Natural Suppressor Cells Research Articles

Immune microenvironment of human papillomavirus-positive head and neck squamous cell carcinoma.

Research progress of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) based on immune microenvironment. This article preliminarily discusses the composition of immune microenvironment components and immune therapy and elaborates and analyzes the involvement and impact of T cells, B cells, natural killer (NK) cells, tumor-associated fibroblasts, and bone marrow-derived suppressor cells in HPV-positive HNSCC on tumor progression and prognosis. Furthermore, the application of immune-related therapies in HPV-positive HNSCC is explored. It is found that immune microenvironment research plays an important role in the pathogenesis and treatment of HPV-positive HNSCC. Immune microenvironment research as an important means to explore tumors has played an important role in the study of HPV-positive HNSCC. We describe the biological significance of important components of HNSCC immune microenvironment by analyzing the effects of HNSCC immune microenvironment components and immunotherapy on HPV-positive HNSCC. May to provide new strategies for experimental research and clinical prevention and treatment of this disease.

The role of innate immune cells in the colorectal cancer tumor microenvironment and advances in anti-tumor therapy research.

Innate immune cells in the colorectal cancer microenvironment mainly include macrophages, neutrophils, natural killer cells, dendritic cells and bone marrow-derived suppressor cells. They play a pivotal role in tumor initiation and progression through the secretion of diverse cytokines, chemokines, and other factors that govern these processes. Colorectal cancer is a common malignancy of the gastrointestinal tract, and understanding the role of innate immune cells in the microenvironment of CRC may help to improve therapeutic approaches to CRC and increase the good prognosis. In this review, we comprehensively explore the pivotal role of innate immune cells in the initiation and progression of colorectal cancer (CRC), alongside an extensive evaluation of the current landscape of innate immune cell-based immunotherapies, thereby offering valuable insights for future research strategies and clinical trials.

Abstract 3559: Redirection of anti-virus immunity towards anti-tumor immunity using nanoparticle-induced immune tolerance for oncolytic adenovirus therapy

Abstract Recent clinical observations that some coronavirus infections induced complete remissions in lymphoma patients emphasized again the potential of cancer virotherapy. Infection of cancer cells with oncolytic viruses reshapes the tumor microenvironment by activating anti-viral and anti-tumor immunity. A phase 1 clinical trial using oncolytic adenovirus Delta-24-RGD (DNX-2401) to treat recurrent malignant gliomas demonstrated activation of CD8+ T-cells and significant clinical benefits for a subset of patients. However, both anti-virus and anti-tumor immune responses are contingent on the activation of respective clones of CD8+ T-cells, which compete for clonal expansion. Thus, overexpansion of T-cells against viral antigens reduces the frequency of subdominant clones against tumor antigens. We hypothesized that inducing immune tolerance for viral antigens will decrease anti-viral immunity and in turn derepress anti-tumor immunity, resulting in enhanced efficacy of cancer virotherapy. In this work, we used nanoparticles encapsulating adenoviral antigens E1A, E1B and hexon that distributed to liver resident macrophages (P<0.0001) and induced peripheral immune tolerance. Functional experiments to restimulate immune cells with viral or tumor antigens showed that injection of nanoparticles induced virus-specific immune tolerance and redirected the focus of the immune response towards tumor peptides as measured by interferon-gamma secretion (P<0.0001). Co-culture experiments also showed increased activation of immune cells against fixed tumor cells after nanoparticle treatment (P<0.0001). Reduction of virus-specific T-cells and concurrent expansion of tumor-specific T-cell clones were further confirmed with E1A or OVA tetramers (P<0.05). Flow cytometry analysis suggested increased anti-tumor responses were due to differences in T-cell clones and not due to other immune populations including natural killer cells or myeloid-derived suppressor cells (P=0.3). Importantly, virotherapy in combination with nanoparticle-induced immune tolerance towards viral antigens in tumor-bearing mice increased the overall survival and doubled the percentage of long-term survivors compared to virus treatment alone. Our data should propel the development of a future clinical trial aiming to maximize the potential of anti-tumor immunity during cancer virotherapies. Citation Format: Dong Ho Shin, Hong Jiang, Debora Kim, Teresa T. Nguyen, Sagar Sohoni, Xuejun Fan, Yanhua Yi, Arie C. Van Wieren, Gheath Al-Atrash, Chantale Bernatchez, Ramon Alemany, Marta Alonso, Frederick Lang, Candelaria Gomez-Manzano, Bulent Ozpolat, Juan Fueyo. Redirection of anti-virus immunity towards anti-tumor immunity using nanoparticle-induced immune tolerance for oncolytic adenovirus therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3559.

Anti-Tumor Effects of Chinese Medicine Compounds by Regulating Immune Cells in Microenvironment.

As the main cause of death in the world, cancer is one of the major health threats for humans. In recent years, traditional Chinese medicine has gained great attention in oncology due to the features of multi-targets, multi-pathways, and slight side effects. Moreover, lots of traditional Chinese medicine can exert immunomodulatory effects in vivo. In the tumor microenvironment, tumor cells, immune cells as well as other stromal cells often coexist. With the development of cancer, tumor cells proliferate uncontrollably, metastasize aggressively, and modulate the proportion and status of immune cells to debilitate the antitumor immunity. Reversal of immunosuppressive tumor microenvironment plays an essential role in cancer prevention and therapy. Immunotherapy has become the most promising strategy for cancer therapy. Chinese medicine compounds can stimulate the activation and function of immune cells, such as promoting the maturation of dendritic cells and inducing the differentiation of myeloid-derived suppressor cells to dendritic cells and macrophages. In the present review, we summarize and discuss the effects of Chinese medicine compounds on immune cells in the tumor microenvironment, including innate immune cells (dendritic cells, natural killer cells, macrophages, and myeloid-derived suppressor cells) and adaptive immune cells (CD4+/CD8+ T lymphocytes and regulatory T cells), and the various immunomodulatory roles of Chinese medicine compounds in cancer therapy such as improving tumor-derived inflammation, enhancing the immunity after surgery or chemotherapy, blocking the immune checkpoints, et al., aiming to provide more thoughts for the anti-tumor mechanisms and applications of Chinese medicine compounds in terms of tumor immunity.

The Role of Myeloid-Derived Suppressor Cells (MDSCs) in Graft-versus-Host Disease (GVHD)

Background: Myeloid-derived suppressor cells (MDSCs) are implicated in the complex interplay involving graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) in hematologic malignancies. Methods: A review of literature through PubMed was undertaken to summarize the published evidence on the pathophysiology and clinical implications of MDSCs in allo-HCT. Literature sources published in English since 1978 were searched, using the terms Natural Suppressor (NS) cells, MDSCs, GVHD, and allo-HCT. Results: In vivo studies demonstrated that MDSCs derived from mobilization protocols could strongly suppress allo-responses mediated by T cells and enhance T-Reg activity, thus inhibiting GVHD toxicity. However, the influence of MDSCs on the GVL effect is not fully defined. Conclusions: The induction or maintenance of MDSC suppressive function would be advantageous in suppressing inflammation associated with GVHD. Pathways involved in MDSC metabolism and the inflammasome signaling are a promising field of study to elucidate the function of MDSCs in the pathogenesis of GVHD and translate these findings to a clinical setting.

Morpho functional changes in thymus of white rats in acute stress

In the thymus of animals subjected to acute stress, a decrease in lymphoid tissue was found, accompanied by the death of lymphocytes in the cortex and medulla. Acute stress leads to the appearance in the thymus of a large number of degranulating mast cells and actively functioning epithelial tubules. Psychological stress has great impacts on the immune system, particularly the leukocytes distribution. Although the impacts of acute stress on blood leukocytes distribution are well studied, however, it remains unclear how chronic stress affects leukocytes distribution in peripheral circulation. Furthermore, there is no report about the role of spleen in the blood leukocytes distribution induced by stress. Here we show that spleen contributes to the alteration of restraint stress induced blood leukocytes distribution. Our data confirmed that restraint stress induced anxiety-like behavior in mice. Furthermore, we found that restraint stress decreased the CD4/CD8 ratio and elevated the percentages of natural killer cells, monocots and polymorph nuclear myeloid-derived suppressor cell. We demonstrated that activation of hypothalamic-pituitary-adrenal axis (HPA) and sympathetic nervous system (SNS) contributes to restraint stress induced alteration of blood leukocyte distribution. Interestingly, we found that splenectomy could reverse the change of CD4/CD8 ratio induced by restraint stress. Together, our findings suggest that activation of HPA axis and SNS was responsible for the blood leukocyte subsets changes induced by restraint stress. Spleen, at least in part, contributed to the alteration in peripheral circulation induced by restraint stress.

A Preemptive Behaviour-based Malware Detection through Analysis of API Calls Sequence Inspired by Human Immune System

This study detects malware as it begins to execute and propose a data mining approach for malware detection using sequences of API calls in a Windows environment. We begin with some background of the study and the influence of Human Immune System in our detection mechanism, i.e. the Natural Killer (NK) and Suppressor (S) Cells. We apply the K = 10 crosses fold data validation against the dataset. We use the n-grams technique to form the data for the purpose of establishing the Knowledge Bases and for the detection stage. The detection algorithm integrates the NK and S to work in unison and statistically determine on whether a particular executable deemed as benign or malicious. The results show that we could preemptively detect malware and benign programs at the very early beginning of their execution upon inspecting the first few hundreds of the targeted API Calls. Depending on the speed of the processor and the ongoing running processes, this could just happen in a split of a second or a few. This research is as part of our initiative to build a behaviour based component of a cyber defence and this will enhance our readiness to combat zero-day attacks.

Toll-like receptor\xa02 induced cytotoxic T-lymphocyte-associated protein\xa04 regulates Aspergillus-induced regulatory T-cells with pro-inflammatory characteristics

Patients with cystic fibrosis, chronic obstructive pulmonary disease, severe asthma, pre-existing pulmonary lesions, and severely immunocompromised patients are susceptible to develop infections with the opportunistic pathogenic fungus Aspergillus fumigatus, called aspergillosis. Infections in these patients are associated with persistent pro-inflammatory T-helper (TH)2 and TH17 responses. Regulatory T-cells, natural suppressor cells of the immune system, control pro-inflammatory T-cell responses, but can also contribute to disease by shifting to a pro-inflammatory TH17-like phenotype. Such a shift could play an important role in the detrimental immunopathology that is seen in aspergillosis. Our study demonstrates that Aspergillus fumigatus induces regulatory T-cells with a TH17-like phenotype. We also demonstrate that these regulatory T-cells with a pro-inflammatory TH17-like phenotype can be reprogrammed to their “classical” anti-inflammatory phenotype by activating Toll-like receptor 2 (TLR2), which regulates the induction of cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Similarly, soluble CTLA4 could reverse the pro-inflammatory phenotype of Aspergillus-induced regulatory T-cells. In conclusion, our results suggest a role for regulatory T-cells with a pro-inflammatory TH17-like phenotype in Aspergillus-associated immunopathology, and identifies key players, i.e. TLR2 and CTLA4, involved in this mechanism.

Abstract LB-192: Phenotyping human myeloid derived suppressor cells (MDSC) subsets

Abstract MDSCs are heterogeneous occurring at varying stages of commitment and differentiation. They increase in cancer and other patients with inflammatory diseases and may best be defined based on their ability to suppress T and B cell responses. In recent years these cells have demonstrated clinical relevance, including a negative correlation with prognosis and overall survival in cancer patients increasing with tumor progression and stage. MDSCs were originally described in mice based on a lack of phenotypic markers, i.e. null cells, or predicated on their function, as natural suppressor (NS) cells. Subsequently they were found in humans, based on CD34 expression supporting a hematopoietic progenitor phenotype. The identification of human phenotype(s) is complicated by the association of suppressor cell function with multiple phenotypes. This includes two main subsets defined based on the expression or lack of myeloid and lymphoid markers, with specific phenotypes extent investigator dependent. There is a consensus that MDSCs constitute a continuum of immature to differentiated myeloid cells ranging from multi-potential hematopoietic progenitors to morphologically differentiated granulocytic and monocytic leukocytes. One trending hypothesis is that MDSC phenotypes form three subsets include macrophage (M-) MDSCs with a monocytic morphology, expressing CD14 and no CD15 or CD66b and granulocytic (G)-MDSCs phenotypically characterized by CD15 and/or CD66B expression and no CD14; and an immature (i-) MDSC defined as linage negative, CD33+ cells. Unfortunately, there is no consensus on markers extent to CD14 and CD15 although linage negative and DR- provide a common theme; although not commonly utilized between laboratories and MDSC subset. We provide herein a Flow cytometric strategy utilizing single staining tube and a linear phenotypic characterization that is supported by density and T-cell suppression confirmation. We suggest that staining with Lin, HLA-DR, CD14, CD15, CD11b, CD33 antibodies provides sufficient markers to subset into the three MDSC phenotypes that can be further subset with CD16. PDL1 and CD34 expression. Interestingly the majority of iMDSC express CD34 on the CD33+ cells together with CD14 or CD15 supporting a plastic phenotype with myeloid commitment. All subset can be further, delineated based on CD16 expression further suggesting immaturity. We will note, that some cancer patients express these cell phenotypes at very high levels in the circulation; although the preponderance of G-MDSC vs M-MDSC varies between patients. Citation Format: James E. Talmadge, Holly Britton, Alicia Dafferner, Phyllis Warkentin, Kathryn Cole. Phenotyping human myeloid derived suppressor cells (MDSC) subsets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-192. doi:10.1158/1538-7445.AM2017-LB-192

Abstract 3242: In depth myeloid cell characterization in the murine syngeneic CT26 colon carcinoma model by 10 color flow cytometry

Abstract The efficacy of immune-modulating anti-cancer therapeutic antibodies that have been FDA-approved in recent years, such as anti-CTLA-4 and anti-PD-1, has driven growing interest in methods that provide a mechanistic understanding of drug function. Development of new mono- and combination therapies with immune-modulatory effects requires more powerful immunophenotyping techniques capable of in depth cell characterization. To this end, using the CT26 murine syngeneic colorectal cancer model we have developed a 10 color flow cytometry antibody panel that focuses on the identification of tumor-infiltrating immune cell subsets derived from myeloid lineage precursors utilizing the high-throughput-capable 4-laser, 14-color Attune NxT Flow Cytometer with autosampler. The panel includes a combination of antibodies against CD45, CD3, CD19, CD49b, CD335, CD11b, CD11c, Ly-6G, Ly-6C, F4/80, and CD115. By excluding cells of lymphoid lineage, we show that this panel facilitates analysis of myeloid derived cells including natural killer (NK) cells, macrophages, neutrophils, dendritic cells (DCs), and monocytic or granulocytic myeloid-derived suppressor cell (mMDSCs and gMDSCs) subsets in tumor and peripheral blood. In addition, this combination of antibodies allows for a more complete analysis of MDSCs which can differentially express several disease-relevant myeloid specific markers including Ly-6G, Ly-6C, F4/80, CD11c, and CD115. In the tumor, the Ly-6G-high population demonstrates differential expression of Ly-6C, 21% Ly-6C-high (granulocytes) and 77% Ly-6C-low (mMDSCs). The majority of the granulocytic population was identified as gMDSCs and the remainder as neutrophils based on CD115 expression. Macrophages constitute 27% of Ly-6G-low cells. In blood, 98% of the Ly-6G-high population was also Ly-6C-high, and this population is predominantly neutrophils. No macrophages (Ly6G-low and F4/80+) were identified in the peripheral blood. These data confirm the expected distribution of myeloid lineages in the tissue types investigated. Finally, we show that the accuracy of analysis is enhanced by the use of fluorescence minus-one (FMO) controls to identify those markers that generate dim signals, as well as a viability dye used to exclude dead cells from analysis. Identification of additional potentially responsive immune compartments will facilitate identification and development of potential combination therapies otherwise overlooked by looking primarily at T-cells. This panel allows for a significant expansion of our ability to provide a complex description of the myeloid subset. Citation Format: Matt Thayer, David Draper, Daniel Saims, Maryland Rosenfeld-Franklin, Scott C. Wise. In depth myeloid cell characterization in the murine syngeneic CT26 colon carcinoma model by 10 color flow cytometry. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3242.

Natural suppressor cells; past, present and future

Myeloid Derived Suppressor Cells (MDSCs) are a mixed group of bone marrow-derived myeloid cells containing macrophages, granulocytes, immature DCs and early myeloid precursors that have immune suppressive activity. MDSCs infiltrate the BM, spleen and peripheral blood of tumors-bearing experimental animals and are found in the blood of cancer patients as a result of tumor-induced alterations in myelopoiesis. Evidence from murine model systems indicated that myeloid-derived cells with suppressor activity also accumulate in non-tumor bearing hosts in response to infection, chemotherapy, stress, and immune senescence. MDSCs are considered key negative regulators of immune responses. Their association with tumor-associated immune defects make MDSCs an attractive target for therapeutic intervention in cancer.

Natural suppressor cells past present and future

Myeloid Derived Suppressor Cells (MDSCs) are a mixed group of bone marrow-derived myeloid cells containing macrophages, granulocytes, immature DCs and early myeloid precursors that have immune suppressive activity. MDSCs infiltrate the BM, spleen and peripheral blood of tumors-bearing experimental animals and are found in the blood of cancer patients as a result of tumor-induced alterations in myelopoiesis. Evidence from murine model systems indicated that myeloid-derived cells with suppressor activity also accumulate in non-tumor bearing hosts in response to infection, chemotherapy, stress, and immune senescence. MDSCs are considered key negative regulators of immune responses. Their association with tumor-associated immune defects make MDSCs an attractive target for therapeutic intervention in cancer.

The Future of Stem Cell Transplantation in Autoimmune Disease

We have previously found that conventional allogeneic bone marrow transplantation (allo BMT) can be used to treat various spontaneously developed autoimmune diseases in mice. In addition, we have found that autoimmune diseases can be transferred into the normal mice by conventional BMT from autoimmune-prone mice. Based on these findings, we have proposed that autoimmune diseases are "stem cell disorders." To apply allo BMT to humans, we extensively carried out BMT to clarify which cells are essential for successful BMT, and finally found that three types of cells are essential for successful allogeneic BMT: (1) hemopoietic stem cells (HSCs), (2) natural suppressor cells, and (3) stromal cells (including mesenchymal stem cells, MSCs). We have very recently found that MSCs play a crucial role in preventing graft failure, since there is a major histocompatibility complex restriction between HSCs and MSCs. To recruit donor-derived MSCs, we have found that the injection of whole bone marrow cells into the bone marrow cavity (intra-bone marrow-BMT, IBM-BMT) is the best strategy for the treatment of various otherwise intractable diseases, including autoimmune diseases. In this review article, we provide evidence that IBM-BMT heralds a revolution in the field of transplantation and regeneration medicine.

Prognostic value of FDG uptake by the bone marrow in squamous cell carcinoma of the head and neck

The appearance of natural suppressor cells and circulating endothelial progenitor cells in tumour tissue has been associated with myelopoetic stimulation by growth factors that may increase fluorodeoxyglucose (FDG) uptake by the bone marrow and high FDG uptake by bone marrow in patients suffering from human malignancies is a not uncommon finding. This study looked at the relationship between bone marrow FDG uptake, biochemical (Hb level, RBC count, WBC count and platelet count), clinical and radiological findings and outcome in a series of 35 patients suffering from squamous cell carcinoma of the head and neck (SCCHN), consecutively referred for FDG PET as part of their routine staging procedure. In SCCHN, mean FDG standardized uptake values (SUVs) of the primary tumour correlate significantly with blood WBC count (r=0.44; P=0.011, Bonferroni corrected P=0.04) and mean FDG SUVs of bone marrow are significantly correlated to the maximum FDG SUVs of the primary tumour (r=0.523; P=0.002). Finally, FDG uptake by the bone marrow is related to disease-free and overall survival. These findings warrant confirmation in a larger patient series.

The Influence of Alpha-fetoprotein on Natural Suppressor Cell Activity and Ehrlich Carcinoma Growth

The influence of alpha-fetoprotein (AFP) on the bone marrow (BM) natural suppressor (NS) cells of intact Ehrlich carcinoma -bearing CBA mice was studied. Bone marrow NS cells were fractionated into three fractions by isopycnic centrifugation on percoll gradients: NS1 (rho=1.080 g/ml), NS2 (rho=1.090 g/ml) and NS3 (1.100>rho>1.090 g/ml). These fractions were highly different in their sensitivity to known NS cell inductors (interleukin (IL)-2, IL-3 or histamine). None of the NS fractions isolated from the intact mice spontaneously produced antiproliferative activity, however, they showed a high level of NS (antiproliferative and natural killer cell inhibitory) activity under the influence of AFP. A single injection of AFP to intact mice led to an increase of spontaneous NS activity and the inhibition of natural killer cell activity. NS activity, especially NS2, was increased in when tumor cells were subcutaneously inoculated three days after AFP injection. In the AFP-treated mice, the tumor mass at 14 days was 60% larger than that in the untreated mice. Our data confirmed that AFP is a tumor marker that can inhibit cancer immunity and plays a role in cancer pathogenesis.

Effects of natural suppressor cells on production of Th1 and Th2 cytokines and proliferation of polarized T cells

Natural suppressor cells from the bone marrow of intact animals and mice with Th1- and Th2-dependent immune response largely suppressed the production of Th1 (IFN-gamma, IL-2) and Th2 cytokines (IL-4). Antiproliferative activity of natural suppressor cells from intact and immunized animals was mediated by NO. Proliferation of Th1 cells was suppressed greater than that of Th2 cells. This selective effect of natural suppressor cells on the proliferation of target lymphocytes was due to higher stimulatory potential of Th1 cells (in comparison with Th2) towards natural suppressor cells.

Peptide‐Based Instruction of Suppressor Commitment in Naïve T Cells and Dynamics of Immunosuppression in vivo

Recent years have witnessed the revival of suppressor T cells that control immunity by interfering with the generation of effector T-cell function in vivo. The discovery that CD4 T cells with the CD25 surface marker were enriched in suppressor activity enabled further phenotypic and functional analysis of the so-called natural suppressor cells. In vitro characterization showed that these cells were anergic, i.e. did not respond to antigenic stimulation with proliferation and, instead they suppressed other cells through direct cell contact resulting in inhibition of interleukin-2 gene transcription. We have analysed the generation and function of suppressor T cells in T-cell receptor (TCR) transgenic mice. The results showed that such cells can be generated intrathymically when agonist TCR ligands are expressed on thymic epithelial cells. Thus generated cells constitute a lineage of cells committed to suppression only with the ability to survive for prolonged periods of time in the absence of the inducing ligand. Because of appropriate homing receptors such cells can accumulate and proliferate in antigen draining lymphnodes after antigenic stimulation and suppress proliferation and cytokine secretion of CD4 and CD8 T cells as well as CD8 T-cell-mediated cytotoxicity. We also attempted to generate such cells from naïve T cells in secondary lymphoid tissue under conditions where expansion of already preformed suppressor T cells could be excluded. The results showed that subimmunogenic peptide delivery by osmotic minipumps or by peptide containing DEC 205 antibodies yielded CD25+ suppressor cells that were phenotypically and functionally indistinguishable from intrathymically generated suppressor cells. The experiments with DEC205 antibodies revealed (i) dose-dependent proliferation of naïve T cells and (ii) conversion into suppressor T cells of only those T cells that underwent a limited number of cell divisions. These results are compatible with other studies that were, however, less rigorous in excluding expansion of existing cells as opposed to de novo generation of suppressor cells from naïve T cells. The fact that natural suppressor cells have an essential role in preventing autoimmunity and that they can be specifically induced by TCR agonist ligands opens new perspectives in preventing autoimmunity, transplant rejection and allergy.

Mechanism of Antitumor Activity of Bone Marrow Natural Suppressor Cells

Co-culturing of P-815 tumor cell strain and intact mouse bone marrow cells nonadherent to plastic resulted in the appearance of soluble mediators with antitumor activity. Bone marrow cells start releasing these antiproliferative factors only after signal exchange with the target tumor cells. The cell-cell contact is an important factor for the induction of antitumor activity. Antitumor activity of bone marrow cells (similarly as immunosuppressive activity) is realized through suppressor factors; the appearance of these factors is induced by target tumor cells.

Injection of the immuno-modulatory drug α-galactosylceramide results in the recruitment of a large population of antigen-presenting cells into the liver of C57BL/6 mice

Injection of the immuno-modulatory drug α-galactosylceramide into C57BL/6 mice leads to the already known apoptosis of natural killer T (NKT) cells and to thus far undescribed large changes in the leukocyte populations of the liver. These changes are characterized by the recruitment of neutrophils and that of a population of large monocytic cells. The latter cells display the morphological and immunological features of natural suppressor cells. Their recruitment in the liver depends on the presence of NKT cells, most probably through the local release of cytokines and chemokines by activated NKT cells. We discuss the ubiquitous, long-term effects of α-galactosylceramide injection on immuno-pathological processes mediated through the NKT-triggered recruitment of a subset of large macrophages/monocytes.

Radiation damage and immune suppression in splenic mononuclear cell populations.

We have examined alterations in all of the major splenic mononuclear cell (SMNC) populations in C57B1/6 mice following whole-body irradiation (0-700 cGy) in order to determine which populations may play a role in active immune suppression and/or haematopoietic recovery. A protocol has been established for characterization and differentiation by flow cytometric analysis (FCA) of the major MNC populations in the mouse spleen: T lymphocytes (CD4+ and CD8+ cells), B lymphocytes, natural killer (NK) cells, and monocytes/macrophages. Ionizing radiation caused decreased spleen cellularity and decreased ability of surviving SMNC to respond to mitogen. FCA revealed alterations in the relative composition of the constituent splenic cell populations following irradiation, reflecting differential radiosensitivity, with selective enrichment of NK cells (seven-fold) and CD4+ T lymphocytes (three-fold). Enrichment developed during the 7-day post-irradiation period. In addition, some MNC became activated in a dose- and time-dependent fashion following whole-body irradiation, as indicated by expression of CD71, the transferrin receptor. These cells were CD34+ and Thy 1.2+, but were CD4- or CD8- as well as CD45- (B cell). The observed increase in NK cells corresponds with a previously reported increase in natural suppressor (NS) cells following total-lymphoid irradiation (TLI). The balance of recovery-inhibiting NK cells and recovery-enhancing CD4+ T lymphocytes following irradiation may reflect or influence the degree of haematopoietic recovery, and may provide an indication of the extent of damage (biological dosimetry).