Reduction In Suppressor Cells Research Articles

Dendritic cell vaccination with a toll-like receptor agonist derived from mycobacteria enhances anti-tumor immunity.

Dendritic cell (DC)-based vaccines are considered useful in cancer immunotherapy, and the interaction of DC and adjuvants is important in the design of the next generation vaccines. In this study, whether DC combined with Rv2299c derived from mycobacteria could improve anti-tumor immune responses in a colon cancer mouse model was evaluated. MC38 cell lines were injected subcutaneously to establish colon-cancer-bearing mice and the following four groups were evaluated: PBS control, tumor antigen (TA) loaded-DC, Rv2299c, and a combination of TA-loaded-DC and Rv2299c. The combination treatment with TA-loaded-DC and Rv2299c exhibited greater inhibition of tumor growth compared to other groups. These effects were associated with the reduction of suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, and the induction of effector cells, such as CD4+ T cells and CD8+ T cells, in spleen, and with the activation of cytotoxic T Lymphocytes and NK cells. These results suggest that TA-loaded-DC vaccination with Rv2299c derived from mycobacteria enhanced anti-tumor immunity in a mouse colon cancer model by inhibiting the generation of immune-suppressive cells and recovering numbers of effector cells, and demonstrated superior polarization of the Th1/Th2 balance in favor of the Th1 immune response.

The Requirement of Multimodal Therapy (Vaccine, Local Tumor Radiation, and Reduction of Suppressor Cells) to Eliminate Established Tumors

Numerous immune-based strategies are currently being evaluated for cancer therapy in preclinical models and clinical trials. Whereas many strategies look promising in preclinical models, they are often evaluated before or shortly following tumor implantation. The elimination of well-established tumors often proves elusive. Here we show that a multimodal immune-based therapy can be successfully employed to eliminate established tumors. This therapy consists of vaccines directed against a self-tumor-associated antigen, the use of external beam radiation of tumors to up-regulate Fas on tumor cells, and the use of a monoclonal antibody (mAb) to reduce levels of CD4+CD25+ suppressor cells. We show here for the first time that (a) antigen-specific immune responses induced by vaccines were optimally augmented when anti-CD25 mAb was given at the same time as vaccination; (b) anti-CD25 mAb administration in combination with vaccines equally augmented T-cell immune responses specific for a self-antigen as well as those specific for a non-self antigen; (c) whereas the combined use of vaccines and anti-CD25 mAb enhanced antigen-specific immune responses, it was not sufficient to eliminate established tumors; (d) the addition of external beam radiation of tumors to the vaccine/anti-CD25 mAb regimen was required for the elimination of established tumors; and (e) T cells from mice receiving the combination therapy showed significantly higher T-cell responses specific not only for the antigen in the vaccine but also for additional tumor-derived antigens (p53 and gp70). These studies reported here support the rationale for clinical trials employing multimodal immune-based therapies.

Lymphoid subpopulation changes after thermal injury and thermal injury with infection in an experimental model.

Subpopulation analysis of peripheral blood lymphocytes is a frequently used measure of immunocompetence. Yet, little is known about the lymphocyte subpopulations in the circulation and lymphoid organs after severe trauma. Blood, spleen, and lymph node (LN) subpopulations were compared in a rat model of burn injury (B) and burn injury with infection (BI). B and BI rats received 30% total body surface scald burns. Infection was induced by seeding wounds with Pseudomonas aeruginosa. Subpopulations were identified by flow cytometry 48 hours after burn. Helper lymphocytes were selectively depleted from the circulation of BI but not B animals, which caused the ratio of helper to suppressor cells (HSR) in BI animals to decrease significantly compared with the unburned controls. Both LN helper and suppressor cells were decreased in BI animals and the HSR was unchanged, but a selective reduction in suppressor cells in B LN increased the HSR relative to unburned controls. Spleen subpopulations were unchanged for both B and BI groups. Subpopulation changes after trauma and infection were different for each tissue examined.

Intrapleural administration of OK432 in cancer patients: activation of NK cells and reduction of suppressor cells.

Twelve patients with carcinomatous pleural effusions were treated with single intrapleural (i.pl.) administration of OK432 on day 0 and the effects of i.pl. OK432 on natural killer (NK) cell activity were followed on day 7. Two patients showed no clinical evidence of therapeutic benefit from i.pl. OK432. In the other 10 patients, pleural effusions and/or tumor cells in the effusions had decreased or disappeared by day 7. NK cell activity was markedly low or absent in pleural effusions of untreated patients due to the presence of adherent effusion cells capable of suppressing the maintenance and interferon-induced augmentation of NK cell activity. I.pl. injection of OK432 resulted in enhancement of NK cell activity and abrogation of NK suppressor cell activity in the effusions. On the other hand, blood NK cell activity was not consistently altered by i.pl. OK432. In vitro treatment of effusion mononuclear cells from untreated patients with OK432, but not with interferon, augmented NK cell activity. In addition, adherent effusion cells of untreated patients lost their NK suppressor function following in vitro OK432 treatment. These results suggest that i.pl. administration of OK432 will result in augmentation of NK cell activity and reduction of NK suppressor cell activity in pleural effusions, which could be responsible for the antitumor activity of i.pl. OK432.

Studies on the lymphocyte subpopulation in systemic lupus erythematosus by monoclonal antibodies

T cells and T-cell subsets were studied with monoclonal antibodies in 15 patients with systemic lupus erythematosus (SLE) during a 6-wk period. During active states of disease, all investigated T-cell subsets decreased, but the reduction of suppressor cells seemed to be more pronounced, therefore the helper/suppressor ratio increased. Less suppressor cells could be detected during clinical impairments and more during improvements.

T cell subsets in patients with acute and chronic HBV infection, primary biliary cirrhosis and alcohol induced liver disease

The proportions of inducer and cytotoxic/suppressor T cells and their concentrations in peripheral blood have been determined in patients with acute and chronic type B hepatitis, hepatitis B virus (HBV) carriers with normal hepatic histology, patients with alcohol-induced liver disease (ALD), primary biliary cirrhosis (PBC) and chronic extrahepatic cholestasis. During acute type B hepatitis the inducer/suppressor ratio was decreased due to an increase in suppressor cell concentrations. When this ratio returned to normal the HBs antigen was cleared and HBs antibody was detectable. Similar abnormalities were found in patients with HBs + ve chronic hepatitis. In HBs antigen-positive patients with normal histology, normal T cell subsets were found. In some patients with primary biliary cirrhosis the ratio of inducer to suppressor cells was low due to a reduction in the concentration of inducer cells and in others high due to a reduction in suppressor cells. Administration of cyclosporin A to the latter group produced an increase in the concentration of suppressor cells and there was an improvement in liver biochemistry. In alcohol-induced hepatitis and cirrhosis the ratio of inducer/suppressor cells was normal. Whether these imbalances of the regulatory cells of the immune system in patients with chronic HBV-induced hepatitis and PBC are of primary or secondary importance is uncertain. The relationship of the depressed ratio to persistence of the hepatitis B virus is worthy of further study.

Reduction of suppressor cells in cancer patients treated with OK-432 immunotherapy.

OK-432, a streptococcal preparation, was intradermally injected daily into patients with advanced cancer of the stomach or lung for 4 weeks and the effects of OK-432 on the mitogenic responses of cancer patients were followed. The cells involved in the depression of the response of untreated cancer patients were characterized. The cells responsible for impaired responses were nylon wool non-adherent and suppressed the mitogen responses of autologous and allogeneic lymphocytes. These cells lost their suppressive activity during 7 days' culture in vitro. Following OK-432 immunotherapy, mononuclear cells from cancer patients showed increased responses to PHA and Con A, and nylon wool non-adherent cells did not inhibit the mitogen responses. These results suggest that the cells suppressing non-specific mitogen responses are sensitive to in vitro culture, belong to nylon wool non-adherent cells and are lost during 4 weeks of OK-432 therapy.

Reduction of suppressor cells in cancer patients treated with OK-432

Reduction of suppressor cells in cancer patients treated with OK-432