Thymus-like activities of sulphur derivatives on T-cell differentiation.

Levamisole and sodium diethyldithiocarbamate can induce in vivo thymocyte differentiation from precursor spleen cells of nu/nu mice and evoke indirect plaque-forming cells in nude mice immunized with sheep red cells. These sulphur drugs induce in thymusless mice the production of a serum factor which transfer in vivo immune enhancement and in vitro thymocyte differentiation. In vivo treatment with sulphur derivative can substitute for an alleged thymice hormone.

A semi-automated rapid and sensitive microcytotoxicity assay for antibody-mediated cytolysis.

This technique used a Coulter counter to enumerate the target cells remaining after partial lysis with antibody and complement, followed by the destruction of the lysed cells with pronase. Results obtained by this method are compared with those from conventional dye exclusion tests where the final enzymatic step is omitted. Comparisons were made with an anti-Thy-1.2 serum, a monoclonal anti-Thy-1.2 preparation and an anti-H-2k serum. In all cases the semi-automated test gave better results than the dye exclusion test and proved to be highly sensitive and reproducible.

A balanced brain asymmetry modulates T cell-mediated events.

Partial ablation of the left fronto-parietal cerebral cortex decreases the number of spleen T cells, impairs IgG-alpha SRBC and T mitogen-induced responses, and delays the response to alloantigens. In contrast, these events are increased following a symmetric lesion of the right neocortex. The findings extend previous results showing that the neocortex modulates NK activity and the efficacy of T cell-specific serum factors. B cells and macrophages are not affected. In these assays, mice subjected to ablation of one lateral cerebral neocortex serve as controls for symmetrically lesioned mice, in addition to no surgery or sham-operated controls. The findings suggest that brain lateralization for cognitive processes should be extended to T cell immune recognition. The phenomenon is present at a population level.

The general immunopharmacology of levamisole.

The need for treatments to correct an immunological defect, or to restore an impaired immune response asociated with disease or ageing, has led to the development of nonspecific immunoactive agents. Levamisole, a synthetic low molecular weight compound, is the first member of a new class of drugs which can increase the functions of cellular immunity in normal, healthy laboratory animals. The properties of levamisole have contributed to improved understanding of the molecular events which mediate or trigger immune responses. Levamisole can act either as an immunostimulant agent or an immunosuppressive agent. These apparently paradoxical effects depend upon the dose administered, the timing of its administration, the experimental assay used to measure effects, and the host genetic background. Levamisole's potential for opposite effects explains certain apparent inconsistencies observed in experimental or clinical assays. The drug's actions are modulated by the interaction between the T-cell recruiting efficacy of the sulphur moiety and the cholinergic effects of the imidazole ring. The clinical implications resulting from the immunopharmacological properties of levamisole are obvious: one should avoid its use in diseases without known association with an immune defect, and always attempt to correlate clinical data with modifications of immune parameters, since the therapeutic usefulness of correctly administered levamisole parallels improvement in tests of cellular immunity. Immunomodulators act by modifying the functions of the host cells involved in defences against invaders, and the effectiveness of an immunotherapeutic drug is dependent upon characteristics of the individual host. Thus, therapy with such drugs must be individualised; the appropriate agent and dosage should be chosen according to the immune capabilities of individual patients.

Favorable influences of imuthiol on mouse reproduction and immune system of offspring.

A physiological immature immune system in newborns is a common feature frequently associated with increased susceptibility to infections. The properties of imuthiol (purified sodium diethyldithiocarbamate), an agent specifically active on the T-cell lineage, and virtually devoid of toxicity for man or animals, encouraged us to determine whether imuthiol administered to the dams could increase the immune capability of offspring without altering fecundability and birth rate. Experiments performed either in histocompatible or histoincompatible mating systems, show that chronic administration of imuthiol prior to mating and/or during pregnancy stimulated newborn mice to increased T-cell-dependent responses, without altering birth rates and growth curves in progenies. The data suggest that imuthiol has no teratogenicity or deleterious influences on mouse gametes, and might be useful to prevent immunodepression-associated infections in newborns.

Sodium diethyldithiocarbamate protects against the MPTP-induced inhibition of immune responses in mice.

The effects of 1-methyl-4-phenyl - 1,2,3,6-tetrahydropyridine (MPTP) on immune parameters, and the restorative influence of sodium diethyldithiocarbamate (DTC) or deprenyl were evaluated in mice. The concentrations of dopamine (DA), 3-methoxytyramine (3-MT), 3-4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA), were concomitantly measured in the striatum. MPTP depressed T-cell responses. DTC restored these responses as well as the concentration of striatal DA. Deprenyl had no effect on the concentrations of DA and its metabolites, yet it modified the immune responses alike MPTP. The findings suggest a dopamine pathway could be involved in the brain-controlled immunostimulation afforded by DTC.

The thymic factor system.

Thymus is widely thought as playing the central role in the control of T-cell differentiation. A review of the literature suggests a more general role is displayed by the thymus, envisioned as a part of a hypothalamo-hypophyseal-thymic axis to control the production of hormones and transmitters which, in turn, regulate immune function. Products of macrophages and lymphocytes interfere with the hypothalamus to modify behavior and immune response, in the presence of a foreign body. Brain neocortex controls thymic and extrathymic factors involved in T-cell differentiation.

Sex-associated relationships between cell counts and lymphoproliferative responses in healthy young adults.

Correlation analyzes of lymphoproliferative responses, total T (E-rosettes) cell levels and autologous rosette-forming cell (A-RFC) levels of healthy human volunteers revealed previously unsuspected sex-associated differences. A negative association existed between response to Con A and E-rosette levels in men, and between PHA lymphoproliferation and E-rosette counts in women, whereas mitogen-induced responses and A-FRC levels varied independently in either sex. Total T cell and A-RFC counts correlated only in man.

The ten commandments for immunotherapeutic drugs at the example of sulfur-containing agents.

Immunotherapeutic agents (IMT) are intended to restore or reequilibrate a faltering immune system. Levamisole was the first chemically defined IMT endowed with immunomodulatory effects. In order to clarify the mechanisms of its ambivalent activities, thiocompounds were tested for their ability to modify immune responses. All thiomidazoles are immunomodulatory drugs which dose-dependent effectiveness is related with the cholinergic-like influence of the imidazole moiety. The findings suggest also a relationship among thiodrugs between chemical structure and influence on the immune system. These studies lead to the development of sodium diethyldithiocarbamate (Imuthiol), as a non-toxic immunostimulant agent, specifically active on the T-cell lineage. Our studies unequivocally put forth on the specific requirements that are essential to characterize a potential IMT prior to clinical release: in vivo activities no immunosuppression through prolonged administration no antigenicity or hapten-like activity no carcinogenicity or tumor-promoting influence experimental route of administration related to that in humans assays in various animal strains pharmacokinetics chemical characterization known toxicities, teratogenesis, and mutagenesis assays on models of cancer, autoimmune diseases, immunodeficiencies, and infections. The results will allow to determine a range of doses, and predict most direct and secondary effects. They will also specify whether the agent is an adjuvant, a reticulostimulant, an immunomodulatory, an immunostimulatory, an immunorestorative, or an immunoregulating drug. Clinicians will therefore be provided with the data which are essential to perform useful clinical testing.

Sodium diethyldithiocarbamate (imuthiol) and cancer.

Sodium diethyldithiocarbamate (imuthiol), a nonantigenic, nontoxic and noncarcinogenic compound, evinces distinctive properties in recruitment and activation of T cells, and no direct influences on B cells or macrophages. The biological attributes of imuthiol (destruction of neoplastic cells, bacteria, fungi and parasites; a detoxifying influence against carcinogens or agents toxic for the liver) could strengthen its activity as a biological response modifier. Preliminary clinic testings show that imuthiol restores T cell activities and regulates the ratio among T cell subsets in cancer patients, without untoward side effects.

Characterization of immunotherapeutic agents: the example of imuthiol.

Immunotherapeutic (IMT) agents are intended to restore or reequilibrate a faltering immune system. These aims will be attained provided the agent fulfills minimum requirements: in vivo defined activities; lack of suppressive, sensitizing, or autoimmunity-inducing influence; no immunotoxicity and carcinogenicity. Known chemical structure, analytical procedure, toxicology and pharmacology are also prerequisites. A follow-up pattern of sequential and progressively more demanding assays through which IMT agents could be screened for therapeutic potential is suggested. The example of Imuthiol, tested accordingly, demonstrates the usefulness of the proposed procedure.

Clinical characterization of imuthiol.

Imuthiol is a nontoxic agent recruting and regulating T cells. Phase III studies in chronic bronchitis and bronchiectasis showed that immune functions were restored to normal, or near normal values. Cure was obtained in rheumatoid arthritis, tuberculosis and chronic infections in the elderly. Imuthiol is an effective agent for the treatment of syndromes and disease states where the underlying defect is a T-cell deficiency or dysfunction.

Sodium diethyldithiocarbamate influences the early immunological changes evoked by an acute non-antigenic inflammation process.

Calcium pyrophosphate (CaPp) produces an acute local inflammatory process when administered intra-pleurally. It is the simplest model of an inflammation uncomplicated by pharmacological properties of the agent or the presence of an antigen. Spleen or lymph-node T- or B-cell numbers and activities, including NK activity, are modified within 2 h under these conditions. A treatment with sodium diethyldithiocarbamate (lmuthiol), already known as a T-cell augmenting agent, restores towards normal values both the inflammatory reaction and the modified immune parameters induced in mice by CaPp pleurisy. The use of lmuthiol as a non-toxic, non-steroidal antiinflammatory agent is therefore suggested.