Effect of Statin Use on Inflammation and Immune Activation Biomarkers in HIV-Infected Persons on Effective Antiretroviral Therapy.

Immune activation and inflammation are hallmarks of chronic HIV infection and are etiologically linked to major causes of morbidity and mortality among HIV-infected persons, including coronary artery disease and cancer. Systemic immune activation is dampened, but not resolved, with use of combination antiretroviral therapy (cART). Statins are cardioprotective drugs that also appear to have immunomodulatory and anti-inflammatory properties.

Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice.

Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab.

Predictive Value of Cytokines and Immune Activation Biomarkers in AIDS-Related Non-Hodgkin Lymphoma Treated with Rituximab plus Infusional EPOCH (AMC-034 trial).

Purpose: The aims of this study were to determine whether pretreatment plasma levels of cytokines and immune activation-associated molecules changed following treatment for AIDS-NHL with rituximab plus infusional EPOCH, and to determine whether pretreatment levels of these molecules were associated with response to treatment and/or survival.

Experimental Design: We quantified plasma levels of B-cell activation-associated molecules (sCD27, sCD30, and sCD23) and cytokines (IL6, IL10, and CXCL13) before and after the initiation of treatment in persons with AIDS-NHL (n = 69) in the AIDS Malignancies Consortium (AMC) 034 study, which evaluated treatment of AIDS-NHL with EPOCH chemotherapy and rituximab.

Results: Treatment resulted in decreased plasma levels of some of these molecules (CXCL13, sCD27, and sCD30), with decreased levels persisting for one year following the completion of treatment.

Efficacy of an Anti-transferrin Receptor 1 Antibody Against AIDS-related Non-Hodgkin Lymphoma: A Brief Communication.

The transferrin receptor 1 (TfR1), also known as CD71, is a target for antibody-based cancer immunotherapy due to its high expression on the surface of cancer cells and its ability to internalize. We have previously developed a mouse/human chimeric IgG3 specific for human TfR1 genetically fused to avidin, as a vector to deliver biotinylated anticancer agents into malignant cells. However, we found that this fusion protein (ch128.

Serum levels of cytokines and biomarkers for inflammation and immune activation, and HIV-associated non-Hodgkin B-cell lymphoma risk.

Background: HIV infection is associated with a marked increase in risk for non-Hodgkin lymphoma (AIDS-NHL). However, the mechanisms that promote the development of AIDS-NHL are not fully understood.

Methods: In this study, serum levels of several cytokines and other molecules associated with immune activation were measured in specimens collected longitudinally during 1 to 5 years preceding AIDS-NHL diagnosis, in 176 AIDS-NHL cases and 176 HIV(+) controls from the Multicenter AIDS Cohort Study (MACS).

Levels of murine, but not human, CXCL13 are greatly elevated in NOD-SCID mice bearing the AIDS-associated Burkitt lymphoma cell line, 2F7.

Currently, few rodent models of AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL) exist. In these studies, a novel mouse/human xenograft model of AIDS-associated Burkitt lymphoma (AIDS-BL) was created by injecting cells of the human AIDS-BL cell line, 2F7, intraperitoneally into NOD-SCID mice. Mice developed tumors in the peritoneal cavity, with metastases to the spleen, thymus, and mesenteric lymph nodes.

Serum levels of the chemokine CXCL13, genetic variation in CXCL13 and its receptor CXCR5, and HIV-associated non-hodgkin B-cell lymphoma risk.

Background: CXCL13 and CXCR5 are a chemokine and receptor pair whose interaction is critical for naïve B-cell trafficking and activation within germinal centers. We sought to determine whether CXCL13 levels are elevated before HIV-associated non-Hodgkin B-cell lymphoma (AIDS-NHL), and whether polymorphisms in CXCL13 or CXCR5 are associated with AIDS-NHL risk and CXCL13 levels in a large cohort of HIV-infected men.

Methods: CXCL13 levels were measured in sera from 179 AIDS-NHL cases and 179 controls at three time-points.

Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation.

Objective: Chronic inflammation and B-cell hyperactivation are seen in HIV infection, contributing to an increased risk for the accrual of genetic errors that may result in B-cell lymphoma. The primary objective of this study was to determine the effect of highly active antiretroviral therapy (HAART) on serum levels of molecules that are associated with immune activation and/or inflammation, including several that are associated with B-cell activation, specifically IL-6, sCD30, sCD27, IgG, IgA, CXCL13 (B lymphocyte chemoattractant, BLC), a B-lymphocyte chemokine involved in B-cell trafficking, as well as C-reactive protein, an acute-phase protein.

Design: We used a retrospective cohort study design, measuring serum levels of these markers at each of four 1-year intervals, 2 years before and 2 years after HAART initiation, in a subgroup of 290 HIV-infected men enrolled in the Multicenter AIDS Cohort Study (MACS).

Expression and Function of the Chemokine, CXCL13, and Its Receptor, CXCR5, in Aids-Associated Non-Hodgkin's Lymphoma.

Background. The homeostatic chemokine, CXCL13 (BLC, BCA-1), helps direct the recirculation of mature, resting B cells, which express its receptor, CXCR5. CXCL13/CXCR5 are expressed, and may play a role, in some non-AIDS-associated B cell tumors.

Pathogenesis of AIDS lymphoma: role of oncogenic viruses and B cell activation-associated molecular lesions.

Purpose Of Review: We discuss recently published studies that elucidate the pathogenesis of AIDS-associated lymphoma.

Recent Findings: Several recent reports have provided valuable new information on the role of gamma-herpesviruses in the pathogenesis of AIDS-associated lymphoma. In addition to this, significant new information has become available on how B cell activation-associated DNA-modifying events, involving activation-induced cytidine deaminase and DNA polymerase-eta, contribute to the molecular lesions that result in AIDS-associated lymphoma.

Serum levels of the homeostatic B cell chemokine, CXCL13, are elevated during HIV infection.

HIV infection is associated with B cell dysfunction, which includes B cell hyperactivation, hypergammaglobulinemia, impaired production of antibodies against specific antigens, and a loss of B cell memory. Because lymph node architecture is progressively destroyed during HIV infection, it is possible that normal B cell trafficking is impaired as well, which could be a cause or a result of these abnormalities. Because the homeostatic chemokine, CXCL13 (BLC, BCA-1), is a major regulator of B cell trafficking, we assessed circulating levels of this molecule in HIV infection.

CXCR3 and its ligands participate in the host response to Bordetella bronchiseptica infection of the mouse respiratory tract but are not required for clearance of bacteria from the lung.

Intranasal inoculation of mice with Bordetella bronchiseptica produces a transient pneumonia that is cleared over several weeks in a process known to require both neutrophils and lymphocytes. In this study, we evaluated the roles of the chemokines MIG (CXCL9), IP-10 (CXCL10), and I-TAC (CXCL11) and their common receptor, CXCR3. Following bacterial inoculation, message expression of interleukin-1 (IL-1), IL-6, and the neutrophil-attracting chemokines KC, LIX, and MIP-2 was rapidly induced, with maximal expression found at 6 h.

Expression and function of CD28 on Epstein-Barr virus-positive B cell lines and AIDS-associated non-Hodgkin's lymphoma cell lines.

CD28, which is expressed on most T cells, can provide a costimulatory signal during T cell activation. Although principally considered to be a T cell-associated molecule, CD28 has been seen to be expressed on mast cells and natural killer cells, as well as on plasma and myeloma cells, but not on cells representing earlier stages of B cell development. Here were report that CD28 was expressed on Epstein-Barr virus (EBV)-positive B lymphoblastoid and AIDS-associated non-Hodgkin's lymphoma cell lines.

Murine GBP-5, a new member of the murine guanylate-binding protein family, is coordinately regulated with other GBPs in vivo and in vitro.

A new murine member of the interferon (IFN)-inducible guanylate-binding protein (GBP) family was cloned in a search for glucocorticoid-attenuated response genes induced in the lung during endotoxemia. The full-length MuGBP-5 cDNA encodes a 590 amino acid residue protein with GTP binding motifs identical to those in human GBP-1 (HuGBP-1) and a similar isoprenylation sequence at the C-terminus. An alternatively spliced form of MuGBP-5 that lacks the second GTP binding motif and differs at the C-terminus was also identified.

Glucocorticoid-attenuated response genes induced in the lung during endotoxemia.

Cytokines and other mediators whose induction in inflammatory lung disease is attenuated by glucocorticoids are potential targets for development of selective anti-inflammatory treatments. We refer to genes with these regulatory characteristics as glucocorticoid-attenuated response genes, or GARGs. Systematic identification of GARGs has not been attempted previously in vivo.

The murine chemokine CXCL11 (IFN-inducible T cell alpha chemoattractant) is an IFN-gamma- and lipopolysaccharide-inducible glucocorticoid-attenuated response gene expressed in lung and other tissues during endotoxemia.

A new murine chemokine was identified in a search for glucocorticoid-attenuated response genes induced in the lung during endotoxemia. The first 73 residues of the predicted mature peptide are 71% identical and 93% similar to human CXCL11/IFN-inducible T cell alpha chemoattractant (I-TAC) (alias beta-R1, H174, IFN-inducible protein 9 (IP-9), and SCYB9B). The murine chemokine has six additional residues at the carboxyl terminus not present in human I-TAC.

Aberrant expression of CD27 and soluble CD27 (sCD27) in HIV infection and in AIDS-associated lymphoma.

CD27 is a member of the tumor necrosis factor receptor superfamily that is expressed primarily on T cells, as well as on subsets of B cells and NK cells. CD70, which is expressed on activated B and T cells, but not on resting lymphocytes, is a ligand for CD27. Cell surface CD27 can be proteolytically cleaved to produce a 32-kDa soluble CD27 (sCD27) molecule.

Immune dysfunction and the pathogenesis of AIDS-associated non-Hodgkin's lymphoma.

Much has been learned about how HIV-induced immune dysfunction contributes to B cell hyperactivation, and potentially, to the pathogenesis of AIDS-lymphoma. However, further studies are needed to fully understand how HIV infection and immune dysfunction promote B cell hyperactivation and the development/growth of AIDS-lymphoma. In particular, studies are needed to define the role of HHV8 vIL6, IL6 receptor-expression, and lymphocyte surface stimulatory molecules, in promoting B cell hyperactivation or lymphoma cell growth.

Effects of zidovudine on B lymphocyte activation.

B cell dysfunction associated with HIV infection includes polyclonal B cell activation and hypergammaglobulinemia. There is also an elevated frequency of B cell malignancies, especially non-Hodgkin's lymphoma, in HIV infection. It is believed that chronic polyclonal activation of B cells might increase the chances for the occurrence of a genetic accident, resulting in tumorigenesis.