Immunodeficiencies

04.08.2023

Spirulina Lipopolysaccharides Inhibit Tumor Growth

Source: Oncology Reports; Authors: Hiromi Okuyama Akira Tominaga, z Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan

Spirulina lipopolysaccharides inhibit tumor growth in a Toll-like receptor 4-dependent manner by altering the cytokine milieu from interleukin-17/interleukin-23 to interferon-γ
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Spirulina lipopolysaccharides inhibit tumor growth in a Toll-like receptor 4-dependent manner by altering the cytokine milieu from interleukin-17/interleukin-23 to interferon-γ

Hiromi Okuyama Akira Tominaga Satoshi Fukuoka Takahiro Taguchi Yutaka Kusumoto Shiro Ono
Oncology Reports; 2017 Feb; 37(2): 684–694.

Abstract

Th17 cells and the cytokine they produce, interleukin (IL)-17, play an important role in tumor progression in humans and in mice. IL-6 and IL-23 are critical cytokines for the differentiation and propagation of Th17 cells, respectively. Bacterial lipopolysaccharides (LPS) are known to stimulate immune cells to produce such inflammatory cytokines. Contrary to Escherichia coli (E. coli) LPS, LPS from Spirulina has low toxicity and barely induces in vivo production of IL-6 and IL-23 in mice. We examined the antitumor effects of Spirulina LPS compared to E. coli LPS in an MH134 hepatoma model. Administration of Spirulina LPS suppressed tumor growth in C3H/HeN mice, but not in Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice, by reducing serum levels of IL-17 and IL-23, while increasing interferon (IFN)-γ levels. The antitumor activity and IFN-γ production were mediated by T cells. Moreover, in vitro experiments showed that Spirulina LPS impaired the antigen-presenting function that supports the generation of IL-17-producing cells in a toll-like receptor (TLR)4-dependent manner. Of note, injection of anti-IL-17 antibody in tumor-bearing C3H/HeN mice in the absence of Spirulina LPS markedly suppressed tumor growth and augmented IFN-γ responses. Thus, our results support the notion that IFN-γ and IL-17/IL-23 mutually regulate Th17 and Th1 responses in tumor-bearing hosts, and Spirulina LPS modulates the balance of the IFN-γ-IL-17/IL-23 axis towards IFN-γ production, which leads to tumor inhibition. Furthermore, Spirulina LPS effectively inhibited the spontaneous development of mammary tumors. This study has important implications for the exploitation of TLR-based immunomodulators for cancer immunotherapy.

Introduction

Although the immune system generally recognizes abnormal proteins on tumor cells as tumor antigens, spontaneous immune responses are too weak to suppress tumor growth. To overcome this problem, a variety of adjuvants, including toll-like receptor (TLR) ligands, are investigated to potentiate antitumor immunity. The bacillus Calmette-Guérin (BCG), historically known for its effective adjuvant properties, is often used in the treatment of cancer patients (1).

The innate immune system recognizes pathogen-associated molecular patterns expressed on microorganisms through corresponding TLRs, and the activation of innate immunity by TLRs produces proinflammatory cytokines such as interleukin (IL)-6 and IL-12, leading to the subsequent induction of adaptive immune responses (2,3). IL-12 is produced by macrophages (MΦ) and dendritic cells (DC) and dictates the differentiation of CD4 Th1 cells, which produce interferon (IFN)-γ and activate natural killer (NK) cells and cytotoxic CD8 T cells (4). IFN-γ plays an important role in the prevention of primary tumor development and intracellular pathogen invasion (5–7). Among the different TLR ligands, lipopolysaccharide (LPS) from gram-negative bacteria exhibits antitumor activity in addition to marked toxicity (8). The study of the bioactivity of LPS from various species revealed that LPS prepared from Bordetella pertussis and a synthetic analog of the LPS lipid A subunit are less toxic than E. coli LPS, and display antitumor effects (9,10).

Recent studies have revealed that IL-23/IL-17 signaling plays an important role in tumorigenesis and metastasis in humans and in mice (11–16). IL-17 is primarily produced by T cells and acts on tumor cells and tumor-associated stromal cells to induce angiogenesis and the production of IL-6, IL-8, and matrix metalloproteinases. IL-23 is produced by Mϕ/DC and facilitates the expansion and survival of IL-17-producing CD4 T (Th17) cells and therefore, the production of IL-17 (17,18). Moreover, it has become evident that a combination of IL-6 and transforming growth factor (TGF)-β induces Th17 differentiation from naive T cells (19,20). Since Mϕ/DC produces both antitumor (IL-12) and tumor-promoting (IL-6/IL-23) cytokines upon stimulation with TLR ligands (21,22), the regulation of this balance is critical for TLR-based cancer immunotherapy (17,18). Moreover, IL-17 stimulates tumor cells and tumor-surrounding cells to induce IL-6 expression, which in turn leads to the activation of signal transducer and activator of transcription 3 (STAT3) (16,23). STAT3 is linked to numerous oncogenic signaling pathways and is constitutively activated both in tumor cells and in immune cells under tumor microenvironment-like conditions. Thus, ideal candidate molecules for tumor immunotherapy are TLR-based immunomodulators that do not induce or partially induce IL-6/IL-23.

While exploring TLR4 responsiveness of the material extracted from algae and cyanobacteria (24), we found that LPS phenol-water extracts from Spirulina (Arthrospira) were able to induce IL-12. Noteworthy, Spirulina LPS showed a much lower in vitro induction of IL-6 and IL-23 by Mϕ/DC than E. coli LPS. Spirulina is a gram-negative, oxygenic, photosynthetic, filamentous cyanobacterium (blue-green alga), and since the Aztec civilization in Mexico, it has been widely used as a nutritional and therapeutic supplement (25). Spirulina LPS is reported to be less toxic compared to LPS from Salmonella abortus (26), but its effects on cytokine production or antitumor activities have not been studied extensively. Thus, it would be very interesting to study how Spirulina LPS affects tumor growth and in vivo production of inflammatory cytokines.

Although most experiments examined the in vitro production of IL-17-associated inflammatory cytokines thus far, the expression patterns of these cytokines in tumor host tissue remain to be established. We report here that Spirulina LPS did not induce or only partially induced IL-6 and IL-23 and efficiently suppressed the growth of hepatocellular carcinoma MH134 in a TLR4-dependent manner, by reducing the serum levels of IL-17 and IL-23, while increasing those of IFN-γ. Interestingly, anti-IL-17 monoclonal antibodies (mAb) clearly suppressed tumor growth as efficiently as Spirulina LPS. Furthermore, Spirulina LPS was quite effective in inhibiting spontaneous development of mammary tumors in an oncogene transgenic mouse model.

Hereinfater you will find link to the full paper.

Okuyama H, Tominaga A, Fukuoka S et al. Spirulina lipopolysaccharides inhibit tumor growth in a Toll-like receptor 4-dependent manner by altering the cytokine milieu from interleukin-17/interleukin-23 to interferon-γ Oncology Reports; 2017 Feb; 37(2): 684–694.

Secondary Immunodeficiencies

Otherwise known as acquired immunodeficiencies, they are much more common than primary immunodeficiencies. Secondary immunodeficiencies most often occur in diseases such as diabetes, sickle cell anaemia, rubella, leukaemia, chicken pox and various bacterial infections. The cause of secondary immunodeficiency can be malnutrition, surgery, burns or organ transplants and the administration of immunosuppressive drugs. Other causes can be diseases of the haematopoietic system, as well as autoimmune diseases. It can also be caused by HIV (Human Immunodeficieny Virus). AIDS, a disease caused by HIV, is also referred to as Acquired Immunodeficiency Syndrome. The result of HIV infection is a decrease in the number of lymphocyte-T cells, which makes the body more susceptible to diseases which, with normal immunity, pose no threat, but which can be fatal for HIV-positive people. Patients very often have atypical pneumonias, fungal infections, tumours and defects in the nervous system that eventually lead to death. Secondary immunodeficiencies are acquired and most often caused by iatrogenic disorders. The use of various immunosuppressive drugs, anti-cancer drugs or certain antibiotics further reduces immunity.

A number of situations in which immune disorders/deficiencies occur are summarised below.

Immune disorder of the elderly

Related to cellular immunity

  •   Gradual decline in the number of T lymphocytes after the age of 70
  •   An increase in the number of CD4 lymphocytes and a decrease in the number of CD8 lymphocytes
  •   Residual thymus function
  •   Increase in CD45RO expression, decrease in CD45RA expression
  •   Decrease in the expression of IL-2, IL-4 and INF-γ
  •   Weakening of the proliferative response of lymphocytes after stimulation with PHA and ConA
  •   Reducing the frequency of positive DTH reactions and weakening their intensity

Related to humoral immunity

  •   Decrease in IgM, IgE and IgD levels, increase in IgG levels
  •   Decrease in the titer of natural antibodies
  •   Increased titer of autoantibodies and anti-idiotypic antibodies
  •   Decrease in the number of CD5(-) B cells and increase in CD5(+) B cells after the age of 70
  •   Increased synthesis of IL-4, IL-5, IL-6, increased INF-γ activity

Immune disorders in renal failure

  •   Prolonged tolerance to allogeneic transplant
  •   Increased susceptibility to infections
  •   Increased cases of neoplasia
  •   Incorrect reaction to vaccines against viral infections (flu, hepatitis)

Immune disorders in uremia

  •   Chronic protein and calorie deficiency (insufficient supply, absorption disorders, excessive loss)
  •   Deficiencies of Zn, vitamins B6 and E
  •   Iron overload (ferritin over 500 mcg/l)
  •   Low- and high-molecular-weight uremic toxins
  •   Chronic dialysis therapy

Immune disfunction after surgery

  •   Occurrence of cutaneous anergy
  •   Decrease in IgG and IgM (preoperatively) against bacterial endotoxins
  •   A large decrease (>50%) in the number of lymphocytes on the 1st day after the procedure
  •   Increased neutrophil activity on the 1st - 2nd day
  •   Decrease (20-30%) of activated monocytes
  •   Increased IL-6 concentration

Drug-induced immune disorders

          After treatment with cytostatics

  •      Late neutropenia 35 – 45 days (irreversible damage to the myeloid stem cell)
  •      Early neutropenia 7 – 14 days (reversible damage to the myeloid stem cell)

          With other drugs - the drug (hapten) triggers abnormal destruction of granulocytes

          After long-term use of glucocorticosteroids - inhibition of granulocyte function

Effect of glucocorticosteroids

  •   Apoptosis of lymphocytes activated by allo- and autoantigens
  •   Reducing the expression of MCH antigens and adhesion molecules on cell surfaces
  •   Inhibition of nitric oxide synthase induction in macrophages
  •   Impaired function of cytotoxic lymphocytes and NK cells
  •   Inhibition of monocyte and macrophage functions

Infections complicating immunosuppressive treatment

  •   Cytomegalovirus (CMV) infection - in 80% of the population in youth it is asymptomatic, symptoms occur with reduced immunity
  •   Acute varicella zoster virus (VZV) infection
  •   Acute herpes virus infection (Herpes Simplex Virus – HSV)
  •   Tuberculosis and mycobacterioses
  •   Fungal infections (candida, cryptococcus, aspergillus)
  •   Pneumocystis pneumonia or PCP is a fungal infection

Stress and Immunity

Experimental studies on animals under stress show a decrease in cellular response indexes.

  •   Decrease in the number of lymphocytes
  •   Quantitative disorders of subpopulations
  •   Decrease in NK cell activity
  •   Decrease in the proliferative response to the antigen
  •   Phagocytosis disorders

Chronic stress → hypothalamus → pituitary gland → sympathetic system → ACTH, catecholamines, opioids → decreased IL2 production

Immune Disorders due to Ionising Radiation

  •   Total body irradiation = Total Lymphoid Irradiation
  •   The greatest excitability of dividing cells, e.g. lymphocytes stimulated by alloantigen
  •   Th lymphocytes more sensitive than Ts lymphocytes
  •   Macrophages and NK cells relatively resistant to irradiation

Immune disorders and certain cancers

The immune system performs immunological surveillance that prevents cancer by early detection and destruction of atypical cells. Immunosuppression and impaired immunity may lead to viral infections, which in turn may contribute to the development of a number of cancer diseases:

  •       Non-Hodgkin lymphomas (Epstein-Barr Virus – EBV)
  •       Kaposi sarcoma (human immunodeficiency virus – HIV)
  •       Skin cancer and rectal cancer (human papilloma virus – HPV)
  •       Primary liver cancer (hepatitis B virus – HBV)

Humoral Immune Disorders in the Course of Cancer

  •   Cytokines (mainly TGF-beta transforming growth factor) secreted by cancer cells (oat cell carcinoma, mesothelioma, Hodgkin's disease)
  •   Prostaglandins (mainly PGE2) secreted by macrophages (head and neck cancer)
  •   Gangliosides produced, i.a., by macrophages, erythrocytes, liver cells

Cellular Immune Disorders in the Course of Cancer

General:

  •   Reduction in the number of lymphocytes
  •   Decrease in the population of CD4 lymphocytes
  •   Decrease or reversal of CD4/CD8 ratio
  •   Weakened NK cells activity

Local (Cancer region, regional lymph nodes):

  •   Reduction in the number and dysfunction of mononuclear cells

Immune Disorders in the Course of Famine Disease

Fortunately, in our country and in Europe, hunger disease practically does not occur spontaneously. It may manifest itself in the course of other severe and long-term diseases, including: in the course of cancer, tuberculosis, pneumonia, severe diarrhea. Hunger disease is typical of war-affected regions and sub-Saharan Africa. In Europe in the 20th century, there were regions affected by famine, e.g. the great famine in Ukraine in 1932 - 1933, and famine in Nazi concentration camps or in the Nazi ghettos for Jews. In the course of starvation disease, a number of body disorders occur, including those in the immune system.

  •   Impaired cellular response
  •   Impaired phagocytosis
  •   Impaired production of cytokines, antibodies and complement system proteins
  •   Atrophy of the thymus and thymus-dependent lymph node zones

Other Secondary Immune Disorders

  •   In the course of infection (HIV, HTLV1 (Human T-cell Leukemia Virus), measles virus, tuberculosis
  •   Nutritional deficiencies (zinc, iron, vitamins A, E, B, folic acid)
  •       Endocrinopathy (hyperthyroidism, Cushing's disease, diabetes, hyperparathyroidism)
  •   Conditions after injuries, after extensive burns, deep hypothermia
  •   Protein loss (exudative enteropathies, nephrotic syndrome)
  •   Alcoholism, drug addiction

Structure of the Immune System

The immune system is a very complex structure consisting of cells, tissues and organs that work together to protect (defend) our body against "foreign" invaders . . .

How the Immune System Works?

It is one of nature's most fascinating inventions. It easily protects us against billions of bacteria, viruses and pathogens. We don't realize that the immune system . . .

Immunodeficiencies

Immunodeficiencies are disorders of the immune system that are characterized by a reduced or lack of ability to . . .

Maintain Healthy Immune System

If we are not dealing with an immune system disease, it is usually enough to use a few simple . . .

News

The European Medicines Agency (EMA) has approved gene therapy for the treatment of severe combined immunodeficiency due to adesine deaminase deficiency (ADA-SCID), which is the result of a genetic mutation - reports New Scientist. You can read about gene therapy, what it is and its prospects, on the website News Medical Life Sciencies

17.01.2024
COVID Impacts: Immune Dysfunction

Source: Memorial Sloan Kettering Cancer Center Library / LibGuides / COVID Impacts / Immune Dysfunction

Detailed information and resources on the long-term health consequences of COVID-19 infection and the broad social impacts of the COVID-19 pandemic.

One of the most concerning long-term effects of COVID-19 is the dysregulation and dysfunction of the immune system.

08.08.2023
Immunomodulating Effects of Fungal Beta-Glucans: From Traditional Use to Medicine

Source: Nutrients Authors: van Steenwijk H, Bast, A and de Boer A.

Beta-glucans derived from mushrooms are bioactive long-chain polysaccharide compounds, insoluble in water and with immunomodulatory properties. Knowledge of the action and functions of beta-glucans, which have been used in traditional medicine for centuries, is developing thanks to modern immunological and biotechnological methods.

04.08.2023
Spirulina Lipopolysaccharides Inhibit Tumor Growth

Source: Oncology Reports; Authors: Hiromi Okuyama Akira Tominaga, z Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan

Spirulina lipopolysaccharides inhibit tumor growth in a Toll-like receptor 4-dependent manner by altering the cytokine milieu from interleukin-17/interleukin-23 to interferon-γ