—Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively expressing β-galactosidase under the transcriptional regulation of an endothelial cell–specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant donors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transcripts, were identified in corpus luteal and endometrial neovasculature after inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were implanted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Tie-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1/lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal demonstrated that the neovasculature of the developing tumor frequently comprised Flk-1– or Tie-2–expressing EPCs. Cutaneous wounds examined at 4 days and 7 days after skin removal by punch b...

Bone Marrow Origin of Endothelial Progenitor Cells Responsible for Postnatal Vasculogenesis in Physiological and Pathological Neovascularization

Publisher Summary Studies of cytotoxicity by human lymphocytes revealed not only that both allogeneic and syngeneic tumor cells were lysed in a non-MHC-restricted fashion, but also that lymphocytes from normal donors were often cytotoxic. Lymphocytes from any healthy donor, as well as peripheral blood and spleen lymphocytes from several experimental animals, in the absence of known or deliberate sensitization, were found to be spontaneously cytotoxic in vitro for some normal fresh cells, most cultured cell lines, immature hematopoietic cells, and tumor cells. This type of nonadaptive, non-MHC-restricted cellmediated cytotoxicity was defined as “natural” cytotoxicity, and the effector cells mediating natural cytotoxicity were functionally defined as natural killer (NK) cells. The existence of NK cells has prompted a reinterpretation of both the studies of specific cytotoxicity against spontaneous human tumors and the theory of immune surveillance, at least in its most restrictive interpretation. Unlike cytotoxic T cells, NK cells cannot be demonstrated to have clonally distributed specificity, restriction for MHC products at the target cell surface, or immunological memory. NK cells cannot yet be formally assigned to a single lineage based on the definitive identification of a stem cell, a distinct anatomical location of maturation, or unique genotypic rearrangements.

Biology of natural killer cells.

A newly-constructed antibody-like molecule containing the gp120-binding domain of the receptor for human immunodeficiency virus blocks HIV-1 infection of T cells and monocytes. Its long plasma half-life, other antibody-like properties, and potential to block all HIV isolates, make it a good candidate for therapeutic use.

Designing CD4 immunoadhesins for AIDS therapy

Microglia are associated with central nervous system (CNS) pathology of both Alzheimer's disease (AD) and the acquired immunodeficiency syndrome (AIDS). In AD, microglia, especially those associated with amyloid deposits, have a phenotype that is consistent with a state of activation, including immunoreactivity with antibodies to class II major histocompatibility antigens and to inflammatory cytokines (interleukin-1-beta and tumor necrosis factor-alpha). Evidence from other studies in rodents indicate that microglia can be activated by neuronal degeneration. These results suggest that microglial activation in AD may be secondary to neurodegeneration and that, once activated, microglia may participate in a local inflammatory cascade that promotes tissue damage and contributes to amyloid formation. In AIDS, microglia are the primary target of retroviral infection. Both ramified and ameboid microglia, in addition to multinucleated giant cells, are infected by the human immunodeficiency virus (HIV-1). The mechanism of microglial infection is not known since microglia lack CD4, the HIV-1 receptor. Microglia display high affinity receptors for immunoglobulins, which makes antibody-mediated viral uptake a possible mechanism of infection. In AIDS, the extent of active viral infection and cytokine production may be critically dependent upon other factors, such as the presence of coinfecting agents. In the latter circumstance, very severe CNS pathology may emerge, including necrotizing lesions. In other circumstances, HIV infection of microglia probably leads to CNS pathology by indirect mechanisms, including release of viral proteins (gp120) and toxic cytokines. Such a mechanism is the best hypothesis for the pathogenesis of vacuolar myelopathy in adults and the diffuse gliosis that characterizes pediatric AIDS, in which very little viral antigen can be detected.

Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease

Pathogenesis of human immunodeficiency virus infection.

Monocytes and macrophages, which may play a central role in the pathogenesis of infection with human immunodeficiency virus type 1 (HIV-1), express the CD4 molecule and Fc receptors (FcR) for immunoglobulin G (IgG). To explore the possibility that FcR mediate HIV-1 infection of monocytes, studies were conducted with the human monocytic cell line U937. These cells were exposed to HIV-1 complexed with various concentrations of serum from HIV-1 antibody-positive individuals and monitored for HIV-1 replication. Serum samples from antibody-negative normal individuals did not affect virus yields. High concentrations of antibody-positive sera showed virus-neutralizing activity; however, cells infected with HIV-1 in the presence of antibody-positive sera at subneutralizing concentrations significantly enhanced virus replication. This infection enhancement was blocked by heat-aggregated gamma-globulin. Moreover, the IgG fraction from an HIV-1 antibody-positive serum enhanced HIV-1 infection at the same serum dilution equivalents. In contrast, IgG-F(ab')2 did not enhance HIV-1 infection but showed neutralizing activity with HIV-1. These results are compatible with the concept of FcR-mediated infection enhancement and suggest that this immunological response to HIV-1, instead of protecting the host, potentially facilitates the infection.

https://science.sciencemag.org/content/sci/242/4878/580.full.pdf

Antibody-enhanced infection by HIV-1 via Fc receptor-mediated entry.

PURPOSE: To assess the effectiveness of magnetic resonance (MR) imaging for the diagnosis of early-stage rheumatoid arthritis (RA). MATERIALS AND METHODS: Fifty subjects (nine men and 41 women) with polyarthralgia who were suspected of having early-stage RA on the basis of clinical and radiographic findings were selected to undergo gadolinium-enhanced MR imaging of the hands. The MR imaging criterion for the diagnosis of early RA was bilateral enhancement in both wrists and/or the metacarpophalangeal and/or proximal interphalangeal joints. Follow-up continued until a final diagnosis was determined. Two patients left the study before the end of follow-up. RESULTS: Final diagnoses were established after a mean follow-up of 776 days: rheumatoid arthritis in 26 patients and nonrheumatoid disease in 22. Use of the MR imaging criterion yielded the correct diagnosis in 25 patients with RA and three false-positive results in three patients without RA. As compared with the traditional format and classification tre...

Early-stage rheumatoid arthritis: prospective study of the effectiveness of MR imaging for diagnosis.

PURPOSE: To investigate the role of magnetic resonance (MR) imaging in diagnosing early rheumatoid arthritis (RA). MATERIALS AND METHODS: Twenty patients (three men, 17 women; age range, 21-72 years) with clinically and radiologically proved RA underwent evaluation to define an MR imaging criterion for diagnosing synovial inflammation due to RA. Twenty-seven patients (16 with RA, 11 without RA [control patients]; three men, 24 women; age range, 19-75 years) suspected to have early RA but without radiographic abnormalities underwent evaluation to test the accuracy of using the criterion to diagnose RA. In each patient, coronal, fat-suppressed, and gadolinium contrast material-enhanced, T1-weighted images of both hands were obtained. RESULTS: The MR imaging criterion was periarticular contrast material enhancement of the wrists or the metacarpophalangeal and/or proximal interphalangeal joints in both hands. In the diagnosis of early RA, sensitivity and negative predictive value were both 100%, specificity w...

Early-stage rheumatoid arthritis: diagnostic accuracy of MR imaging.

Evidence of antibody-dependent enhancement of human immunodeficiency virus type 1 (HIV-1) infection via Fc receptor (FcR) was published previously (A. Takeda, C. U. Tuazon, and F. A. Ennis, Science 242:580-583, 1988). To define the entry mechanism of HIV-1 complexed with anti-HIV-1 antibody, we attempted to determine the receptor molecules responsible for mediating enhancement of HIV-1 infection of monocytic cells. Monoclonal antibodies to FcRI for immunoglobulin G substantially blocked antibody-dependent enhancement of HIV-1 infection. Furthermore, we demonstrate a requirement for the CD4 molecule in antibody-enhanced HIV-1 infection via FcR. Soluble CD4 prevented infection by HIV-1 antibody-treated virus, and enhancement of infection of virus-antibody complexes was abrogated by a monoclonal antibody to CD4 (anti-Leu3a antibody). Treatment of human macrophages with an anti-CD4 antibody also inhibited antibody-enhanced HIV-1 infection of macrophages, supporting our contention that antibody-dependent enhancement of HIV-1 infection via FcR requires CD4 interaction with the virus glycoprotein.

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Two receptors are required for antibody-dependent enhancement of human immunodeficiency virus type 1 infection: CD4 and Fc gamma R.

The natural killer (NK)-interferon (IFN) system is shown to be significantly involved in the resistance of host to viral infections and to tumours in numbers of animal models (1-4). The patients with Sjogren syndrome (SS) as well as those with collagen diseases were systematically investigated for the functions of NK-IFN system, including endogenous and augmented NK activity, IFN production, and responsiveness of NK cells to IFN stimulation, using virus persistently infected cells (heLa-measles cells) as target and stimulator cells. Although endogenous NK activity was not reduced, augmented NK activity by HeLa-measles cells in vitro was significantly depressed in patients with SS compared with that in age-matched normal controls. The patients with SS had also impaired capacity to produce IFN, which is shown to be a major factor regulating NK activity (5,6) in response to HeLa-measles cells in vitro. In three patients with SS who showed severely depressed NK activity, the effect of exogenous IFN was examined, and virtually no augmentation of NK activity was observed in all cases. Under the same condition, the normal controls demonstrated a dramatic increase in NK activity. The reduced IFN production was observed in all examined patients with SS, whereas impaired augmentation of NK activity by the stimulation with HeLa-measles cells as well as IFN seemed to be more striking in patients with the systemic manifestations of the disease, such as hypergammaglobulinemia and lymphoid hyperplasia. The possible involvement of dysfunction of NK-IFN system in the systemic manifestations of SS is discussed.

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Akira Takeda

Papers

Antibody-enhanced infection by HIV-1 via Fc receptor-mediated entry.

Early-stage rheumatoid arthritis: prospective study of the effectiveness of MR imaging for diagnosis.

Early-stage rheumatoid arthritis: diagnostic accuracy of MR imaging.

Two receptors are required for antibody-dependent enhancement of human immunodeficiency virus type 1 infection: CD4 and Fc gamma R.

Studies of the function of natural killer-interferon system in patients with Sjögren syndrome.