Suanne F. Dougherty

Center for Biologics Evaluation and Research

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Joost J. Oppenheim

Frederick National Laboratory for Cancer Research

Sharon M. Wahl

Johns Hopkins All Children's Hospital

Stephan E. Mergenhagen

National Institute of Dental and Craniofacial Research

D H Pluznik

United States Food and Drug Administration

J B Allen

American Thoracic Society

Richard J. Howard

Barking, Havering And Redbridge University Hospitals NHS Trust

L M Wahl

Paracelsus Medizinische Privatuniversität

Abner Louis Notkins

National Institute of Dental and Craniofacial Research

L R Ellingsworth

National Institute of Dental and Craniofacial Research

H.L.S. Wong

University of Minnesota

Cooperative Institutions

National Institutes of Health

National Institute of Dental and Craniofacial Research

National Cancer Institute

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Johns Hopkins University

National Institute of Neurological Disorders and Stroke

Uniformed Services University of the Health Sciences

George Washington University

Center for Biologics Evaluation and Research

University of California, San Diego

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Capacity of human large granular lymphocytes (LGL) to produce multiple lymphokines: interleukin 2, interferon, and colony stimulating factor.

The Journal of Immunology (1983)

Tadashi Kasahara J Y Djeu Suanne F. Dougherty Joost J. Oppenheim

Human large granular lymphocytes (LGL), which are known to be responsible for natural killer (NK) cell activity, also produced a variety of lymphokines including interleukin 2 (IL 2), colony stimulating factor (CSF), and interferon (IFN) in response to phytohemagglutinin (PHA) or concanavalin A (Con A). Human peripheral blood LGL, which were purified by removal of monocytes adhering to plastic flasks and nylon columns, followed by separation on a discontinuous Percoll gradient, and additional treatment with anti-OKT3 and Leu-M1 plus complement, were more potent producers of these lymphokines than unseparated mononuclear cells (MNC), nylon column-eluted cells, or purified T lymphocytes. Moreover, IL 2 production by LGL could be further distinguished in that it was not enhanced by the addition of macrophages or macrophage-derived factor, i.e., IL 1, whereas addition of macrophages did potentiate IL 2 production by T lymphocytes. Further analysis of cells in the LGL population using various monoclonal antibodies revealed that removal of cells with OKT11 or AF-10, a monoclonal antibody against human HLA-DR antigen, decreased IL 2 production, whereas removal of OKT8+, OKM1+, Leu-M1+, or Leu-7+ cells led to enhanced IL 2 production. The LGL population is therefore heterogeneous and includes at least three functionally and phenotypically distinct subsets. An atypical T cell subset (OKT3-, Leu-1-, OKT11+) rather than the myeloid subset of LGL (Leu-M1+ or OKMI+) was the source of LGL-derived IL 2, whereas the latter subset and/or another subset of OKT8+ cells appear to regulate this IL 2 production. In addition to performing NK activity, LGL on a per cell basis seem to be more effective than T lymphocytes in producing lymphokines, namely, IL2, CSF, and IFN.

Interleukin 3

10.4049/jimmunol.131.5.2379

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Citations (294)

Absolute Macrophage Dependency of T Lymphocyte Activation by Mitogens

The Journal of Immunology (1976)

David L. Rosenstreich John J. Farrar Suanne F. Dougherty

A T lymphocyte subpopulation that contains only 0.3% macrophages and less than 2% B lymphocytes has been prepared from guinea pig lymph node cells by the use of two different types of adherence columns. This subpopulation does not porliferate in response to the mitogens Con A or PHA unless additional macrophages are added. The means by which macrophages restore T cell responsiveness to PHA has been investigated. Marcophages appear to function via two different distinct mechanisms in this experimental situation. The first mechanism involves the binding of PHA to the macrophage followed by the "presentation" of the mitogen to the T lymphocyte in a manner that induces cell activation. This presentation function requires that the macrophage be viable and metabolically active. The second mechanism by which macrophages function is by the elaboration of a soluble factor or factors. The presence of these factors has been reliably and reproducibly demonstrated by using a double-chambered, Marbrook-type tissue culture vessel. This soluble factor can induce activation of T lympohcytes with surface bound PHA in the apparent absence of any form of macrophage presentation. In contrast, the function of this factor is clearly distinct from that of the reducing agent, 2-mercaptoethanol, (2-ME) since 2-ME does not enable this T cell subpopulation to be activated by mitogens. On the basis of these observations, we propose that two distinct signals are required to activate this T lymphocyte subpopulation. One signal is delivered by the interaction of the mitogen with the T cell surface, and the second signal is delivered by a soluble factor(s) produced by macrophages. Whether all types of T lymphocytes require two signals to be activated, remains to be established.

Macrophage-activating factor

10.4049/jimmunol.116.1.131

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Citations (425)

Prostaglandin E2 rather than lymphocyte-activating factor produced by activated human mononuclear cells stimulates increases in murine thymocyte cAMP

Cellular Immunology (1980)

Joost J. Oppenheim William J. Koopman Larry M. Wahl Suanne F. Dougherty

Thymocyte

Phorbol

10.1016/0008-8749(80)90056-8

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Citations (46)

Transforming growth factor-beta is a potent immunosuppressive agent that inhibits IL-1-dependent lymphocyte proliferation.

The Journal of Immunology (1988)

Sharon M. Wahl D A Hunt H.L.S. Wong Suanne F. Dougherty Nancy McCartney‐Francis

Transforming growth factor-beta (TGF-beta), a product of neoplastic and hemopoietic cells, is a bifunctional regulator of the immune response. At femtomolar concentrations, TGF-beta stimulates monocyte migration, and picomolar quantities induce synthesis of monocyte growth factors, including IL-1, that may promote tissue repair by regulating fibrosis and angiogenesis. Paradoxically, TGF-beta at picomolar concentrations also blocks the ability of IL-1 to stimulate lymphocyte proliferation. At 0.01 to 1.0 ng/ml, TGF-beta 1 and its homologue, TGF-beta 2, suppress the IL-1-dependent murine thymocyte proliferation assay. TGF-beta also inhibits human peripheral blood T lymphocyte mitogenesis. Inhibition of cell division appears to occur after activation of the lymphocytes inasmuch as neither gene expression nor translation of IL-2R is suppressed. Furthermore, TGF-beta does not block synthesis of IL-2. Therefore, TGF-beta 1 and TGF-beta 2 likely act at a site distal to IL-1 to block lymphocyte DNA synthesis. These findings suggest that TGF-beta secreted in an inflammatory site may be beneficial in diminishing lymphocyte function while promoting fibrosis and tissue repair. However, TGF-beta generated by neoplastic tissues may provide a mechanism for unrestricted tumor cell growth through its selective immunosuppressive effects.

BETA (programming language)

TGF beta 1

Thymocyte

Monocyte

10.4049/jimmunol.140.9.3026

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Citations (393)

Antagonistic and agonistic effects of transforming growth factor-beta and IL-1 in rheumatoid synovium.

The Journal of Immunology (1990)

Sharon M. Wahl J B Allen H.L.S. Wong Suanne F. Dougherty L R Ellingsworth

We investigated potential mechanisms by which lymphocytes infiltrating rheumatoid synovium become immunosuppressed. In 20 of 22 synovial fluids and 12 of 13 synovial tissue culture supernatants, no IL-1 bioactivity could be detected in the thymocyte proliferation assay. These same preparations could, however, support proliferation of fibroblast monolayers, consistent with the presence of IL-1 and/or other fibroblast growth factors. Addition of either rheumatoid synovial fluids or synovial culture supernatants to exogenous IL-1 in the IL-1 bioassay caused marked inhibition of the assay indicative of an IL-1 inhibitor. This inhibition of IL-1 could be reversed by treating the effusions or supernatants with a neutralizing antibody to transforming growth factor-beta (TGF-beta). Furthermore, monocyte-macrophages isolated from rheumatoid synovial fluid constitutively released both latent and active TGF-beta in culture at levels sufficient to completely block the biologic activity of 100 U/ml IL-1. The production of substantial levels of TGF-beta by synovial macrophages, as well as the apparent ability of these inflammatory macrophages to activate latent TGF-beta, implicates TGF-beta not only as an important inhibitor of IL-1-induced lymphocyte proliferation, but also as a key cytokine in promoting synovial fibroblast hyperplasia and pathology.

Agonistic behaviour

BETA (programming language)

10.4049/jimmunol.145.8.2514

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Citations (112)

T lymphocyte-dependent evolution of bacterial cell wall-induced hepatic granulomas.

The Journal of Immunology (1986)

Sharon M. Wahl J B Allen Suanne F. Dougherty V. Evêquoz D H Pluznik

Injection of streptococcal cell walls (SCW) i.p. into susceptible rats results in dissemination of SCW primarily to the liver, spleen, bone marrow, and peripheral joints. Within the liver, the SCW are phagocytized by the Kupffer cells, initiating a sequence of events leading to the formation of hepatic granulomas. The granulomas are characterized by large numbers of W3/13+, W3/25+ T lymphocytes and Ia+, esterase-positive macrophages. The generation of inflammatory mediators by these mononuclear cells appears to be central to the evolution of the granulomas and the subsequent fibrotic sequelae evoked by the SCW. In the absence of functional T lymphocytes (athymic rats), injection of SCW does not trigger lymphokine production, and organized granulomas do not develop in the livers. Furthermore, inhibition of T lymphocyte proliferation and lymphokine synthesis pharmacologically by cyclosporin A administration in euthymic animals inhibits SCW-induced hepatic granuloma development. Although macrophage function is apparently not impaired as evidenced by IL 1 and PGE2 production, a chronic inflammatory response to SCW cannot be sustained in the absence of T lymphocyte participation. These studies provide insight into the cellular and molecular mechanisms leading to formation and maintenance of chronic granulomatous lesions.

10.4049/jimmunol.137.7.2199

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Citations (48)

Enhanced Humoral Immunity in Mice Infected with Attenuated Venezuelan Equine Encephalitis Virus

The Journal of Immunology (1969)

R J Howard Charles P. Craig G. S. Treviño Suanne F. Dougherty S. E. Mergenhagen

Abstract Attenuated Venezuelan equine encephalitis virus (VEE) infection increased the antibody response to human γ globulin (HGG) in adult Balb/c mice. Mice infected 1 or 11 days before but not 29 days before immunization with 1 mg HGG showed increased rates of elimination of 131I-HGG and elevated hemagglutination titers to HGG. In addition, VEE infection prevented the induction of tolerance to HGG and converted a tolerance-inducing stimulus into an immunizing stimulus. However, VEE infection did not prolong the survival of skin allografts across weak or strong histocompatibility barriers. Two to 6 days after infection, mice showed increased rates of clearance of colloidal carbon. This may have been related to the proliferation of reticuloendothelial cells, since VEE infection caused a proliferation of these cells in germfree mice. In addition, germfree mice infected with VEE had increased spleen weights, and germinal centers appeared in histologic sections of spleens. Increased γ globulin concentrations were seen in the sera of infected germfree mice, which could be attributed only partially to antivirus antibody. Thus, VEE behaves as an adjuvant for humoral antibody responses.

Hemagglutination assay

10.4049/jimmunol.103.4.699

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Citations (24)

Relationship of cell cycle to recovery of IL 2 activity from human mononuclear cells, human and mouse T cell lines.

The Journal of Immunology (1981)

B. M. Stadler Suanne F. Dougherty Jeremy Farrar Joost J. Oppenheim

Human cell

10.4049/jimmunol.127.5.1936

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Citations (148)

Macrophage Production of TGF-? and Regulation by TGF-?

Annals of the New York Academy of Sciences (1990)

Sharon M. Wahl Nancy McCartney‐Francis J B Allen Elizabeth Dougherty Suanne F. Dougherty

Dental research

Section (typography)

10.1111/j.1749-6632.1990.tb16111.x

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Citations (149)

Prolongation of Skin Homografts by Rabbit Anti-Mouse Lymphocyte Serum in Mice Rendered Tolerant to Rabbit γ-Globulin

The Journal of Immunology (1968)

Richard J. Howard Suanne F. Dougherty Stephan E. Mergenhagen

Summary Balb/C mice readily form antibodies to the γ-globulin portion of rabbit anti-mouse lymphocyte serum (ALS) as indicated by immune elimination of 131I-rabbit γ-globulin. Mice were rendered tolerant to rabbit γ-globulin (RGG) by injection of “biologically filtered” RGG prior to grafting with tail skin from C3H mice. Animals were shown to be tolerant by their failure to demonstrate immune elimination of 131I-RGG and by the lack of precipitating antibodies to RGG in their sera. Tolerant and nontolerant mice were given either a single injection or a series of injections of ALS after grafting. In all cases, whether single or multiple injections of ALS were given, animals tolerant to RGG retained their grafts for a longer period than nontolerant animals. These results were attributed to a decreased rate of elimination of the active γ-globulin component of ALS in mice rendered tolerant to RGG. However, both tolerant and nontolerant mice showed the same suppression of white blood cell count and lymphocyte count after an injection of ALS and both groups showed the same rate of return toward normal. Of interest was the finding that heat-treated (63°C) RGG, as well as “biologically filtered” RGG, induced immunologic tolerance to the γ-globulin fraction of ALS and prolonged skin grafts after administration of ALS. On the other hand, active immunization with RGG in complete Freund's adjuvant did not shorten graft survival in ALS-treated mice.

Immunologic Tolerance

10.4049/jimmunol.101.2.301

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Citations (17)