Zanvil Alexander Cohn 1926-1993

Zanvil Alexander Cohn, an editor of this Journal since 1973, died suddenly on June 28, 1993. Cohn is best known as the father of the current era of macrophage biology. Many of his scientific accomplishments are recounted here, beginning with seminal studies on the granules of phagocytes that were performed with his close colleague and former editor of thisJournaI, James Hirsch. Cohn and Hirsch identified the granules as lysosomes that discharged their contents of digestive enzymes into vacuoles containing phagocytosed microbes. These findings were part of the formative era of cell biology and initiated the modern study of endocytosis and cell-mediated resistance to infection. Cohn further explored the endocytic apparatus in pioneering studies of the mouse peritoneal macrophage in culture. He described vesicular inputs from the cell surface and Golgi apparatus and documented the thoroughness of substrate digestion within lysosomal vacuoles that would only permit the egress of monosaccharides and amino acids. These discoveries created a vigorous environment for graduate students, postdoctoral fellows, and junior and visiting faculty. Some of the major findings that emerged from Cohn’s collaborations included the radioiodination of the plasma membrane for studies of composition and turnover; membrane recycling during endocytosis; the origin of the mononuclear phagocyte system in situ; the discovery of the dendritic cell system of antigen-presenting cells; the macrophage as a secretory cell, including the release of proteases and large amounts of prostaglandins and leukotrienes; several defined parameters of macrophage activation, especially the ability of T cell-derived lymphokines to enhance killing of tumor cells and intracellular protozoa; the granule discharge mechanism whereby cytotoxic lymphocytes release the pore-forming protein perforin; the signaling of macrophages via myristoylated substrates of protein kinase C; and a tissue culture model in which monocytes emigrate across tight endothelial junctions. In 1983, Cohn turned to a long-standing goal of exploring host resistance directly in humans. He studied leprosy, focusing on the disease site, the parasitized macrophages of the skin. He injected recombinant lymphokines into the skin and found that these molecules elicited several cell-mediated responses. Seeing this potential to enhance host defense in patients, Cohn was extending his clinical studies to AIDS and tuberculosis. Zanvil Cohn was a consummate physician-scientist who nurtured the relationship between cell biology and infectious disease. He guided with a warm but incisive manner the careers of many individuals. He was deeply committed to several institutions of biomedical research; to medicine in the developing world; to The Rockefeller University, especially its programs for graduate study and patient-oriented research; and to the energy and spirit of this Journal

Prevention of rejection of murine islet allografts by pretreatment with anti-dendritic cell antibody

Faustman, D., Steinman, R.M., Gebel, H., Hauptfeld, V., Davie, J., and Lacy, P. Prevention of rejection of murine islet allografts by pretreatment with anti-dendritic cell antibody. Proc. Natl. Acad. Sci. USA. 81: 3864-3868, 1984https://digitalcommons.rockefeller.edu/historical-scientific-reports/1013/thumbnail.jp

Prevention of rejection of murine islet allografts by pretreatment with anti-dendritic cell antibody

Previously we have demonstrated that islets of Langerhans treated with donor-specific anti-Ia serum and complement survive when transplanted across the major histocompatibility complex of the mouse. In this study, using immunofluorescence, we demonstrate two morphologically distinct populations of Ia-positive cells scattered within the Ia-negative islet tissue. A large irregularly shaped Ia-positive subset of cells were identified as dendritic cells by using the 33D1 antibody specific for a mouse dendritic cell antigen. The other small, round Ia-positive subset was 33D1 negative. Islets pretreated with anti-dendritic cell antibody and complement prior to transplantation survived in their histoincompatible recipients for \u3e200 days. Rejection of stable islet allografts promptly occurred when transplant recipients were challenged with 1 x 105 donor dendritic cells 60 days after transplantation. These results demonstrate an important in vivo role for donor dendritic cells in the stimulation of allograft rejection

Anatomy of germinal centers in mouse spleen, with special reference to \u27follicular dendritic cells\u27

Lymphocyte proliferation in germinal centers (GC\u27s) is thought to be triggered by antigen retained extracellularly on the surface of special \u27dendritic\u27 cells. The anatomy and function of these cells have not been studied directly or in detail. We therefore examined mouse spleen GC\u27s developing in response to sheep erythrocyte stimulation. We found that distinctive \u27follicular dendritic cells\u27 (FDC\u27s) were present in both the GC and adjacent mantle region of secondary follicles. The large, irregularly shaped nucleus, containing little heterochromatin, allowed for the light microscope (LM) identification of FDC\u27s. By EM, the cell was stellate in shape sending out long, thin sheets of cytoplasm which could fold and coil into complex arrays. The processes were coated extracellularly by an amorphous electron-dense material of varying thickness, as well as particulates including variable numbers of virions. The FDC cytoplasm lacked organelles of active secretory and endocytic cells, such as well-developed rough endoplasmic reticulum (RER) and lysosomes. These anatomical features readily distinguished FDC\u27s from other cell types, even those that were extended in shape. To pursue these descriptive findings, we injected three electron-dense tracers i.v. and sacrificed the mice 1 h-10 days thereafter. Colloidal carbon, colloidal thorium dioxide (cThO2), and soluble horseradish perixidase (HRP) were actively sequestered into the vacuolar system of macrophages but were interiorized only in trace amounts by FDC\u27s. Therefore, FDC\u27s are not macrophages by cytologic and functional criteria. FDC\u27s did display a unique property. Both colloidal carbon and thorium dioxide, which are nonimmunogens, could be visualized extracellularly on the cell surface for several days. The meaning of this is unclear, but the association of colloid with FDC\u27s appeared to slow the movement of particulates through the extracellular space into the GC proper. FDC\u27s were not readily identified in splenic white pulp lacking GC\u27s. They must develop de novo then, possibly from novel dendritic cells that we have identified in vitro

Neutralizing monoclonal antibodies block human immunodeficiency virus type 1 infection of dendritic cells and transmission to T cells

Prevention of the initial infection of mucosal dendritic cells (DC) and interruption of the subsequent transmission of HIV-1 from DC to T cells are likely to be important attributes of an effective human immunodeficiency virus type 1 (HIV-1) vaccine. While anti-HIV-1 neutralizing antibodies have been difficult to elicit by immunization, there are several human monoclonal antibodies (MAbs) that effectively neutralize virus infection of activated T cells. We investigated the ability of three well-characterized neutralizing MAbs (IgG1b12, 2F5, and 2G12) to block HIV-1 infection of human DC. DC were generated from CD14+ blood cells or obtained from cadaveric human skin. The MAbs prevented viral entry into purified DC and the ensuing productive infection in DC/T-cell cultures. When DC were first pulsed with HIV-1, MAbs blocked the subsequent transmission to unstimulated CD3+ T cells. Thus, neutralizing antibodies can block HIV-1 infection of DC and the cell-to-cell transmission of virus from infected DC to T cells. These data suggest that neutralizing antibodies could interrupt the initial events associated with mucosal transmission and regional spread of HIV-1

Distribution of horseradish peroxidase (HRP)- anti-HRP immune complexes in mouse spleen with special reference to follicular dendritic cells

The distribution of immune complexes has been studied in mouse spleen stimulated to contain many germinal centers (GC′s). Horseradish peroxidase (HRP)-anti-HRP complexes were used as an appropriately precise and sensitive model. We were primarily interested in the relative abilities of three cell types to interact with complexes: lymphocytes, macrophages, and follicular dendritic cells (FDC′s). The latter are distinctive, nonendocytic, stellate cells located primarily at the transition of mantle and GC zones of 2° lymphoid follicles (Chen, L. L., J. C. Adams, and R. M. Steinman, 1978, J. Cell Biol. 77: 148). Binding of immune complexes to lymphocytes could not be visualized in situ. Macrophages avidly interiorized complexes into lysosomes, but did not retain them extracellularly. In contrast, FDC′s could retain HRP-anti-HRP extracellularly under appropriate conditions, but did not endocytose them. Cytochemical reactivity accumulated progressively on FDC′s 1-6 h after administration of complexes i.v., remained stable in amount and location for 1 day, and then was progressively lost over a 1- to 5-day period. Several variables in the association of complexes with macrophages and FDC′s were pursued. Only 1 /xg of complexed HRP had to be administered to visualize binding to both cell types. Macrophages interiorized complexes formed in a wide range of HRP/anti-HRP ratios, while FDC′s associated with complexes formed in HRP excess only. Quantitative studies with [125I]HRP-anti-HRP demonstrated that 20 of the splenic load of HRP associated with FDC′s. Complexes formed with an F(ab′)2 anti-HRP were distributed primarily in macrophages. When the levels of the third component of serum complement were depleted by prior treatment with cobra venom factor, uptake of complexes by macrophages was reduced some 50 whereas association with FDC′s was abolished. The fact that antigen excess complexes are retained extracellularly strengthens the idea that they are immunogenic. Finally, the association of complexes with FDC′s seems to retard the entry of antigen into the GC proper

Critical role for prokineticin 2 in CNS autoimmunity

Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease. Methods: We investigated the expression of PK2 in mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activated against myelin antigen to explore the immune-modulating effects of this peptide in vitro. Results: Pk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demyelination, and decreased the production of interferon (IFN)-γ and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN-γ and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen. Conclusion: These data suggest that PK2 is a critical immune regulator in CNS autoimmune demyelination and may represent a new target for therapy

Human Dendritic Cells Activate Resting Natural Killer (NK) Cells and Are Recognized via the NKp30 Receptor by Activated NK Cells

During the innate response to many inflammatory and infectious stimuli, dendritic cells (DCs) undergo a differentiation process termed maturation. Mature DCs activate antigen-specific naive T cells. Here we show that both immature and mature DCs activate resting human natural killer (NK) cells. Within 1 wk the NK cells increase two– to fourfold in numbers, start secreting interferon (IFN)-γ, and acquire cytolytic activity against the classical NK target LCL721.221. The DC-activated NK cells then kill immature DCs efficiently, even though the latter express substantial levels of major histocompatibility complex (MHC) class I. Similar results are seen with interleukin (IL)-2–activated NK cell lines and clones, i.e., these NK cells kill and secrete IFN-γ in response to immature DCs. Mature DCs are protected from activated NK lysis, but lysis takes place if the NK inhibitory signal is blocked by a human histocompatibility leukocyte antigen (HLA)-A,B,C–specific antibody. The NK activating signal mainly involves the NKp30 natural cytotoxicity receptor, and not the NKp46 or NKp44 receptor. However, both immature and mature DCs seem to use a NKp30 independent mechanism to act as potent stimulators for resting NK cells. We suggest that DCs are able to control directly the expansion of NK cells and that the lysis of immature DCs can regulate the afferent limb of innate and adaptive immunity