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Biomedical subjects

M K Hoffmann

Publications and source records attributed to M K Hoffmann.

At least 73 records · Page 4Linked to original sources
PubMed1984

Ia-restricted interaction of normal lymphoid cells and SJL lymphoma (reticulum cell sarcoma) leading to lymphokine production. II. Rapid production of antibody-enhancing factor, interleukin 2, and immune interferon.

Mixed cell cultures of syngeneic lymph node (LN), spleen, or thymus and gamma-irradiated, syngeneic lymphoma cells of transplantable reticulum cell sarcomas (gamma-RCS) produced within 24 hours high titers of interleukin 2 (IL-2) and immune interferon in their supernatant (SN). These lymphokine titers were much higher than those seen after stimulation with allogeneic cells. SN also had marked enhancing activity for antibody production by anti-T-cell serum plus complement-treated spleen cells to trinitrophenylated polyacrylamide in vitro. This activity could be removed by absorption with cells of an IL-2-dependent cytotoxic cell line. Mixtures of gamma-RCS and LN cells from SJL/J F1 hybrid mice produced these lymphokines only when the non-SJL parent contributed H-2s or H-2b, but not H-2k or H-2d, in the I-region. These I-region restrictions were similar to those observed previously with respect to the ability of T-cells from SJL F1 hybrids to give proliferative responses to gamma-RCS in vitro and of these mice to support tumor growth in vivo. gamma-RCS also induced rapid interferon production in vivo, but serum titers 24 hours after injection consisted primarily of interferon resistant to pH 2 and neutralized by antibody to virally induced interferon (IFN-alpha/beta), and the production of IFN-alpha/beta was not subject to the same genetic restrictions. Although reticulum cell sarcoma cell extracts had no detectable effect in vitro, they were capable of inducing transient IFN production in vivo.

Animals↗
PubMed1983

Endotoxin-induced in vitro release of interleukin-1 by cancer patients' monocytes: relation to stage of disease.

The in vitro release of IL-1 by monocytes in response to endotoxin was subnormal in many patients with breast cancer, malignant melanoma or colorectal cancer but not in patients with benign tumors of the breast or colon. In each of these groups, IL-1 release was low in patients with early cancer, normal in patients with regional metastases, and low in patients with disseminated cancer.

Adult↗
PubMed1983

Characterization of T lymphocyte subsets with monoclonal antibodies: discovery of a distinct marker, Ly-m22, of T suppressor cells.

The study of cell surface antigens has accelerated in the few years since the advent of hybridoma technology to the point where many dozens of such markers have now been described. The functional heterogeneity of post-thymic T cells in the immune response, however, still exhibit complexities beyond the resolving power of our current repertoire of marker antigens. In this study, we investigated the surface phenotype of three types of effector T cells: helper cells, nonspecific suppressor cells, and cytotoxic T cells, using four recently discovered alloantigen systems of T cells: Ly-m10, Ly-m18, Ly-m19, and Ly-m22. SRBC-primed spleen cells were used as a source of specific helper T cells, and they were tested by their ability to promote antibody synthesis by B lymphocytes. Concanavalin A-activated suppressor cells were assayed by their ability to inhibit that response. Cytotoxic T cells were activated by alloantigen. We found Ly-m10 to be expressed on all three cell types tested, whereas Ly-m18 and Ly-m19 were absent from all three. Ly-m22, whose controlling locus is closely linked to the Mls region, had a unique distribution, being present solely on suppressor cells. Thus Ly-m22 emerged as a new marker that distinguishes nonspecific T suppressor cells (Ly-m22+) from T helper as well as cytotoxic T cells (Ly-m22-). Ly-m22 is the only antigen besides I-J so far known to be restricted to suppressor cells.

Animals↗
PubMed1982

Deletion of active human suppressor T lymphocytes from peripheral blood by Sephadex G-10 filtration.

A method for antigen-specific generation of antibody-forming B cells in cultures of human peripheral blood mononuclear (PBM) cells based on the Mishell-Dutton system has recently been established in this laboratory. Comparing PBM cell cultures from healthy donors and from patients with advanced cancer we found the latter to be unresponsive in our assay. Passage of PBM cell suspension over Sephadex G-10 columns restored the response of patient PBM cells to normal levels. The cell population trapped on the column can be recovered and its inhibitory potential demonstrated by its graded addition to cells eluted from the column. The cell responsible for inhibition is sensitive to treatment with OKT8 antibody and complement, indicating its T cell nature. Passage of PBM cells from healthy individuals did not alter antibody responses substantially but made the activation requirements less stringent.

Animals↗
PubMed1982

Modulation of interferon-induced NK cells by interleukin 2 and cAMP.

The mechanism by which interferon (IFN) and interleukin 2 (IL-2) activate NK cells has been examined. Added alone, either lymphokine activates NK cells; together they synergize. NK cells generated by IFN, IL-2 or IFN plus IL-2 are indistinguishable on the basis of their cell surface phenotype. Precursor NK cells are Qa5+, MK 2.2-, Ly-6- and effector NK cells are Qa5+, MK 2.2+, Ly-6+. Sequential factor addition showed that IFN must be present at the start of culture, whereas IL-2 could be added later with no loss of effect. Antibody to IFN was shown to block not only the action of IFN but also to prevent NK cell activation by IL-2. These results are taken to suggest that IFN initiates NK cell activation and IL-2 controls later stages. The synergistic effect of IL-2 is counteracted by cAMP. Considering the variety of systems in which IL-2 is active and the diversity of its effects, it is proposed that its antagonism with cAMP may be a basis for the biologic activity of IL-2.

Animals↗
PubMed1982

Lymphokine-induced suppressor B cells.

Accessory activity required for in vitro antibody production by murine B cells is mediated by macrophage- and helper T-cell-derived lymphokines (IL-1 and TRF, respectively). The synergistic helper activity that occurs when TRF is added early rather than late in the response cannot be attributed to the initiation. We found that the suboptimal helper activity which occurs when TRF is added early rather than late in the response cannot be attributed to the inactivation of the mediator, but results instead from the generation of helper factor-induced suppressor cells. Serological examination revealed that these suppressor cells exhibit the cell surface phenotype (Thy 1-, Ia+, IgG+, IgD+) of a B cell. In an attempt to attribute the generation of suppressor B cells to a distinct T-cell product we examined two T-cell mediators believed to be present in TRF, namely IL-2 and a second factor recently introduced as (DL) TRF. Our results point to a dichotomy of the induction pathways involved in the generation of antibody-forming cells and the activation of suppressor B cells, the former involving IL-1 and IL-2, and the latter involving IL-1 and (DL) TRF.

Animals↗
PubMed1982

Helper cell factors restore antibody responses of allogeneic bone marrow chimeras: evidence for ineffective cellular interactions.

We investigated the nature of deficient antibody responses to SRBC in stable, fully allogeneic bone marrow chimeras. No evidence for a suppressor cell-mediated mechanism was found. Chimera spleens possessed adequate numbers of antigen-reactive B cells to produce a normal antibody response. Using separated chimera cell populations and soluble helper factors, we assessed the functional capabilities of chimera B cells, T cells, and macrophages. Our data suggest that the failure of allogeneic chimeras to produce antibody is not the result of impaired B cell, T cell, or macrophage function, but rather that it is due in ineffective cellular interactions that normally result in the generation of helper factors. In vitro stimulation of chimera macrophages with LPS, and of chimera spleen cells with Con A, resulted in the release of soluble helper factors that were capable of fully restoring chimera B cell responses.

Animals↗
PubMed1982

Functionally different T lymphocyte subpopulations determined by their sensitivity to complement-dependent cell lysis with the monoclonal antibody 4A.

A human T lymphocyte antigen 4A (40,000 daltons) is defined by a monoclonal, complement- (C) fixing, hybridoma-produced antibody (moAb 4A). This antigen, which is identical to the previously reported antigen 3A 1, is expressed at quantitatively different levels on functional subsets of peripheral T lymphocytes as determined by the cell sensitivity to antibody and C. Peripheral T lymphocytes can be divided into two populations: 4A high-density T cells (4A increases), which are killed in vitro by moAb 4A + C, and 4A low-density T cells (4A decreases), which are not affected in vitro by moAb 4A + C treatment. The helper/inducer T cell lineage, defined by moAb Leu 3a, and the cytotoxic/suppressor T cell lineage, defined by moAb Leu 2A, contain both 4A increases and 4A decreases T cell populations. Functional studies by moAb 4A + C treatment show that 1) the 4A increases T cell population contains T helper cells, which are necessary for in vitro antibody production against red cell-bound determinant; 2) the 4A decreases T cell population contains the precursor T cells, which proliferate in vitro in MLC, and the precursor T cells, which are necessary for the in vitro generation of the alloreactive cytotoxic T cells; and 3) the cytotoxic activity of alloreactive T cells generated in CML assay is abrogated by moAb 4A + C treatment; 4) the activation of T cells by PHA and Con A increases the quantitative expression of 4A antigen.

Antibodies, Monoclonal↗
PubMed1981

The role of mitogens and antigens in the generation of antibody-producing human B lymphocytes.

Satisfactory experimental systems with which to study the antigen specific humoral immune response of human peripheral blood lymphocytes have not been available until recently. A commonly used method for the study of antibody production by human lymphocytes is that developed by Fauci and Pratt. This system is considered to be antigen nonspecific since the antigen against which the determined antibody is directed is not added to the cultures. We show here that the assumption of the Fauci-Pratt system being antigen nonspecific is not justified. An essential ingredient of this culture system is human serum that has been exhaustively absorbed with antigen (sheep red blood cells). This absorption procedure causes shedding of highly immunogenic antigenic fragments whose immunogenic activity we demonstrated using a recently developed antigen-dependent culture system. In the latter system, we have shown that the control of suppressor cells is a critical factor for the successful induction of antibody responses, particularly in view of the fact that lymphocyte mitogens must be added to cultured human lymphocytes to support their responsiveness. Appropriate timing of mitogen addition to the cultures was found to be an effective means of preferentially stimulating helper or suppressor activity. Pokeweed mitogen, a mitogen known to act on B and on T lymphocytes, Stimulates B cells responses readily but abrogates them prematurely by the simultaneous activation of suppressor cells. When pokeweed mitogen is added to an ongoing response with a delay of 48 hr, it enhances antibody responses markedly, presumably by providing additional help to B cells at a time when they have lost susceptibility to suppressor-cell effects.

Absorption↗
PubMed1981

Mechanism of NK cell activation: relationship between Qa5+ NK cells and lymphocytes.

Interferon (IF) induces within 20 hr of incubation Qa5+Thy-1- NK cells but Qa5-Thy-1+ cytotoxic cells in cultures of murine splenocytes. The mechanism of Qa5+ NK cell activation has been studied by using tumor necrosis serum (TNS), concanavalin A (Con A), and lipolysaccharide (LPS) as additional NK cell-inducing reagents. It was found that IF and TNS activate precursor NK cells directly without the involvement of accessory cells. The T cell mitogen Con A and the B cell mitogen LPS, on the other hand, induced Qa5+ NK cells only in the presence of lymphocytes. Con A-stimulated T cells and LPS-stimulated B cells release factors into the culture medium that activate Qa5+ NK cells. Since Con A and LPS are known to be interferon inducers, it is inferred that Con A-induced and LPS-induced activation of NK cells is mediated by IF. The data demonstrate that NK cells become activated as a consequence of lymphocyte activation and thus suggest a relationship between lymphocyte dependent- and NK cell-dependent defense systems. This relationship is also implied by observations made with NZB mice. NZB mice lose NK cell activity at the time when they develop autoimmune diseases.

Animals↗
PubMed1980

Endotoxin-induced tumor necrosis factor.

The serum of BCG-infected mice treated with endotoxin contains a substance (tumor necrosis factor, TNF) which mimics the tumor-necrotizing action of endotoxin itself. TNF is not residual endotoxin, but a factor released from host cells, probably macrophages. TNF induced in the same way in rats and rabbits also causes necrosis of transplanted murine tumors. Unlike endotoxin, TNF is toxic in vitro for neoplastic murine and human cell lines but not for mouse embryo culture. TNF has striking effects on immunologic reactions in vitro, some like those of endotoxin and others unlike those of endotoxin. TNF is a glycoprotein; its molecular weight is less than 70,000. Highly purified preparations do not contain lysosomal or nonlysosomal serum enzymes, interferon or prostaglandin E1.

Animals↗
PubMed1980

Antigen-specific induction and regulation of antibody synthesis in cultures of human peripheral blood mononuclear cells.

Culture conditions suitable for specific sensitization of human peripheral blood lymphocytes were established. Production of antibody to sheep erythrocytes and to the 2,4,6-trinitrophenyl group conjugated to burro erythrocytes was investigated in terms of cross-sensitization, feedback control by antibody to the immunogen, and regulation by helper and suppressor T cells. Generation of antigen-specific antibody-forming cells was found to be restricted to a narrow concentration range of cultured peripheral blood lymphocytes. The data suggest that antibody formation is limited by suppressor T cells in high-cell-density cultures and by low frequencies of helper T cells in low-cell-density cultures.

Antibody Formation↗
PubMed1980

Macrophages and T cells control distinct phases of B cell differentiation in the humoral immune response in vitro.

The differentiation of B cells in the in vitro PFC-response to red blood cell antigen proceeds through 2 phases. Antigen-reactive B cells acquire the ability to interact with helper T cells in the first phase. This phase is controlled by macrophages through a mediator that they release (Interleukin 1 ([Il-1]). B cells convert into antibody-secreting cells (PFC) in the second phase, which is controlled by helper T cells or by a mediator that they release (T cell-replacing factors [TRF]). This is demonstrated in experiments in which Il-1 increases the number of B cells capable of responding to T cell help. The majority of antigen-reactive B cells reaches that state of differentiation within 40 hr of incubation with Il-1. After this time, the response of B cells depends no longer on the presence of Il-1 but on the presence of T cells or TRF. The presented data suggest that antigen-primed helper T cells (but not unprimed T cells) induce the release of Il-1 by macrophages, thereby also influencing the early phase of B cell differentiation.

Animals↗
PubMed1979

Tumor necrosis serum induces a serologically distinct population of NK cells.

Murine spleen cells generate nonspecific cytotoxic cells, referred to as natural killer (NK) cells, within 4 d of incubation in Mishell-Dutton cultures. This NK cell type does not arise in cultures of BALB/c.nu spleen cells or in cultures of T-cell depleted C57BL/6 spleen cells, indicating that its activation depends on T cells. Another type of NK cells is induced by tumor necrosis serum in murine spleen-cell cultures. It arises within 24 h and its activation does not depend on T cells. This cell type (and its precursor) expresses the recently discovered cell-surface marker Qa5 (controlled by the Q region of chromosome 17) that distinguishes this NK cell from the NK cell that depends for its activation on thymic function. Qa5+ NK cells are also induced by interferon.

Animals↗
PubMed1979

Bacterial lipopolysaccharide activates suppressor B lymphocytes.

Lipopolysaccharide (LPS) extracted from the outer cell wall of Gram-negative bacteria modulates the immune response in vivo and in vitro. Depending on the experimental conditions, it may enhance or inhibit the production of humoral antibody. The pathway by which LPS suppresses antibody production is examined in this study. C57BL/6 spleen cells incubated with LPS (greater than 10 micrograms/ml) not only fail to produce antibody to sheep erythrocytes in vitro but also, when transferred 24 hr after stimulation with LPS, inhibit antibody production in spleen cells that were not treated with LPS. This observation suggested that LPS activates suppressor cells. We have identified a suppressor B cell as mediator of LPS-induced immune suppression and determined its cell surface antigen phenotype as Ig+, Ia+, CR+, Ly-B-2+,PC1-.LPS does not induce suppressor macrophages or suppressor T cells, nor are macrophages or T cells required for the generation of suppressor B cells by LPS.

Animals↗