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

Abstract

Levamisole (LMS), the levoisomer of 2,3,5,6-tetrahydro-6-phenylimidazo [2, l-b] thiazole hydrochloride, has demonstrated immunoenhancing activities on mouse responsiveness to antigenic stimuli (1-4). This activity depended upon T-cell potentiation as evidenced by increased gra~-versus-host reaction when donors were treated by LMS (5), by accelerated rejection of isogeneic skin grafts (6, 7), or by enhanced levels of delayed hypersensitivity in LMS-treated mice (7). Sodium diethyldithiocarbamate, DTC, a noncyclic sulphur drug, induced similar responses (8). LMS effect can be transferred by a serum factor obtained from animals after treatment with LMS. In transfer experiments, this factor enforced immune responses to sheep red cells (SRC) in recipient mice and induced regression of tumor size in leukemic AKR mice, even when leukemic mice have failed to respond to treatment with LMS (9, 10). On the other hand, the impaired development of T ceils in nu/nu mice has been ascribed to lack of the maturation stimulus, or stimuli, normally provided by thymus factors (11-15).In this report, we present evidences that LMS or DTC induce in vivo acquisition of specific T-cell markers by undifferentiated precursor lymphoid cells of thymusless nude mice and concomitantly induce functional immune activation. Also, that serum from treated nu/nu mice can transfer these in vivo activities and allow in vitro differentiation of precursor cells into T cells. Materials and MethodsHealthy nu/nu mice from the Edinburgh strain (16), obtained from the Centre de Sdlection des Animaux de Laboratoire (CNRS, Orldans, France), were maintained in an air-conditioned room and partially protected from environmental infections by Isocap filters (Iffa-Credo, l'Arbresle, France).LMS or DTC were dissolved in pyrogen-free saline and subcutaneously administered in vol of 0.2 mt, at the doses indicated in the individual experiments. Doses of the drug were expressed in milligrams of the salt per kilogram body weight.In in vivo assays, 5-to 6-wk-old female nu/nu mice were killed 4 days after a single drug administration. Any mouse showing evidence of liver disease (17) was discarded from the experiment. In vitro induction assays were performed for 2.5 h at 37°C in a humidified CO2 incubator in the absence or presence of LMS or DTC. Amounts of the drugs varied from 10 -s to 10 -~ mM/10 ~ lymphocytes per ml of medium. Expression ofT-cell antigens on the cell surface was tested on either in vitro or in vivo induced lymphocyte suspensions in the cytotoxicity assay (18), using Thy-l.2 and TL 1, 2, 3 antisera kindly provided by E. A. Boyse. Each cytotoxicity assay was performed in duplicate. Induction of an acquired functional (helper) activity was assayed on day 4 after immunization of nu/nu mice with SRC and simultaneous treatment with LMS or with DTC

Sensitization of Guinea Pigs to Levamisole

“…Levamisole has been shown to act as an immunoenhancer by T-cell potentiation and can induce increased T-cell production and differentiation both in man and experi mental animals [5]. Although it has been found to induce T-cell differentiation in thy mus-less mice, we suggest that this drug and similar compounds might also stimulate non-specific T-cell proliferation as part of its action as a sensitizer.…”

Effect of Levamisole on the Auto-Antibody Formation in Nude Mice

“…In nu/nu mice, the for mation of antibody to ds-DNA was sup pressed also by the treatment with ievamisole, as described in this paper. Renoux and Renoux [6] showed recently that levamisole induces T cell differentiation from pre-T cell in nu/nu mice and evokes indirect pla que-forming cells in mice immunized with SRBC. In our study, Thy-1+ cells were in duced in the nu/nu mice by the treatment with levamisole.…”

“…The fol lowing evidence suggests that the effects of levamisole are due to its influence on T cells; this drug enhances the formation of antibody to sheep red blood cells (SRBC) in mice [1]; it accelerates the rejection of skin graft in mice [2]; it delays the develop ment of antinuclear antibody in NZB/W mice [3]; it reduces the 'null' cell population in human peripheral blood [4,5]; and it in duces the expression of T cell antigen on spleen cells of nude (nu/nu) mice (6].…”

Kinetics of the Histological Changes in Lymphoid Organs and of the T-Cell Inducing Capacity of Serum in Mice Treated with Imuthiol® (Sodium Diethyldithiocarbamate)

“…The findings cannot be ascribed to Imuthiol in serum as addition of the agent does not induce the specific T (Thy-1) cytotypic marker and as Imuthiol has a halflife of less than 20 min [3]. The definition of Thy-1 alloantigens by the use of specific antibodies is widely accepted as a specific marker of murine T cells [2,5,6,8,11,12], although it is well known that these antigens can be expressed also in other cells, such as neuronal cells, myoblasts or hematopoietic stem cells [ 12], When the results of induction of the Thy-1 pheno type by serum are put together with the histological study, the data show an early homing of T cells in lymphoid organs and rejuvenation of thymic lymph oid cells before obvious changes in thymus secretory cells, and associated with an increased production of a specific serum factor. About 1 week post-Imuthiol administration, thymic hyperactivity is revealed both by changes in the serum dose-response curves and in crease in the number of Hassall's corpuscles.…”

“…Imuthiol and the serum of Imuthiol-treated animals selectively induce in vivo prothymocyte ma turation, and nu/nu mice respond to a treatment with Imuthiol, suggesting that an extrathymic factor might be involved in T-cell recruitment [4,6,8,10].…”