Suppressor-inducer Research Articles

Essential oil of Zataria multiflora Boiss upregulates retinoblastoma tumor suppressor in the liver of rat

The Zataria multiflora Boiss is endemic plant of Iran, Pakistan and Afghanistan. Several traditional purposes have been indicated for this medicinal plant including medical purposes, natural preservative of a wide variety of foods and as a food flavour. Currently, the correlation has been found between the essential oil of Z. multiflora Boiss and anti-carcinogenesis effects by regulation of two controller genes of mammalian cell cycle named ATM and MDM2. The aim of this study is to understand the molecular response of retinoblastoma tumor suppressor gene (Rb1) and protein (pRb) to the essential oil of this plant. Rb1 gene is required for inhibiting of cell cycle entering to S-phase and its inactivation contributes to tumorigenesis. In present study, liver samples of eight normal male rats were examined for expression analysis of retinoblastoma tumor suppressor gene and its product by using Semi-quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and western blotting methods, respectively. The statistical analysis was conducted using SPSS software through independent-sample T-test. The essential oil supplementation at concentration of 50 µl/kg body weight per day induced significantly upregulation in gene and protein expression of Rb1 tumor suppressor in rat liver after one week treatment (P = 0.001). Induction in level of retinoblastoma tumor suppressor by essential oil of Z. multiflora Boiss along with its property in regulation of ATM and MDM2 genes expression appear to play an important role in cell cycle control. This data implicated that the essential oil of Z. multiflora Boiss may offer new tools for therapeutic intervention in the retinoblastoma pathway for cancer prevention and treatment. This is the first report showing the potential role of essential oil of Z. multiflora Boiss as a new class of natural retinoblastoma tumor suppressor inducer and therefore, it could be used as a natural preservative ingredient in food and pharmaceutical industries. Key words: Zataria multiflora Boiss, retinoblastoma tumor suppressor, essential oil, cancer.

The kinetics of cell surface receptor expression in children perinatally exposed to polychlorinated biphenyls

Exposure to polychlorinated biphenyls (PCBs) during pre-natal and early life can alter normal immune system development. Blood specimens from newborns, 6-, and 16-month-old infants were collected in the Michalovce and Svidnik/Stropkov districts, areas with, respectively, high and low environmental PCB contamination, and lymphocyte receptor expression was evaluated by multi-color flow cytometry. The results indicate that the percentage of lymphoid dendritic cells (DC) and naïve/resting T-lymphocytes were significantly increased at 6-months in Michalovce as compared to the same cell types in cord blood samples (p < 0.001), whereas natural regulatory T-lymphocytes and suppressor inducer T-lymphocytes were reduced (p < 0.001). Overall, a positive linear correlation of terminally differentiated effector memory (TEM) T-lymphocyte population with age, but a negative linear correlation for myeloid DC from birth to 6-months in both regions were found. Michalovce samples indicated significantly higher expression of memory T-lymphocytes (birth, 6th, and 16th month), TEM T-lymphocytes (birth and 6th month), and lymphoid DC (6th month) compared to the Svidnik/Stropkov regions. After adjustment for relevant covariates, such as maternal age, parity, season of birth, breastfeeding, birth weight, and gender, the myeloid DC, suppressor inducer T-lymphocytes, truly naïve helper/inducer T-lymphocytes, and TEM T-lymphocytes remained significantly different between districts in cord blood samples. The multivariate analysis models for 6- and 16-month samples showed district differences in all cellular determinants, except for lymphoid DC and macrophage-like cells. This study provides the first evidence that pre-natal and early post-natal exposure to PCBs affects the dynamics of cell surface receptor expression on lymphoid DC and DC-like cells, suggesting impaired immunologic development following pre-natal and early post-natal PCB exposure.

Immunoregulatory CD4+ CD45R+ suppressor/inducer T lymphocyte subsetsand impaired cell-mediated immunity in patients with Down's syndrome

The monoclonal antibodies 2H4 and 4B4 allow CD4+ and CD8+ T lymphocytes to be subdivided into CD45R+ and CDW29+ functional subpopulations. The CD4+ CD45R+ lymphocytes are designated as suppressor/inducer and CD4+ CDW29+ as helper/inducer subsets. Peripheral blood lymphocytes from 19 patients with Down's syndrome and 19 age- and sex-matched normal controls were analysed for the CD45R+ and CDW29+ subsets from the CD4+ and CD8+ T lymphocytes. The percentage of CD4+ CD45R+ cells (suppressor inducer) was markedly increased and of CD4+ CDW29+ cells (helper/inducer) decreased in all patients with Down's syndrome. In contract, the percentage of CD8+ CD45R+ and CD8+ CDW29+ subsets showed no major differences between patients with Down's syndrome and normal controls. Moreover, an alteration in the CD4+ and CD45R+ and CD4+ CDW29+ T cell subsets was accompanied by a markedly reduced proliferative response to phytohaemagglutinin and concanavalin A stimulation of the CD4+ T lymphocytes. Thus, a deficiency exists in patients with Down's syndrome in the CD4+ CDW29+ helper/inducer T cell subset which may contribute to their impaired cell-mediated immunity.

Concomitant augmentation of CD4+ CD29+ helper inducer and diminution of CD4+ CD45RA+ suppressor inducer subset in patients infected with human T cell lymphotropic virus types I or II.

To examine the immunomodulatory effects of HTLV infection, lymphocyte subset analysis was performed on patients infected with human T cell lymphotropic virus type-I (HTLV-I, n = 6) or -II (HTLV-II, n = 12) and on normal blood donors (n = 16). The percentages of total B lymphocytes (CD19), natural killer (NK) cells (CD16), T lymphocytes and their subsets (CD2, CD3, CD4, CD5, CD7, CD8), and IL-2R (CD25) were found to be within the range found in normal donors. However, the expression of CD8+ HLA-DR+ increased significantly in patients with HTLV-I or HTLV-II infection (14.1 +/- 3.9% and 9.7 +/- 2.4% respectively; P less than 0.01) when compared with controls (3.2 +/- 1.1%). In addition, there was a significantly greater proportion of CD4+CD29+ T lymphocytes (29.3 +/- 6.1% and 31.1 +/- 9.0%; P less than 0.05) with concomitant diminution of CD4+CD45RA+ T lymphocytes (8.3 +/- 3.3% and 11.4 +/- 1.5%; P less than 0.01) in patients infected with HTLV-I or HTLV-II respectively, when compared with controls. The increased percentage of CD4+CD29+ subpopulations showed a direct correlation (rs = 0.86; P less than 0.001) with HTLV-specific antibody production. No difference in the CD8 population coexpressing CD29 and S6F1 (an epitope of LFA-1) were observed in the HTLV-infected group when compared with normal donors and functional analysis exhibited minimal cytotoxicity against lectin labelled heterologous target cells. Thus, the shift in the suppressor/cytotoxic to helper/inducer 'memory' CD4+ may be associated with immunoregulatory abnormalities often found in persons infected with HTLV-I or HTLV-II.

Characterization of a monoclonal antibody identifying a CD45RA antigen on feline leukocytes

The antibody produced by a murine hybridoma obtained from the fusion of SP2/0 plasmacytoma cells with splenocytes of a mouse immunized with feline bone marrow was found to react with 60% of bone marrow cells and 80% of peripheral blood leukocytes (PBL); reactivity in the latter tissue was restricted almost entirely to mononuclear cells. Two-color FACScan analyses of this antibody with mAbs specific for feline lymphocytes revealed positive and negative populations of CD4 and CD8 cells. The reactivity for CD4 and CD8 cells was animal age dependent, binding to a higher percentage of the cells in young (2–9 months) versus older animals (>4 years). In a mitogen driven assay for IgG production by PBL the addition of this antibody to the cultures enhanced the suppressor activity of CD8 cells, a function attributed to activation of a CD4 suppressor–inducer population; removal of CD8 cells negated any induction of suppression. Mild papain digestion of bone marrow and PBL completely removed the antigen detected by this antibody while not affecting reactivity of a pan-T antibody. Western blot analysis showed binding of the antibody to polypeptides of approximately 200 kDa on feline bone marrow and PBL. The data suggest that this mAb is identifying the feline homologue of the leukocyte common antigen of cells with a functional specificity characteristic of a CD45RA isoform.

T-cell subpopulations in the cerebrospinal fluid and peripheral blood of patients with multiple sclerosis

We analyzed the relative and absolute numbers of CD4+ cells positive and negative for CD45RA marker as well as the numbers of CD8+ cells positive and negative for CD11b in the cerebrospinal fluid (CSF) and peripheral blood (PB) of 17 patients with multiple sclerosis (MS) during and 60 days after an exacerbation. We also studied samples from 27 control patients, 17 of whom had a noninflammatory neurologic disease and 10 of whom had an inflammatory neurologic disease other than MS. The results confirmed the small number of CD45RA-positive (naive or suppressor inducer) CD4+ cells as well as CD11b-positive (suppressor) CD8+ cells in the CSF compared with the PB for all paired CSF-blood comparisons. The relative numbers of these cells did not significantly differ between samples taken during an exacerbation and those taken 2 months later. In PB, the percentage of CD8+ CD11b-positive lymphocytes was lower in patients with MS or in patients with an inflammatory neurologic disease than in patients with a noninflammatory neurologic disease. The results indicate that there are fewer cells responsible for suppression-related phenomena in CSF than in PB but that this phenomenon is not specific to MS.

Improvement of peripheral blood lymphocyte subsets in primary biliary cirrhosis after ursodeoxycholic acid therapy.

Immunological abnormalities frequently observed in patients with primary biliary cirrhosis are considered to be related to the pathogenesis of this disease. We performed a prospective trial to evaluate whether immune mechanisms play a role in the effectiveness of ursodeoxycholic acid (UDCA) therapy. Fifteen female patients with primary biliary cirrhosis were followed for 1 year and were then treated with UDCA (600 mg/day) for another year. Laboratory tests, including peripheral blood lymphocyte subsets assessed by dual colour fluorescence analysis using monoclonal antibodies against respective T cell markers, were evaluated at the beginning of the study, at the start of therapy and at the end of therapy. In primary biliary cirrhosis, the proportion of cytotoxic T cells, suppressor inducer T cells and alpha beta-receptor bearing T cells were significantly lower than in healthy controls. No significant changes were observed in the proportions during the year before the therapy. These reductions, however, recovered to normal ranges after 1 year of UDCA therapy. These changes were associated with an improvement in the serum levels of aspartate aminotransferase, alkaline phosphatase, gamma-globulin and IgM. The close correlation between the improvement in the imbalance of lymphocyte subsets after the therapy and the clinical status suggests that an immunological process may play a role in the effectiveness of therapy in primary biliary cirrhosis.

Cellular Induction Mechanism of CD8+Suppressor T Cells by DMBA and TPA: Formation of CD4+Suppressor–Inducer T Cells

We investigated the cellular induction mechanism of antigen-nonspecific CD8+T suppressor cells which suppressed delayed-type hypersensitivity to sheep red blood cells, by treating BALB/c mice with 7,12-dimethylbenz[a]anthracene (DMBA), a tumor initiator, and 12-O-tetradecanoylphorbol 13-acetate (TPA), a tumor promoter. Macrophages were activated by painting with 400 nmol of DMBA on mice. And the macrophages plus TPA induced CD4+T suppressor inducer cells in the mice spleens. These cells were efficient at inducing CD8+T suppressor–effector cells. When 8 nmol of TPA was painted daily on mice for 3 days following the treatment with 400 nmol of DMBA, or when spleen cells from mice pretreated with 400 nmol of DMBA were cultured in 32 nmol/5 ml of TPA for 3 days, inducer cells were formed in the spleen. Both T suppressor–inducer cells and macrophages from mice treated with DMBA were shown to act with the formation of soluble factors, which may be different from IL-10.

Immunological abnormality in patients with lysinuric protein intolerance

Lysinuric protein intolerance (LPI) is a rare hereditary disorder manifesting hyperammonemia induced by low levels of basic amino acids, these low levels being due to the impaired transport of these acids in the intestinal mucosa and the renal tubules. Low serum arginine levels and probably the consequently low in vivo levels of nitric oxide (NO), which against acts as a physiological and immunological mediator/modulator, are thought to influence the immunological status in patients with LPI. Accordingly, this study was conducted to. We found that patients with LPI had leukocytopenia, high serum IgG levels, a high ratio of CD44B4-positive lymphocytes (helper inducer) to CD42H4-positive lymphocytes (suppressor inducer), low levels of leukocyte phagocytic, cytotoxic, and natural killer cell activity, and increased spontaneous proliferation of lymphocytes. These results were probably the consequence of persistent low NO levels in vivo.

Evidence for a missed signal to the CD8+ cells in CSF of multiple sclerosis patients.

Peripheral blood (PB) and cerebrospinal fluid (CSF) lymphocyte subpopulations, defined by various T-cell specific monoclonal antibodies and flow cytometry, were analysed in 44 relapsing remitting multiple sclerosis (RRMS) patients (including 21 subjects in the acute phase and 23 in the stable phase), 40 chronic-progressive multiple sclerosis (CPMS) patients, and 24 patients with other neurological diseases (OND), in order to verify the presence of any abnormality in the lymphocyte subset pattern. A significant increase in the total number of T-lymphocytes and the CD4+ subpopulation was found in the PB of the MS patients in comparison with the OND group. Moreover, a not statistically significant increase in CD4+ cells was observed in the CSF of MS patients. A statistically significant increase was also found in the CD4+ Leu 8+ (suppressor inducer) cells in the CSF of all of the MS groups. Finally, the CD8+ (suppressor/cytotoxic) cell levels, were significantly lower in the CSF of CPMS and stable RMS patients than in the CSF of the OND patients. As a whole, our data suggest that the immunosuppressive deficit that seems to be a constant finding in MS is not due to a decrease in suppressor inducer cell levels, as previously suggested, but may be caused by a missed or altered signal from the suppressor inducer to CD8+ suppressor cells.

Cytotoxic T-cell role in renal allograft rejection and regulation: Renal allograft infiltrating cytotoxic T-cell line with suppressor—inducer function

We previously investigated the characteristics of renal allograft infiltrating T-cell lines that were propagated from biopsy and nephrectomy specimens designated as IG-Bip and IG-Neph, respectively, or analogous line designated IG-T-eff, which was generated by co-culturing pretransplant recipient blood with irradiated donor splenocytes (manuscript submitted). The recipient (IG) had no previous sensitization to donor mismatched HLA antigens (A2 and DR1). Phenotypically, all lines were of recipient origin and were CD3 +, TCRαβ +, DR +. However IG-Bip line was low in CD4 (19%) and high in CD8 (50%), whereas IG-Neph and IG-T-eff lines had equal mixture of CD4 + (34%) and CD8 + (38%) subsets). Functionally, all three lines contained donorspecific CTLs. In the present report, we used the in vitro MLR to examine the possible utilization of these CTL lines as inducer cells to generate donor-specific Ts cells from recipient PBLs. Coculturing IG-PBL that was drawn before or after transplantation and immunosuppression with irradiated IG-T-eff or IG-Neph but not IG-Bip CTL lines, generated Ts cells. Ts cells were of recipient origin and were CD3 +, CD8 +, leu 11b +, CD28 −, all characteristic of Ts-effector phenotype. Ts cells inhibited MLR response of recipient PBLs against donor or third-party stimulators that shared with the donor the mismatched HLA antigens. Ts suppression was more pronounced against early phase of MLR response and was not due to a shift in MLR kinetics or nonspecific soluble suppressor or Cytotoxic products. These findings suggest that allograft infiltrating CTLs or their in vitro generated analogous line may modulate allograft rejection by acting as Ts inducers and that Ts induction was dependent on the presence of the CD4 subset within the Ts-inducer cells but was not dependent on renal transplantation or immunosuppression.

Stabilization and characterization of antigen-specific T suppressor inducer and T suppressor effector molecules

H-2 specific T suppressor inducer (Tsfi) and T suppressor effector (Tsfe) factors show a dose-dependent inhibition of one-way mixed lymphocyte responses (MLR) between CBA J responder spleen cells and C57BL 6 mitomycin C-treated stimulator spleen cells. The hydrophobic proteins Tsfi and Tsfe purified by ammonium sulfate precipitation and affinity methods were stabilized by the addition of Tris-saline pH 8 buffered octylglucopyranoside solution. The stabilized Tsfi and Tsfe fractions stored at 4°C for 3–7 months retained a significant (> 72%) amount of their ability to inhibit MLR. Tsfi and Tsfe purified by salt precipitation and affinity methods were analyzed by SDS-PAGE. Enzyme-linked immunoassay (ELISA) and Western blots indicated that these molecules had T cell receptor (TcR) α chain, I-J, and IL-10 epitopes, but not TcR β chain epitopes.

Specific T-Cell Factors That Initiate Cellular Immune Responses Are Produced by CD4-, CD8-, Vβ8- Lymphocytes and Are Present in Nude Mice

The antigen-specific suppressor inducer T-cell factors (TsiF) specific macrophage-arming factor (SMAF) and mast cell-arming T-cell factor (MTCF) are produced by lymphocytes that have a Thy 1+, Lyt-1+, CD4-, CD8-, and Vβ8- phenotype. The SMAF- and MTCF-producing lymphocytes are positive for the monoclonal antibody (mAb) 14-30, which is directed against TsiF and also binds SMAF and MTCF. The SMAF-producing lymphocytes are negative for mAb 14-12, which is directed against suppressor effector T-cell factors. The MTCF-producing lymphocytes are probably CD3+. The CD3 phenotype of SMAF-producing lymphocytes could not be established in the biological assays. Lymphocytes mediating the classical (24 hr) delayed-type hypersensitivity (DTH) response are Thy 1+, CD3+, CD4+, CD8-, Vβ8+. SMAF- and MTCF-producing lymphocytes were also detected in congenitally athymic (nude) mice. We conclude from these results that (i) the subset of lymphocytes (CD4-, CD8-, Vβ8-) that produces SMAF and MTCF (and is involved in the initiation of the cellular immune response) is different from the subset (CD4+, Vβ8+) that exerts effector functions, like DTH or cell-mediated immunity. (ii) In case of a CD3+ phenotype of SMAF- and MTCF-producing lymphocytes, this CD3+, CD4-, CD8- phenotype together with their presence in nude mice suggests that these lymphocytes may bear a γδ T-cell receptor (TCR), although an αβ TCR positive phenotype cannot be excluded. (iii) Since SMAF- and MTCF-producing lymphocytes bind mAb 14-30, these TsiF can be associated with the plasma membrane of the lymphocytes by which they are produced.

Adoptive immunotherapy for unresectable or recurrent pancreatic cancer, using lymphokine-activated killer cells or cytotoxic T cells

Adoptive immunotherapy (AIT) has been reported to be effective for malignancies in some cases. We hypothesized that AIT may be effective for the treatment of pancreatic cancer. Seven patients with unresectable or recurrent pancreatic cancer underwent AIT, carried out with lymphokine-activated killer (LAK) cells or cytotoxic T cells (CTLS) and recombinant interleukin-2 (IL-2). The clinical and immunological effects were evaluated. Of four patients who received CTLs, one had a partial response, one had a minor response, and two showed no change. The three patients who received LAK cells had progressive disease. The CTLs had a significantly higher proportion of CD8 positive T cells and cytotoxic T cells than the LAK cells (P < 0.05), while the LAK cells had a significantly higher proportion of NK cells than did the CTLs (84 ± 12% vs 55 ± 15%,P < 0.05). The LAK activity of the CTLs (61 ± 14%) was significantly higher than that of the LAK cells (42 ± 8%,P < 0.05). Seven days after treatment with LAK cells or CTLs, lymphocyte subsets in the peripheral blood were examined. The proportion of CD8-positive T cells after CTL transfer (46 ± 5%) was greater than that before CTL transfer (28 ± 1%,P < 0.05). The proportion of cytotoxic T cells after CTL transfer increased from 23 ± 1% to 37 ± 2% (P < 0.05). However, these changes were not observed during LAK cell transfer. The proportions of suppressor inducer T cells, helper T cells, and suppressor T cells did not change during therapy. These results suggested that AIT, using CTLs, merits further clinical investigation in patients with pancreatic cancer.

Phenotypic and functional abnormalities in the peripheral blood T‐cells of patients with primary Sjogren's syndrome

Changes in regulatory T-cell subset (including the recently described CD4 helper inducers or suppressor inducers) balance in the peripheral blood may play a role in the pathogenesis of primary Sjogren's syndrome (SS). Direct immunofluorescence and flow cytometry were used to quantitate and analyse peripheral blood lymphocytes in 15 patients with primary SS and 15 control subjects. A reduction in the percentage of circulating CD4 lymphocytes was observed in patients with SS. There was no quantitative abnormality in the percentage of circulating CD4+ 2H4+ (suppressor inducer), CD4+ 4B4+ (helper inducer), CD2, CD3, CD8, CD8+ 2H4+, CD8+ 4B4+, CD25 (IL-2R), CD19, CD16, CD57 lymphocytes in the patients. Circulating CD8 lymphocytes expressing the activation marker HLA-DR were increased in the patients. The functional status of peripheral blood lymphocytes was assessed by PHA (phytohaemagglutinin) stimulation followed by monitoring their proliferative response by radiolabelled thymidine uptake and expression of CD25 (Interleukin-2 receptor). A reduction in the proliferative response of total, CD4-depleted, and CD8-depleted lymphocytes suspensions to PHA was demonstrated. The level of expression of CD25 (IL-2 receptor) was similar in patients and controls before and after 24 h stimulation with PHA. We conclude that there is a disturbance in the functional properties of peripheral blood T cells that can contribute to the immunopathogenesis of SS. Meanwhile, the quantitative reduction of suppressor/inducer lymphocytes as defined by the CD4 2H4 phenotype can be precluded from a role in the development of such an autoimmune condition.

Fine T-cell subsets in alcoholics as determined by the expression of L-selectin, leukocyte common antigen, and beta-integrin.

Alcoholics admitted to the hospital solely for detoxication have been studied by flow cytometry to evaluate changes in the surface markers of peripheral blood leukocytes. As we have shown previously, such patients have an elevated percentage of CD8hi lymphocytes that are HLA DR+; we now demonstrate that they also have striking alterations in the quantitative relationships of the fine T-cell subsets. Both CD4+ and CD8hi lymphocytes have a sharply reduced percentage of the L-selectin+ CD45RA+ subset, increased percentages of the CD45RA- subsets, and several other fine subset alterations. The fine subset profile suggests, according to current correlations of phenotype and function, that both CD4+ suppressor inducer and CD4-dependent CD8+ suppressor effector cells are reduced, whereas other subsets, including CD8+ CTL or their precursors, are increased in relative percentages. Some of the phenotypic changes are reversible over the several days following withdrawal. In other results, the percentage of CD8hi lymphocytes epxressing CD11b (beta-integrin) is shown to be reciprocal with the percentage expressing L-selectin both in normals and alcoholics. However, the regression function of CD11b vs. L-selectin on CD8hi cells is different for the alcoholics than for the normals, indicating an abnormality in the regulation of the expression of these two adhesion markers. Taken together, this abnormality of adhesion molecules and the fine subset alterations previously described indicate widespread changes in the peripheral lymphocytes of currently drinking alcoholics. These changes suggest functional deficiencies that may include alterations of lymphocyte traffic and other adhesion-dependent functions, and a shift in the balance of regulatory interactions.

Immune Modulation during Treatment of Systemic Sclerosis with Plasmapheresis and Immunosuppressive Drugs

Immunologic effects of our previously reported treatment protocol were determined in eight systemic sclerosis (SSc) patients treated with plasmapheresis, cyclophosphamide, and prednisone as tolerated. Prior to treatment total serum IgG and circulating lymphocytes including the percentage of B, T, and NK cells were normal. Peripheral blood lymphocytes showed evidence of activation by increased spontaneous proliferation and expression of CD25 on T cells. In addition, CD4 + T cells showed increased expression of both activation (HLA-DR) and maturation (CD29) markers. The percentage of CD8 + T cells was low, resulting in a high CD4:CD8 T cell ratio. During treatment all patients showed clinical improvement. Laboratory testing showed that their NK cells had declined by 81%, B cells declined by 96%, and serum IgG declined by 49%; high titer ANA were abrogated. Total T cells declined by 52%, and the CD4:CD8 ratio fell to normal, due to an almost twofold increase in the percentage of CD8 + T cells. Spontaneous lymphocyte proliferation increased further and was accompanied by increased maturation and activation of both CD4 + and CD8 + T cells, as well as a reduction of immature CD4 + T cells. Among CD8 + T cells the percentage of cytotoxic cells increased as shown by an increase in the CD11b -, CD38 +, and CD29 + phenotypes, a finding confirmed on follow-up three-color flow cytometry which showed an increase in activated CD8 cells bearing the cytotoxic CD28 marker. Three-color cytometry also showed that cells with the CD4 +CD45RA +CD31 + suppressor inducer phenotype were low and those with the CD4 +CD45RO +CD31 - helper inducer phenotype were high in treated SSc patients. Deficient CD4 +CD45RA +CD31 + and CD8 + T cell populations suggest an immune regulatory imbalance in SSc which could have led to CD4 + T cell activation and autoimmunity. Depletion of B cells, in conjunction with augmentation of cytotoxic CD8 + T cells through combined therapy, may have diminished the autoimmune response.

Active intralymphatic immunotherapy of uterine cervical carcinoma with viral oncolysate: a pilot study.

A pilot clinical trial was conducted in patients with squamous carcinoma of the uterine cervix to evaluate the clinical and biologic effects of active intralymphatic immunotherapy (AILI) with allogenic viral oncolysate (VO) prior to radiation therapy. Sixteen patients with advanced primary squamous carcinoma of the uterine cervix and lymph node metastases underwent bipedal intralymphatic injections of VO. VO was derived from lysates of cervical carcinoma cells that had been infected with influenza A virus. AILI was repeated after 2 weeks and followed one week later by standard or extended-field radiation therapy (RT). The first seven patients were treated at one of the three dose levels: 6 mg (three patients), 12 mg (three patients) and 18 mg (one patient). Remaining patients were treated at the 12 mg dose level. Sixteen patients received 63 injections (one patient received three of four doses) of AILI-VO without significant toxicity. Eleven patients have died of persistent or recurrent carcinoma with a total median survival of 19.4 months. Examination of humoral and cellular immunity during AILI-VO showed an increase in the serum liters of antibodies to a surface antigen on cervical carcinoma cells and to the influenza virus. Increased non-MHC restricted lymphocyte cytotoxicity was exhibited by three of four patients treated above the first dose level. Two of the three patients are survivors. By contrast, lymphocytes of patients treated with AILI-VO exhibited either an increase or a decrease in proliferation responses to cervical carcinoma cells. Similarly, post-treatment lymphocytes exhibited either helper or suppressor inducer effects on pre-treatment lymphocytes.

5196526 cDNA clone for T-cell suppressor inducer factor: Kenneth D Beaman assigned to University of Health Sciences/The Chicago Medical School

5196526 cDNA clone for T-cell suppressor inducer factor: Kenneth D Beaman assigned to University of Health Sciences/The Chicago Medical School

H-2-SPECIFIC T SUPPRESSOR CELLS I. EVIDENCE FOR T SUPPRESSOR INDUCER AND EFFECTOR MOLECULES IN SUPPRESSION

The induction of H-2-specific Ts cells was accomplished by the i.v. injection of X-irradiated (2000R) C57BL/6 spleen cells into CBA/J mice. These Ts cells significantly (78%) suppressed the delayed type hypersensitivity (DTH) response in CBA/J mice injected s.c. with X-irradiated (2000R) C57BL/6 spleen cells and given a footpad challenge with the same cell population 5 days later. We have shown that both CD4 and CD8 T cells were involved in the observed suppression, and these cells secrete T suppressor inducer (Tsfi) and T suppressor effector (Tsfe) molecules. Both Tsfi and Tsfe molecules were shown to significantly inhibit (> 87%) one-way mixed lymphocyte responses between CBA/J and mitomycin C-treated C57BL/6 spleen cells. Using an adoptive transfer method, we showed that mice given both a primary and secondary immunization with X-irradiated C57BL/6 spleen cells to induce H-2-specific Ts cells contain a significantly greater number of Ts cells than mice given only a primary immunization, suggesting the presence of memory Ts cells.