Immune System

The immune system is the collection of cells, tissues and molecules that protects the body from pathogens and toxins in our environment, as well as against cancerous cells within our body.

It is divided into two general types of immune reactions, innate immunity and adaptive immunity.

The two differ with respect to how quickly and for how long they respond to pathogens, but are considered to be equally important parts of the immune system.

Foreign substances that are recognized by the immune system and induce an immune response are called antigens.

Innate Immunity

  • Innate immunity provides the early line of defense against pathogens.
  • It consists of cellular and biochemical defense mechanisms that exist even before infection and are designed to respond to infections rapidly, in matter of hours.
  • The components of the innate immunity recognize by specialized receptors (Pattern Recognition Receptor – PRR) structures that are common to groups of pathogens and not to specific microbes.

The principal components of innate immunity are:

  • Physical and chemical barriers, such as epithelia and  chemicals produced at epithelial surfaces.
  • Phagocytic cells (neutrophils, macrophages), dendritic cells, natural killer (NK) cells and other innate lymphoid cells.
  • Blood proteins, including the components of the complement system.

Adaptive Immunity

  • The adaptive immune system recognizes and reacts to a large number of organisms and substances.
  • A hallmark of adaptive immunity is its ability to specifically detect and respond more vigorously to repeated exposures of the same pathogen, known as memory.

The components of adaptive immunity are:

  1. T-cells (T-helper and cytotoxic-T cells)
  2. B-cells and the antibodies they secrete

There are two general responses of the adaptive immune system: humoral response, which is antibody-mediated B cell response, and cell-mediated T cell response.

Humoral Response

The humoral response defends against extracellular pathogens by binding to the pathogens and either directly neutralize them or making them easier targets for phagocytes and complement.

Cell-mediated immune response

The cell-mediated immune response defends against intracellular pathogens and cancerous cells.

Helper T cells play an important role in both responses.

Cooperation between the innate and adaptive immune systems

The members of both immune systems cooperate with each other to facilitate an effective immune response.

The adaptive-immune system requires members of the innate system, such as DCs and macrophages, to present antigens, in order to launch and direct its responses.

Phagocytes of the innate system recognize through their FC receptors antibodies bound to pathogens, enabling them to more efficiently identify and destroy pathogens.

In their turn, activated cells of the innate immune system secrete cytokines and growth factors that  support T cell responses.

Immunotherapy

Immunotherapy comprises a variety of treatments that use the power of the immune system to fight diseases, mainly cancer.

Below are some common type of immunotherapies:

  • Tumor Infiltrating Lymphocytes (TILs)
  • Chimeric Antigen Receptor (CAR) T- Cells therapy
  • Cytokine-induced killer (CIK) cells therapy
  • Natural Killer (NK) cells therapy
  • Dendritic Cell (DC) therapy
  • Immune Checkpoints therapy

Adoptive Cell Therapy (ACT)

ACT is a form of personalized immunotherapy, which utilizes naturally occurring, ex-vivo modulated and expanded, or genetically engineered, immune cells that are given to a patient to help the body to fight diseases such as cancer.

In autologous ACT the patients own cells are used as the source of the transplanted cells, while allogeneic transplant is performed with cells from a matched donor.

The advantage of using autologous ACT is minimizing the risk of rejection.

When the issue of rejection will be solved, allogeneic transplants will enable off-the-shelf ACT treatments.

ACT therapy methods include:

  • Tumor Infiltrating Lymphocytes (TILs)
  • Chimeric Antigen Receptor (CAR) T-cells
  • Cytokine Induced Killer (CIK) cells
  • Natural Killer (NK) cells  

Tumor Infiltrating Lymphocytes (TILs)

TILs are white blood cells that left the bloodstream and migrated towards and into a tumor. 

Various lymphocyte subsets, including T cells γδ T cells, B cells, NK cells, and NKT cells, infiltrate tumor tissues in variable quantities and play a key role in the regulation of antitumor immunity

Levels of TILs were found to significantly correlated with prognosis of several types of cancer.

TILs are used for the treatment of melanoma and other solid tumors.

CT scans of a woman with breast cancer before TIL therapy showing a lesion invading the chest wall and metastatic lesions in the liver.

Scans 14 months after TIL treatment show all lesions have disappeared.

Chimeric Antigen Receptors T- Cells  (CAR-T)

The CAR construct is composed of an  extracellular antigen-binding  domain, a transmembrane domain, and a cytoplasmic signaling domain.

Although resembling the TCR complex, CAR recognizes cell surface antigens based on the recognition  mechanism of a monoclonal  antibody, independently of HLA whereas, the TCR recognizes the epitope in the context of the specific HLA.

The total white blood cells are collected from the patient by Leukapheresis. T cells are separated from the other cells. The separated T cells are then activated. The activated T cells are genetically modified and expanded. After QC testing and preparatory chemotherapy returned to the patient.

 

Cytokine-induced killer (CIK) cells therapy

CIK cells are a heterogeneous subset of polyclonal natural killer (NK) and T cells, which are ex-vivo expanded and activated by cytokines and antibodies.

CIK cells possess potent non-MHC-restricted cytotoxicity against a variety of tumor target cells.

How do CIK cells kill tumor cells?

  • CIK cells release granules containing cytolytic proteins, such as perforin and granzyme, that destroy the tumor cells.
  • CIK cells release anti-tumor cytokines, such as IL-2, IL-6, TNF-α, IFN-gamma.
  • Activated CIK cells attach to the tumor cells and kill them by inducing apoptosis through the Fas/Fas ligand pathway.
  • CIK cells recognize through their FC receptor antibodies bound to tumor cells and kill the tumor by Antibody Dependent Cellular Cytotoxicity (ADCC)

Natural killer (NK) cells therapy

  • NK cells are lymphoid cells belonging to the innate immune system, which function as both killer cells and regulators of immune responses.
  • NK cells are educated to become self-tolerant by recognition of self MHC class I molecules.
  • NK cells express a variety of receptors that deliver either activating or inhibitory signals, and the relative balance of these signals controls NK cell activity.
  • NK cells are activated following the detection of abnormal and stressed cells.
  • NK cells activation triggers Perforin/Granzyme-induced cell lysis and the production of cytokines including IFN-γ and TNF-α, which allows NK cells to contribute also to the activation of the adaptive immune response.

a. A balance of activating and inhibitory signals regulates the tolerance of healthy, normal cells by NK cells.

b. Tumor cells that downregulate major histocompatibility complex (MHC) class I molecules are detected as ‘missing self’ and are lysed by NK cells.

c. Tumor cells overexpressing stress ligands are recognized by activating NK cell receptors, which override the inhibitory signals.

d. Tumor antigen-specific antibodies bind to CD16 (also known as FcγRIII) and elicit ADCC.

Dendritic Cell (DC) Therapy

Dendritic cells are innate immune cells who play and important role is the recognition, processing and presentation of foreign antigens to the T-cells in the effector arm of the adaptive immune system.

Although dendritic cell are potent antigen presenting cells, they are usually not  present in adequate numbers to allow a potent anti-tumor immune response.

T-cell stimulation and T helper cell polarization require three dendritic cell-derived signals.

Signal 1 is the antigen-specific signal that is mediated through the MHC class-II presenting processed antigen, after internalization through specialized pattern recognition receptors (PRRs), to the T-cell receptor (TCR).

Signal 2 is the co-stimulatory signal, mainly mediated by triggering of CD28 by CD80 and CD86 that are expressed by cells DCs after ligation of PRRs.

Signal 3 is the polarizing signal that is mediated by various factors, such as IL-12 and CCL2, that promote the development of TH1 or TH2 cells, respectively. The nature of signal 3 depends on the type of activation

Immune Checkpoints therapy

Immune responses are regulated by a balance between co-stimulatory and inhibitory signaling pathways which are stimulated by an assortment of receptors and their ligands.

They are crucial in maintaining self tolerance, preventing autoimmunity and controlling the duration and extent of the immune responses in order to minimize collateral tissue damage. The ability to shift the balance towards a desired response can offer a way to ameliorate a variety of diseases.

Immune checkpoints are inhibitory regulators of the immune system.

They can either compete and block activating signals or induce inhibitory signals.

These immune checkpoints are often overexpressed on tumor cells or on non-transformed cells within the tumor microenvironment which compromise the ability of the immune system to mount an effective anti-tumor response.

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