Evidence Of Suppressor Cell Activity Research Articles

Trypanosoma cruzi-induced immunosuppression: blockade of costimulatory T-cell responses in infected hosts due to defective T-cell receptor-CD3 functioning.

A model of experimental Trypanosoma cruzi murine infection with chemically induced metacyclic forms (opossum clone Dm28c) showed a marked state of T-cell unresponsiveness during acute phase, but lacked evidence of suppressor cell activity. Spleen cells from infected mice were suppressed in vitro in responses to T-cell activators concanavalin A, anti-Thy1 monoclonal antibody (MAb), and anti-CD3 MAb compared with spleen cells from control littermates. Activation with accessory cell-independent stimulus provided by immobilized anti-CD3 was defective in splenic CD4-positive T cells from infected mice, but not in such cells from control mice. No evidence of splenic suppressor cell activity was found in cell-mixing experiments using nylon-passed T cells from control and infected donors. Kinetic experiments showed that there was a discrete stage in infection when T cells were already suppressed in response to anti-CD3 but still responded to anti-CD69 MAb. In these T cells, immobilized anti-CD3 failed to enhance simultaneous CD69 responses, although anti-CD3 enhanced CD69 responses in control T cells from uninfected donors. These results demonstrate an intrinsic defect in T-cell receptor-mediated T-cell activation, which could be a mechanism generating T-cell suppression during infection by T. cruzi.

Age-related decline in cell-mediated immunity in the C58 leukemic mouse strain.

The leukemia-prone C58 strain of mouse was examined for age-related changes in cellular immune function. Proliferative responses of lymphocytes to autologous and allogeneic stimulator cells [autologous mixed lymphocyte response (AMLR) and mixed lymphocyte response (MLR), respectively] and to mitogens were tested both prior to and around the usual age of disease onset which occurs at 7-8 months. Leukemia in these animals was defined by elevated peripheral blood and splenic white blood cell counts. The AMLR declined greater than 30% by 6-7 months of age and was virtually absent by 8 months of age even in animals that were not overtly leukemic. The MLR declined precipitously (greater than 95%) at 9 months of age. Both declines occurred at a younger age in C58 mice than in nonleukemic strains. Mixing experiments with cells from young and old animals indicate a defect in the Ly 1+23-, L3T4+ responding T cells. No evidence indicating a role for suppressor cell activity in this decline of cell-mediated immunity could be found. Deficiencies in cytokine (IL-2 and IL-1) production were not observed except in the oldest mice tested. Around the usual time of disease onset, splenic natural killer (NK) cell activity declines sharply even in nonleukemic mice. Cell-mixing experiments showed no evidence of suppressor cell activity by spleen cells from older mice, leukemic or nonleukemic, on the NK cell activity of young adult animals. Interferon alpha, beta treatment enhanced the NK activity of cells from old mice but did not restore the level of activity seen in young mice. Evidence has therefore been found for a premature decline in cellular immune function in two responses with proposed immunoregulatory roles, the AMLR and NK cell activity. It is possible that their decline could play a predisposing role in the onset of this retroviral leukemia or that these cell populations may be the target of the retrovirus.

Effects of the removal of adherent and phagocytic cells on the spleen cell lymphoproliferative response of tumor-bearing mice.

Cell-mediated immunity was investigated in two BALB/c mouse tumor systems using the lymphoblastogenesis test with phytohemagglutinin as the mitogen. This lymphoproliferative response was quantitated using the Stimulation Index (SI). There was little evidence for suppressor cell activity in cell mixing experiments in which spleen cells from #51 cell-injected mice were mixed with spleen cells from normal mice. Following macrophage removal by Sephadex G-10 columns and carbonyl iron ingestion, there were no significant changes in the SI values for spleen cells from the #51 cell-injected mice. In contrast, spleen cells from mice injected with H238 cells, a herpes virus-transformed cell line, had a significantly lower SI value than that of normal mice. Suppressor cell activity was demonstrated in cell mixing experiments in which spleen cells from H238 cell-injected mice were mixed with normal spleen cells. Removal of adherent cells from spleen cells from H238 cell-injected mice by Sephadex G-10 columns restored the SI value to that of normal mice. An increased SI value was also seen after removal of phagocytic cells by carbonyl iron. These results suggested that cells with the functional properties of macrophages played an important part in the immunosuppression observed in the H238 tumor system. Comparison of the two macrophage depletion methods suggested that another cell population was also involved in the suppressive effect. Results of immunofluorescent techniques with anti-Lyt-1 and anti-Lyt-2 monoclonal antibodies show these cells to be Ly 1-, Ly 2,3+ phenotypes of T-lymphocytes.

Effects of Diethylstilbestrol and Estramustine Phosphate (Estracyt) on Lymphoid Cell Populations and Mitogen Responsiveness in Male Mice

Concentrations of diethylstilbestrol phosphate (DES-P) and estramustine phosphate (EMP) above 10-5 M in cultures of spleen lymphocytes from adult male mice resulted in a dose related inhibition of both Con A and LPS induced lymphocyte proliferation. Male mice injected with 5.6mg./kg. DES daily for 7 days had a significantly reduced responsiveness to both Con A and LPS compared to mice injected with olive oil only. Spleen lymphocytes from male mice treated with 100mg./kg. EMP showed a reduction of Con A induced mitogenesis whereas they exhibited a significantly enhanced response to LPS. The effects of DES and EMP on Con A and LPS induced blastogenesis were abolished within 2 weeks after cessation of treatment.DES treatment resulted in preferential depletion of splenic and lymph node T lymphocytes and a disproportionate T lymphocyte subpopulation with respect to Ly subclasses. Exposure to 30 or 100mg./kg. EMP resulted in a dose related loss of mononuclear cells both in spleen and lymph nodes.T lymphocytes predominantly of the Ly 1 phenotype were most sensitive to EMP. Co-cultures of spleen lymphocytes from normal mice and Mitomycin C blocked spleen cells from either normal or treated mice (DES or EMP) gave no convincing evidence of suppressor cell activity in the population of spleen mononuclear cells.

Evidence for histamine-induced auto-anti-idiotypic antibody immunoregulation in vivo

The in vivo effects of histamine injection in LAF 1 male mice on the immune reactivity to trinitrophenylated bovine γ-globulin was studied using plaque-forming cell (PFC) responses and their avidity distributions. Splenic anti-trinitrophenyl (anti-TNP) PFC responses of mice treated with histamine (5 × 10 −6 mol or 1 mg, intravenously) were significantly reduced in number and restricted in heterogeneity and characterized by a preferential loss of high-avidity IgG PFCs. The reduced PFC response in histamine-treated mice was dose and time dependent. No evidence of suppressor cell activity in the spleens from histamine-treated mice was demonstrable. Only histamine-treated mice produced a significantly high percentage of anti-idiotype-blocked, hapten-augmentable IgG PFCs, suggesting the presence of auto-anti-idiotypic activity. Immune sera taken from histamine-treated mice caused an inhibition of anti-TNP PFC in vitro. This PFC-inhibiting factor in immune sera of histamine-treated mice was an antibody of the IgG 1 and IgG 2a class, lacked anti-TNP antibody activity, but reacted with anti-TNP antibody of LAF 1 origin. Passive hemagglutination study of this sera showed anti-(anti-TNP F(ab′) 2-IgG) titer. Thus, the results of this study suggest that histamine in combination with antigen induces auto-anti-idiotypic antibody which, in turn, is involved in the normal regulation of the immune response to trinitrophenylated bovine γ-globulin in vivo.

Phytohemagglutinin response of lymphocyte fractions isolated by velocity sedimentation and enhanced helper cell activity.

Peripheral blood mononuclear cells from patients with histologically confirmed sarcoidosis were examined for the presence of suppressor activity to explain diminished phytohemagglutinin-induced lymphoblastic transformation. Phytohemagglutinin responses of unfractionated cells, cell fractions obtained by velocity sedimentation, and mixtures of various cell fractions were studied by uptake of thymidine labeled with hydrogen-3 in 72-hour cultures. The in vitro impaired response to phytohemagglutinin stimulation of unfractionated sarcoid lymphocytes occurred only in patients with more disseminated disease (group 2). Sarcoid lymphocyte fractions 2 and 4 showed significantly decreased stimulation with phytohemagglutinin, suggesting that the over-all impaired response of unfractionated sarcoid lymphocytes to phytohemagglutinin stimulation could be explained by the sum of impaired phytohemagglutinin responses of lymphocytes in these fractions. No evidence of suppressor cell activity was detected. In contrast, slowly sedimenting sarcoid fraction 4 cells appeared to have helper activity, and this was independent of the extent of disease and results of skin tests.