4121. 9 Carbone A,Gloghini A,Larocca LM, et al. Human immunodeficiency virus-associated Hodgkin's disease derives from post-germinal center B cells. Blood 1999; 93: 2319– 2326. 10 Klein U,Dalla-Favera R. Germinal centres: Role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8: 22– 33. 11 Vockerodt M,Morgan S,Kuo M, et al. The Epstein-Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkin's Reed-Sternberg-like phenotype. J Pathol, [Epub ahead of print]. 12 Colomo L,Loong F,Rives S, et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol 2004; 28: 223– 228. 13 Petitjean B,Jardin F,Joly B, et al. Pyothorax-associated lymphoma: A peculiar clinicopathologic entity derived from B-cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype. Am J Surg Pathol 2002; 26: 724– 732. 14 Carbone A,Gloghini A.Vaccher E, et al. Kaposi's sarcoma-associated herpes virus/human herpes virus type 8-positive solid lymphoma. A tissue-based variant of primary effusion lymphoma. J Mol Diagn 2005; 7: 17– 27. Citing Literature Volume83, Issue10October 2008Pages 763-764 ReferencesRelatedInformation

Diversity of Denizens of the Atherosclerotic Plaque

The atherosclerotic plaque typically harbors cells of several lineages whose conversations, mediated by extracellular or cell surface–associated messengers, influence decisively the biology and clinical consequences of the lesion. Early vascular biology studies defined the resting state of the endothelium, characterized by the elaboration of antithrombotic and vasodilatory mediators. The activated endothelium recruits inflammatory leukocytes, favors clot accumulation, participates in angiogenesis, and can influence the behavior of subjacent smooth muscle cells in ways that favor atherogenesis and vasoconstriction (Figure). More recently, we have come to appreciate that the endothelial cell not only can exhibit a spectrum of functions, but that some may arise postnatally from bone marrow–derived precursors.1 Thus, the heterogeneity of endothelial cells depends not only on the mutability of their function but also on their origin. The diversity of endothelium depends not only on lineage but also location, with increasingly well-understood differences between arterial, microvascular, and venous endothelial cells. Figure. Heterogeneity of major cell types in atherosclerotic plaques. Vascular biologists have long recognized heterogeneity of endothelial cells and smooth muscle cells, now understood to result from local mediator milieu, biomechanical stimuli, and different embryological origins. Indeed, recent data suggest that both of these intrinsic vascular cell types can arise in postnatal life from bone marrow–derived precursors. Immunological dogma recognizes several T-cell populations, exemplified here by the Th1 and Th2 subsets, which on the balance exert opposing influences on atherogenesis. New data now establish the relevance to atherosclerosis and hyperlipidemia of monocyte heterogeneity. Monocytes that bear high levels of the markers Ly6c/Gr-1 and P-selectin glycoprotein ligand exhibit more proinflammatory functions than their …

Antiprion Prophylaxis by Gene Transfer of a Soluble Prion Antagonist

Prion diseases are untreatable neurodegenerative disorders characterized by accumulation of PrP(Sc), an aggregated isoform of the normal prion protein PrP(C). Here, we delivered the soluble prion antagonist PrP-Fc(2) to the brains of mice by lentiviral gene transfer. Although naïve mice developed scrapie at 175 +/- 5 days postintracerebral prion inoculation (dpi), gene transfer before inoculation delayed disease onset by 72 +/- 4 days. At 170 days postintracerebral prion inoculation, PrP(Sc) accumulation and prion infectivity in PrPFc-treated brains were reduced by 3.6 and 4.2 logs, respectively. When PrP-Fc(2) was delivered 30 days after prion inoculation, survival of the treated animals was extended by 25 days. We then used tissue-specific recombination to express PrP-Fc(2) in the entire central nervous system, in only astrocytes, or in only oligodendrocytes. Oligodendrocyte-restricted PrP-Fc(2) expression impaired PrP(Sc) deposition and delayed disease even though oligodendrocytes are completely resistant to prion infection, suggesting that PrP-Fc(2) affords protection via noncell autonomous mechanisms. These results suggest that somatic gene transfer of prion antagonists may be effective for postexposure prophylaxis of prion diseases.

An expanding role of Toll-like receptors in sepsis-induced acute kidney injury

AMONG THE VARIOUS CAUSES OF acute kidney injury (AKI) in hospitalized patients, sepsis remains the most elusive and challenging for the practicing nephrologist. Decades of intensive basic, translational, and clinical research have failed to significantly alter the grim outcome of sepsis and sepsisinduced AKI (13). Nevertheless, active bench research continues to fuel the hope for successful therapies that will eventually

Selection of Substrates for MHC Class I‐Restricted Antigen Processing

We have proposed a model for selection of cytosolic proteins for MHC class I‐restricted antigen processing (Nat Rev Immunol, 2007, 7: 403). In short, incomplete capture of nascent polypeptides by the protein folding machinery, resulting in uncompacted hydrophobic domains, triggers ubiquitin (Ub)‐independent degradation by the 20S proteasome. We have tested this model in three ways. First, we revisited the classic Townsend et al. finding (Nature, 1986, 324: 575) that directing influenza hemagglutinin to the cytosol through signal sequence ablation substantially increases presentation. We hypothesized that the unembeded transmembrane domain (TM), rather than misfolding, stimulates rapid degradation. Indeed, various manipulations of the human IL‐2 receptor alpha chain (Tac) and its TM support this idea. Second, using a dominant‐interfering Ub system, we have probed the role of polyUb’n in the presentation of various antigen processing substrates. To date, all stable cytosolic proteins tested are largely, if not exclusively, presented in a polyUb‐independent manner as opposed to other types of processing substrate. Finally, we have probed the role of the two ribosome‐associated chaperone complexes, RAC and NAC, in antigen processing. NAC, but not RAC silencing resulted in a ~2‐fold increase in peptide/class I complexes at the cell surface. Thus, our proposed pathway remains viable.

Adiponectin and Adaptive Immunity

See related article, pages 218–225 Obesity, characterized by an excess of adipose tissue mass, is closely associated with an increase in cardiovascular morbidity and mortality attributable to atherosclerosis.1 Obesity is a major underlying risk factor for atherosclerosis through other well-known risk factors, including the major risk factors (hypercholesterolemia, hypertension, hyperglycemia) and emerging risk factors (atherogenic dyslipidemia, insulin resistance, proinflammatory and prothrombotic state).2 The clinical value of novel risk factors such as high-sensitivity C-reactive protein are currently subject of ongoing discussions.3 The clustering of major and emerging risk factors that is found in most obese patients is defined as the metabolic syndrome.2 Among various cytokine-like hormones secreted by adipose tissue, the most abundant and adipose-specific is adiponectin (Figure).4 Reduced plasma levels of adiponectin, which are found in obese patients, are closely associated with obesity-related diseases, including atherosclerotic cardiovascular diseases, type 2 diabetes, hypertension, and dyslipidemia.4 Emerging experimental evidence indicates that adiponectin mediates antiatherogenic and antithrombotic effects through direct protective actions on endothelial cells, smooth muscle cells, macrophages, and platelets.1,5,6 Figure. Antiatherogenic effects of adiponectin. The cytokine-like hormone adiponectin, which is selectively expressed by adipose cells, exhibits antiatherogenic properties through direct and indirect effects on endothelial cells (EC), smooth muscle cells (SMC), platelets, macrophages, and T lymphocytes. IL indicates interleukin; IL-1RA, IL-1 receptor antagonist; NF-κB, nuclear factor κB. …

Immunological Consequences of Apoptotic Cell Phagocytosis

Cells undergo apoptosis in development, tissue homeostasis, and disease and are subsequently cleared by professional and nonprofessional phagocytes. There is now overwhelming evidence that phagocyte function is profoundly altered following apoptotic cell uptake, with consequences for the ensuing innate and adaptive immune response. Pathogens and tumors exploit the changes in macrophage function following apoptotic cell uptake. Here, we will outline the consequences of apoptotic cell phagocytosis and illustrate how apoptotic cells could be used to manipulate the immune response for therapeutic gain.