concanavalin-a and Lymphoproliferative-Disorders

Topics: Animals; Antigens, Neoplasm; Cell Line; Concanavalin A; Cytotoxicity, Immunologic; Humans; Interleukin-2; Lymphocyte Activation; Lymphokines; Lymphoproliferative Disorders; Macrophages; Mice; Mice, Inbred Strains; Mitogens; Monocytes; Neoplasms, Experimental; T-Lymphocytes; Time Factors

In A/J (H-2a) (A) mice, the neonatal i.v. injection of (B10 x A)F1 spleen cells (SC) induces partial transplantation tolerance (TT) to C57BL/10ScSn (H-2b) (B10) skin allografts, chronic host-versus-graft disease (HVGD) and lethal lymphoproliferative disorders (LPD). They produce anti-T-cell autoantibodies (ATA), and the proliferative responses of their SC to the T cell mitogen Con A are decreased. We found that, similar to ATA, the hyporeactivity of T cells developed earlier (at 1-2 weeks of age) than splenomegaly. The proportions of both CD4+ and CD8+ T cells were not reduced in the spleens of tolerized mice without manifest LPD. The supernatants (SN) of Con A-stimulated tolerized SC contained no, or only small amounts of interleukin-2 (IL-2). Thus, in the tolerized mice, ATA and T cell deficiency preceded the development of LPD. ATA and the decreased amount of the T cell growth factor IL-2 might play a role in the defective T cell activation.

Topics: Age Factors; Animals; Animals, Newborn; Antigens; Autoantibodies; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Division; Cell Transplantation; Chronic Disease; Concanavalin A; Host vs Graft Reaction; Immune Tolerance; Interleukin-2; Lymphocyte Activation; Lymphocyte Count; Lymphoproliferative Disorders; Mice; Mice, Inbred A; Mice, Inbred C57BL; Mice, Inbred Strains; Mitogens; Skin Transplantation; Spleen; Splenomegaly; T-Lymphocytes; Transplantation Immunology

Interferon-consensus 1 (IFN-Con 1) is a novel synthetic protein generated from codons for the most frequent amino acids in different type 1 IFNs. Compared with natural IFNs, IFN-Con 1 has been shown to have higher specific activity and antiproliferative activity and a higher ability to induce natural killer cells. In this study, the effects of IFN-Con 1 were compared with those of IFN-beta 1b and IFN-alpha 2a on HLA expression and lymphoproliferation. Human umbilical vein endothelial cells (HUVEC) express HLA class I but not class II molecules; however, both class I and class II molecules can be upregulated by IFN-gamma. IFN-Con-1 shared with IFN-beta 1b and IFN-alpha 2a the capacity to enhance HLA class I expression on HUVEC, alone and in combination with IFN-gamma. Although IFN-Con 1 had no effect on the basal expression of HLA class II molecules, it inhibited the IFN-gamma-induced class II expression on the HUVEC in a dose-dependent fashion. When this effect was compared among the three IFNs on mass basis, IFN-Con 1 activity was intermediate between that of IFN-beta 1b and IFN-alpha 2a. IFN-Con 1 also demonstrated an inhibitory effect on mitogen-driven lymphoproliferation similar to that of IFN-alpha 2a and exceeded that of IFN-beta 1b. The results indicate that IFN-Con 1 has immunomodulatory effects similar to those of IFN-beta 1b and IFN-alpha 2a, which could be relevant to the treatment of autoimmune and virus-mediated diseases.

Topics: Adjuvants, Immunologic; Cell Line; Concanavalin A; Drug Evaluation, Preclinical; Histocompatibility Antigens Class II; Humans; Interferon alpha-2; Interferon beta-1a; Interferon beta-1b; Interferon Type I; Interferon-alpha; Interferon-beta; Lymphoproliferative Disorders; Multiple Sclerosis; Recombinant Proteins; RNA, Messenger

The role of the cell-surface molecule CTLA-4 in the regulation of T cell activation has been controversial. Here, lymph nodes and spleens of CTLA-4-deficient mice accumulated T cell blasts with up-regulated activation markers. These blast cells also infiltrated liver, heart, lung, and pancreas tissue, and amounts of serum immunoglobulin were elevated. The mice invariably became moribund by 3 to 4 weeks of age. Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation. Thus, CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis.

Topics: Abatacept; Animals; Antigens, CD; Antigens, Differentiation; Apoptosis; B-Lymphocytes; Cells, Cultured; Concanavalin A; CTLA-4 Antigen; fas Receptor; Female; Gamma Rays; Gene Targeting; Homeostasis; Immunoconjugates; Immunoglobulins; Immunophenotyping; Lymph Nodes; Lymphocyte Activation; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred C57BL; Spleen; T-Lymphocytes

The generalized lymphoproliferative disease (gld) and lymphoproliferation (lpr) mutations induce the development of strikingly similar autoimmune and lymphoproliferative syndromes in C57BL/6 mice (B6). These syndromes are characterized by hyperglobulinaemia, high levels of circulating autoantibodies and significant splenomegaly and lymphadenopathy resulting principally from the accumulation of a double negative CD4/CD8 T-cell population. These similarities led to the suggestion that the gld and lpr mutations affect two different steps of a common metabolic pathway controlling the differentiation of the T cells. By transferring haematopoietic cells into sublethally irradiated recipients we provide evidence for the different aetiology of the gld- and lpr-induced syndromes. The [gld----gld] chimaeras developed a gld-induced syndrome, like the [lpr----lpr] chimaeras developed a lpr-induced syndrome. However, in contrast to the severe lymphoid aplasia observed in the [lpr----wild] chimaeras, the [gld----wild] chimaeras showed an attenuated form of the gld-induced syndrome. The [lpr----gld] chimaeras developed a lymphoid aplasia (as in the [lpr----wild] chimaeras). This result shows that the gld environment cannot substitute for the lpr environment and allow for the emergence of an lpr-induced pathology.

Topics: Animals; Antibody-Producing Cells; Autoimmune Diseases; Bone Marrow; Concanavalin A; Female; Hematopoietic Stem Cell Transplantation; Lipopolysaccharides; Lymph Nodes; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred C57BL; Mutation; Radiation Chimera; Spleen; Thymus Gland

The presence of the homozygous lpr gene (lpr/lpr) in MRL mice has been regarded as mandatory for the development of the early onset of lupus disease, T-cell dysfunction, and polyclonal B-cell activation. Congeneic MRL mice lacking the lpr gene (MRL +/+) display neither the lupus disease nor the immunological abnormalities within the first year of life. In this study we examined the cellular functions of MRL mice heterozygous at the lpr locus. The results indicate that MRL mice heterozygous at the lpr locus display intermediate delayed-type hypersensitivity compared with homozygous lpr/lpr mice on the one hand and congeneic +/+ mice on the other. Furthermore, proliferative responses to concanavalin A, measured by uptake of [3H]thymidine, were significantly lower in MRL mice heterozygous at the lpr locus than in +/+ mice, but significantly higher than in homozygous MRL lpr/lpr mice. Polyclonal B-cell activation, assessed by measurement of frequencies of IgG-secreting spleen cells, a prominent feature in MRL lpr/lpr mice, was significantly lower in lpr/+ mice and totally absent in +/+ mice. Furthermore, spleen cells spontaneously secreting auto-antibodies were found in large numbers in MRL lpr/lpr mice and in considerably lower but still significant numbers in heterozygous MRL +/lpr mice. In contrast, spleen cells from matched MRL +/+ mice did not display any spontaneous autoantibody production. Taken together, these data provide evidence for immunomodulatory properties of the heterozygous lpr gene.

Topics: Animals; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Concanavalin A; Female; Gene Expression; Heterozygote; Hypersensitivity, Delayed; Immunoglobulin G; Interleukin-2; Lymphocyte Activation; Lymphoproliferative Disorders; Male; Mice; Mice, Mutant Strains; Spleen; T-Lymphocytes

Human retroviruses have recently been linked with T cell lymphoproliferative disorders and with the acquired immune deficiency syndrome. We investigated the mechanisms for acquired pure red cell aplasia and cutaneous anergy in a patient with the chronic T gamma-lymphoproliferative disease (T gamma-LPD) syndrome. Patient marrow erythroid progenitors (BFU-E) were 17 +/- 9% of control and were selectively increased to 88-102% of control after marrow T cell depletion. Patient Leu 2+ suppressor T cells spontaneously produced high titers of human gamma-interferon and resulted in a concentration-dependent selective inhibition (74-91%) of BFU-E when co-cultured with autologous or allogeneic marrow. Conditioned media (CM) derived from patient Leu 2+ T cells similarly inhibited growth of autologous or allogeneic marrow BFU-E. The inhibitory factor derived from patient CM was acid-labile (pH 2) and sensitive to trypsin; prior treatment of patient T cells with anti-HLA-DR monoclonal antibody plus complement abrogated the suppressive effect of T cell-derived CM. Patient peripheral blood mononuclear cells (PBMC) were unable to support growth of cultured interleukin 2 (IL 2)-dependent T cells, but responded to exogenous IL 2 in vitro with a 16-21-fold augmentation, relative to control, in mitogen-induced proliferation. Antibodies to HTLV-I core proteins p19 and p24 but not to HTLV-III proteins were detected in patient serum by Western blotting; patient cultured PBMC stained (7-11%) with antibodies to p19 and p24. Patient cultured PBMC demonstrated integrated HTLV-I genomic sequences by the Southern technique and expressed both specific HTLV-I genomic sequences by RNA dot blot plus reverse transcriptase activity. Utilizing a cloned DNA probe for the beta chain of the T cell receptor gene, patient PMBC demonstrated gene rearrangements providing presumptive evidence for clonality. The presence in serum of HTLV-I p19 and p24 antibodies, the expression of p19 and p24 core antigens on patient mononuclear cells, the evidence of HTLV-I proviral integration sequences and the expression of HTLV-I genomic sequences in patient cells, indicates infection with HTLV-I and raises the possibility of an etiologic link between human retrovirus infection and some instances of large granular lymphocytic leukemia (T gamma-LPD).

Topics: Anemia, Aplastic; Antigens, Differentiation; Concanavalin A; Deltaretrovirus Infections; Erythropoiesis; Humans; Interleukin-2; Lymphocyte Activation; Lymphoproliferative Disorders; Male; T-Lymphocytes, Regulatory; Viral Proteins

Lymph node T cells from autoimmune MRL/Mp-lpr/lpr mice, but not from congeneic MRL/Mp-+/+ mice, spontaneously proliferate and produce IL 2 when cultured in vitro for 5 to 7 days. This autologous activation depends critically on the length of in vitro culture and the initial culture density, indicating that cell to cell interaction may be essential. Phenotypic characterization of cultured cells suggests that both L3T4+ and Lyt-2+ T cells proliferate. However, only L3T4+ T cells produce IL 2. Mixing experiments reveal that the inability of freshly isolated lymph node cells from MRL/Mp-lpr/lpr mice to proliferate is not due to the presence of suppressor cells. Supernatant from 7-day cultures failed to induce freshly isolated cells to proliferate. Thus, the failure of freshly isolated cells to spontaneously proliferate and secrete IL 2 is not due to the inability of the cells to produce soluble mediators. Similar to the inactivation of normal T lymphocytes, in vitro addition of monoclonal anti-L3T4 or anti-IL 2 receptor antibody significantly inhibits the activation of these cultured lymphocytes. Spontaneous proliferation and IL 2 production can be blocked by the addition of monoclonal anti-I-Ak but not by monoclonal anti-I-Ad. Spontaneous proliferation and IL 2 production can be detected in young (4-wk-old) MRL/Mp-lpr/lpr mice at a time when their lymphocyte composition and physiology appear to be normal. More interestingly, spontaneous proliferation and IL 2 production cannot be detected in C57BL/6J mice bearing the lpr/lpr gene. These experiments support the notion that aberrant syngeneic autoreactivity may act as an accelerating factor in the pathogenesis of lymphoproliferation and autoimmunity in MRL/Mp-lpr/lpr mice.

Topics: Animals; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Autoimmune Diseases; Cells, Cultured; Concanavalin A; Contact Inhibition; Interleukin-2; Lymph Nodes; Lymphocyte Activation; Lymphoproliferative Disorders; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Phenotype; Receptors, Immunologic; Receptors, Interleukin-2; T-Lymphocytes

Simian acquired immunodeficiency syndrome (SAIDS) was transmitted to four of four rhesus macaques with blood from rhesus macaques naturally infected with a type D retrovirus, simian retrovirus-2 (SRV-2). Three of the four blood recipients died with SAIDS at 13, 15, and 26 weeks postinoculation. The fourth animal is alive with SAIDS. All four test monkeys became viremic and produced antiviral antibody. None of the inoculated monkeys produced measureable neutralizing antibody to SRV-2. The survivor produced higher levels of antiviral antibody than the monkeys that died. Phytohemagglutinin and concanavalin A reactivity of peripheral blood lymphocytes was depressed from weeks 6 to 12 after inoculation. Clinical findings included development of splenomegaly in all four monkeys, and diarrhea in two monkeys. Blood counts remained within the normal range except for a depression in the number of polymorphonuclear lymphocytes in two monkeys. Hematocrits were decreased in two monkeys just prior to their death. All four test monkeys developed lymph node atrophy and bone marrow hypoplasia. Total proteins and immunoglobulin production were normal. This report provides evidence that SRV-2, as well as other type D retroviruses, causes SAIDS in macaque species.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antibodies, Viral; Concanavalin A; Lymphocyte Activation; Lymphocytes; Lymphoproliferative Disorders; Macaca; Macaca mulatta; Monkey Diseases; Phytohemagglutinins; Retroviridae

In order to reveal the activity of polymorphonuclear neutrophil leukocytes (PMNL) representing the first step of defence against infections, measurements of chemiluminescence (CL) were performed in patients suffering from acquired immune deficiency syndrome (AIDS), lymphadenopathy, or hemophilia. In comparison with healthy controls, AIDS patients revealed significant reduction (about 50 per cent) of phagocytic, i.e. CL activity of neutrophils, which had been induced by Zymosan. Only part of the patients suffering from lymphadenopathy answered with decreased granulocyte activity on the application of Zymosan. If concanavalin A was used as stimulant of metabolic activity of PMNL-independently of phagocytosis-again AIDS and some of the lymphadenopathy patients showed a markedly reduced neutrophil response. In conclusion it should be stated that there is some evidence for at least two defects of cellular immunity associated with AIDS and to some extent, with AIDS-endangered homosexuals suffering from lymphadenopathy: first the defect of PMNL to answer to concanavalin A with increased metabolic activity, and secondly the defect of PMNL to start phagocytosis induced by Zymosan with a subsequent release of oxygen radicals which are measurable as chemiluminescence. The appraisal of granulocyte activity by means of measurements of chemiluminescence might become an additional criterion for AIDS diagnostics.

Topics: Acquired Immunodeficiency Syndrome; Acyclovir; Anti-Infective Agents, Urinary; Concanavalin A; Drug Combinations; Hemophilia A; Humans; Immunoglobulins; Luminescent Measurements; Luminol; Lymphoproliferative Disorders; Male; Neutrophils; Phagocytosis; Sulfamethoxazole; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Zymosan