Since the early days of modern medicine it has been known that transplantation of tissues from one individual to other results in immune rejection, except when performed between identical twins. Extensive research done in the past decades has uncovered that differences in protein sequences between individuals are the primary targets for the immune response against allogeneic (genetically non-identical) grafts. These molecules were subsequently defined as histocompatibility antigens as they determine whether implanted cells are accepted or rejected by the immune system. Today, the risk of organ rejection remains high despite efforts to match haplotypes of histocompatibility antigens as well as use of immunosuppressive therapies.

Human embryonic stem cells (hESCs) can be propagated in high numbers in vitro, and have the potential to differentiate into a myriad of cell the application of these cells for organ restoration is of particular importance due to limited availability of donated organs. However, it is unclear whether differentiated hESCs will be recognized by the immune system following implantation in humans. Therefore it is imperative to investigate the immune response against differentiated hESCs for successful clinical translation.

The purpose of this review is to describe the current knowledge of antigenicity and immunogenicity of hESCs and their derivatives. While antigenicity refers only to the capacity of cells to express histocompatibility antigens, immunogenicity is a broader term for the potential to elicit immune response through additional factors, such as co-stimulatory molecules. This review summarizes our current view of the histocompatibility antigens and immunomodulating molecules that are expressed on undifferentiated and differentiated hESCs (u/dhESCs). In addition, adaptive and innate immune processes that may develop against the cells following recognition of histocompatibility antigens will be discussed. As rejection processes could severely limit the use of hESC-derived transplants, multiple approaches are being developed to alleviate these risks. I will focus on techniques for derivation of isogenic (genetically identical) hESC lines and discuss the immunological benefits and remaining challenges for their potential application.

·               Expression of histocompatibility antigens on u/dhESCs

·               Expression of T-cell regulating signals in u/dhESCs

·               T-cell response against u/dhESCs measured by functional assays

·               Generation of patient-specific isogenic hESC lines

·               Evidence that malignant progenitor cells

·               Donor natural killer (NK) cells as mediators

·               Antigen processing and presentation

·               Nucleic Acid Sensing Pathways

An immunologist is a research scientist who investigates the immune system of vertebrates including the human immune system. Immunologists are also called as Allergists. Immunologists include research scientists who work in laboratories. Immunologists also include physicians who can treat patients with immune system disorders. Some immunologists are physician-scientists who combine laboratory research with patient care. They are specially trained to diagnose, treat and manage allergies, asthma and immunologic disorders including primary immunodeficiency disorders which may be very common to very rare.

Toxicologists study the safety and biological effects of drugs, chemicals, agents, and other substances on living organisms. They develop methods to determine harmful effects, the dosages that cause those effects, and safe exposure limits.

All living organisms are continuously exposed to substances that are capable of causing them harm. Most organisms protect themselves against such substances in more than one way with physical barriers, for example, or with chemicals that repel or kill invaders. Animals with backbones, called vertebrates, have these types of general protective mechanisms, but they also have a more advanced protective system called the immune system. The immune system is a complex network of organs containing cells that recognize foreign substances in the body and destroy them. It protects vertebrates against pathogens, or infectious agents, such as viruses, bacteria, fungi, and other parasites. The human immune system is the most complex. Although there are many potentially harmful pathogens, no pathogen can invade or attack all organisms because a pathogen's ability to cause harm requires a susceptible victim, and not all organisms are susceptible to the same pathogens. For instance, the virus that causes AIDS in humans does not infect animals such as dogs, cats, and mice. Similarly, humans are not susceptible to the viruses that cause canine distemper, feline leukaemia, and mouse pox.

Paediatric Immunology is the division of immunology which deals with the allergies or infectious diseases that affects the infant’s immune system. These are rare disorders in which part of the body’s immune system that protects us from infection is absent or does not function properly. Infants are considered to be immunologically “immature” but in fact they may have immune systems that are capable of mature responses but are actively suppressed. Understanding the infant immunology is more important in the development of the vaccines, for example, HIV Vaccines for infants. This type of disorders is specially treated by the Stem cell or bone marrow transplantation which replaces a faulty immune system with healthy cells. The treatment for the paediatric immunological disorders or allergies is supervised by the specially trained paediatric immunologists.

A pathogen is a microorganism that is able to cause disease in a plant, animal or insect. Pathogenicity is the ability to produce disease in a host organism. Microbes express their pathogenicity by means of their virulence, a term which refers to the degree of pathogenicity of the microbe. Hence, the determinants of virulence of a pathogen are any of its genetic or biochemical or structural features that enable it to produce disease in a host. The relationship between a host and a pathogen is dynamic, since each modifies the activities and functions of the other. The outcome of such a relationship depends on the virulence of the pathogen and the relative degree of resistance or susceptibility of the host, due mainly to the effectiveness of the host defence mechanisms. Bacterial infectivity results from a disturbance in the balance between bacterial virulence and host resistance. The “objective” of bacteria is to multiply rather than to cause disease; it is in the best interest of the bacteria not to kill the host. Numerous physical and chemical attributes of the host protect against bacterial infection. These defences include the antibacterial factors in secretions covering mucosal surfaces and rapid rate of replacement of skin and mucosal epithelial cells. Bacteria invading tissues encounter phagocytic cells that recognize them as foreign, and through a complex signalling mechanism involving interleukins, eicosanoids, and complement, mediate an inflammatory response in which many lymphoid cells participate.

Immunology is the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and disease; malfunctions of the immune system in immunological disorders (autoimmune diseases, hypersensitivities, immune deficiency, transplant rejection); the physical, chemical and physiological characteristics of the components of the immune system in vitro, in situ, and in vivo. Viruses are strongly immunogenic and induces 2 types of immune responses; humoral and cellular. The repertoire of specificities of T and B cells are formed by rearrangements and somatic mutations. T and B cells do not generally recognize the same epitopes present on the same virus. B cells see the free unaltered proteins in their native 3-D conformation whereas T cells usually see the Ag in a denatured form in conjunction with MHC molecules. The characteristics of the immune reaction to the same virus may differ in different individuals depending on their genetic constitutions.

·               Human and animal viral immunology

·               Immunological characterization of viral components

·               Pathogenic mechanisms

·               Virus-based immunological diseases, including autoimmune syndromes

·               Research and development of viral vaccines, including field trials

·               Viral diagnostics

·               Tumour and cancer immunology with virus as the primary factor

·               Viral immunology methods

·               EBOLA, FLU, HIV...

Basic Science research includes investigations of the innate and acquired immune systems, cancer immunology, immunology of infectious diseases and intracellular signalling mechanisms used by cells of the immune system, among others. Clinical Applications of Immunology are diverse, and Immunologic methods are used in the treatment and prevention of large number of immune-mediated diseases. Recent advances in Diagnostic Immunology, such as miniaturization, amplified immunoassays, use of monoclonal antibodies in Flow cytometry and immunofluorescence, and incorporation of molecular biology principles in immunological methods, has revolutionized the applicability and scope of immunological methods in multiple therapeutic areas, including, but not limited to, the immunologic aspects of a very broad range of human diseases, encompassing investigations in the fields of cancer and cancer therapeutics; transplantation of solid organs and stem cells; autoimmune diseases including endocrine diseases such as Type 1 diabetes, rheumatologic diseases including rheumatoid arthritis (RA) and systemic lupus erythematosis (SLE); pulmonary diseases including asthma and chronic obstructive pulmonary disease (COPD); neurologic diseases such as multiple sclerosis (MS); gastrointestinal diseases such as Crohn's disease, Celiac’s Disease, and Ulcerative Colitis (IBD); and many others.

Immunotherapy is the treatment or prevention of disease such as an autoimmune disorder, allergy or cancer that involves the stimulation, enhancement, suppression, or desensitization of the immune system. Immunotherapy is also called as biologic therapy. It stops the growth and spreading of the cancer cells in the body.

Immunopathology is the branch of biomedical science concerned with immune responses to disease, with immunodeficiency diseases, and with diseases caused by immune mechanisms. It is also referred as the structural and functional manifestations associated with immune responses to disease or with diseases caused by immune mechanisms.

Neuroimmunomodulation is the bidirectional signalling between the central nervous system (CNS) and the cells and organs of the immune system. The term Neuroimmunomodulation alludes to the adjusting part of the sensory system in connection to resistant capacities. This regulation reflects some portion of the bidirectional correspondence between the sensory system and the safe framework. Neuroimmunomodulation is conceivable because of presence of receptors for neurotransmitters (e.g., norepinephrine, acetylcholine) on insusceptible cells and because of innervation of lymph hubs by thoughtful sensory system (SNS) filaments.

Neuroimmunology, a branch of immunology that deals especially with the interrelationships of the nervous system and immune responses and autoimmune disorders. Its deals with particularly fundamental and applied neurobiology, neurology, neuropathology, neurochemistry, Neurovirology, neuroendocrinology, neuromuscular research, neuropharmacology and psychology, which involve either immunologic methodology (e.g. immunocytochemistry) or fundamental immunology (e.g. antibody and lymphocyte assays).

Toxicologic Pathology is identified with help improvement in the interdisciplinary participation of specialists working in pathology, toxicology free of the strategies connected. Toxicologic pathology is a biomedical strength that consolidates the exploration of toxicology and pathology. Both toxicology and pathology are basic segments of the security valuation technique utilized as a part of foreseeing human and creature reactions to drugs, chemicals including finding the capability of these operators to cause malignancy.
 

Immunomodulator is a substance that adjusts the safe reaction by increasing or lessening the capacity of the invulnerable framework to deliver antibodies or sharpened cells that perceive and respond with the antigen that started their creation. Immunomodulators incorporate corticosteroids, cytotoxic operators, thymosin, and immunoglobulin. Some immunomodulators are normally present in the body, and sure of these are accessible in pharmacological arrangements. Immunomodulators can be administered systemically, intralesionally or intra-dermally, and topically. Immunomodulators are most often used in organ transplantation to prevent rejection of the new organ, and in autoimmune diseases such as rheumatoid arthritis. An immunomodulator may be combined with a corticosteroid to speed up response during active flares of disease. Some of the immunomodulators include Betaseron, dimethyl fumarate, interferons, Purinethol, mercaptopurine, tocilizumab, Actemra.

Allergy occurs when a person's immune system reacts to substances in the environment that are harmless for most people. Allergy is also called as Hypersensitivity. Allergy-producing substances are known as allergens and are found in house dust mites, pets, pollen, insects, moulds, foods and some medicines. Allergy in children is common and becoming more complex, and many children suffer from more than one allergy. It is important that these allergies are carefully assessed and managed appropriately. We are developing a research programme to investigate these disorders. Allergy symptoms include itchy eyes and skin, sneezing, nasal congestion, wheezing, and rash. Allergies can range from minor to severe. Doctors use skin and blood tests to diagnose allergies. Treatments include medicines, allergy shots, and avoiding the substances that cause the reactions.

Autoimmune diseases are a broad range of related diseases in which a person’s immune system produces an inappropriate response against its own cells, tissues and/or organs, resulting in inflammation and damage. There are over 80 different autoimmune diseases, and these range from common to very rare diseases. Depending on the type, an autoimmune disease can affect one or many different types of body tissue. It can also cause abnormal organ growth and changes in organ function. There are many autoimmune disorders. Some of the more common autoimmune disorders include Grave’s disease, rheumatoid arthritis, Hashimoto thyroiditis, type 1 diabetes mellitus, systemic lupus erythematous (lupus), and vasculitis. Additional disorders that are believed to be autoimmune include Addison disease, polymyositis, Sjogren’s syndrome, progressive systemic sclerosis, many cases of glomerulonephritis (inflammation of the kidneys), and some cases of infertility. Symptoms vary depending on the disorder and the part of the body affected. Some autoimmune disorders affect certain types of tissue throughout the body—for example, blood vessels, cartilage, or skin. Other autoimmune disorders affect a particular organ. Virtually any organ, including the kidneys, lungs, heart, and brain, can be affected. The resulting inflammation and tissue damage can cause pain, deformed joints, weakness, jaundice, itching, difficulty breathing, accumulation of fluid (oedema), delirium, and even death. Since many autoimmune diseases share similar symptoms, diagnosis is often challenging. The diagnosis of autoimmune diseases differs based on the specific disease. Diseases can sometimes take years to diagnose because many symptoms of autoimmune disorders mimic other diseases. The treatment for the autoimmune disorders include the drugs that suppress the immune system, including corticosteroids and for some autoimmune disorders, plasma exchange and intravenous immune globulin .

Immunotoxicology is the study of immune dysfunction resulting from exposure of an organism to a xenobiotic. The immune dysfunction may take the form of immunosuppression or alternatively, allergy, autoimmunity or any number of inflammatory-based diseases or pathologies. Because the immune system plays a critical role in host resistance to disease as well as in normal homeostasis of an organism, identification of immunotoxic risk is significant in the protection of human, animal and wildlife health. This guidance makes recommendations to sponsors of investigational new drugs (INDs) on the parameters that should be routinely assessed in toxicology studies to determine effects of a drug on immune function. When additional immunotoxicity studies should be conducted. When additional mechanistic information could help characterize the significance of a given drug’s effect on the immune system. This guidance is intended for drug products and does not apply to biological products. 

Pharmacology is the study of how drugs affect the body and how the body affects drugs. Pharmacology is a branch of biomedical science, encompassing clinical pharmacology, which is concerned with the effects of drugs/pharmaceuticals and other xenobiotics on living systems, as well as their development and chemical properties. Pharmacology is often described as a bridge science because it incorporates knowledge and skills from a number of basic science disciplines including physiology, biochemistry and cell and molecular biology. Pharmacologists are able to 'translate' such knowledge into the rational development of therapeutics. As a result of their multidisciplinary training, pharmacologists are able to offer a unique perspective in solving drug, hormone and chemical-related problems. The principles of Pharmacology are pharmacodynamics and pharmacokinetics.

Verifiably, toxicological standards were discovered fundamentally in the fields of science and pharmacology. Today, toxicology incorporates more extensive and more various fields of concentrate, for example, biological community wellbeing, including water, air and soil quality, plant wellbeing, microorganisms, and bugs, manageable farming and human and creature wellbeing. The current acknowledgment that characteristic substances and in addition made chemicals display hazard to every single living life form and the earth, has duplicated the quantity of conceivably hurtful chemicals that should be inspected. The commitment that eating regimen, herbs and nutraceuticals may make to poisonous quality and wellbeing are being perceived. As of late, concern has been raised with respect to potential lethality of built nanoparticles and has brought about the new field of nanotoxicity.

The cellular receptor used by HIV in fusing with target cells has been identified. The natural ligand for the receptor is capable of blocking HIV transmission in vitro, implying a new. The subdivision of CD4, and now CD8, T lymphocytes into groupings on the basis of cytokine production is promoting a greater understanding of the role of these cells in allergy, autoimmunity and infection.  Immune regulation may depend heavily on killing activated T lymphocytes at the end of an inflammatory episode through the Fas and Fas ligand system. Transplant immunologists are looking to Fas as a way of protecting foreign grafts. The crystallisation of a complex of T cell receptor, peptide antigen, and molecule of the major histocompatibility complex has provided the best insight yet of how these molecules interact to achieve T-cell activation.

An antibody array is an analysis system for profiling protein expression in biological samples, and allows the comparison of the relative abundance of hundreds of proteins. It is also called as antibody microarray.  For detection of the specific antigens in complex samples, the specific antibodies are immobilized on a surface in a spatially addressable manner. The antibody arrays are used for

·         Qualitative protein expression profiling

·         Compare profiles of normal, diseased or treated samples

·         Measure phosphorylation changes at specific sites (Phospho Antibody Arrays)

·         Identify candidate biomarkers