Lymphocyte T-cell immunomodulator

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Lymphocyte T-cell immunomodulator (LTCI) is an immune regulating polypeptide, which is a potent regulator of CD-4 lymphocyte production and function. It increases lymphocyte numbers and interleukin-2 (IL-2) production in animals. It is extracted from bovine thymus.

Contents

History

Prior to 1960, the thymus gland, which lies in the cervical thoracic area, was thought to be of little importance. In adult animals, the thymus is almost non-existent because it atrophies as animals reach adulthood. It was observed, however, that when pre-adolescent animals are thymectomized, they experience a variety of maladies including increased incidence of infection, failure to grow, neuromuscular disorders, cancer, etc., collectively known as “wasting disease”. The greater susceptibility to infection was shown to be directly attributable to a dramatic decrease in peripheral blood lymphocytes in thymectomized animals.

By 1964 it had been demonstrated that regulatory factors extracted from the thymus gland could prevent many of the manifestations of wasting disease. [1] [2] This suggested that the thymus produces substances important in the development of immunity. It was not until 1971 that it was discovered that thymus-derived lymphocytes (T-cells) were important regulators of bone-marrow-derived antibody-producing lymphocytes (B-cells). After the discovery that the thymus was producing profound regulatory factors, several groups of scientists began trying to extract and purify this factor from thymus glands in much the same manner that insulin was prepared from the pancreas for therapeutic use in diabetes. The difficulty was that the thymus is a very small gland and produces very small quantities of the factor. Thus, purification techniques did not allow appropriate pure fractions to be produced in sufficient quantities.

Thymus is a preferred tissue for viral replication of feline immunodeficiency virus, which results in lesions and dysfunction. [3]

In 1983 scientists succeeded in cloning epithelial cell lines from the thymus of various species and began to biochemically and biologically characterize these thymus derived regulatory factors. [4] A protein with a molecular weight of about 50,000 daltons was subsequently described and shown to augment the immune responses of both immature and mature T-cells. [5] This protein came to be known as lymphocyte T-cell immunomodulator.

Production and identity

Lymphocyte T-cell immunomodulator, or T-4 immune stimulating factor (TISF), [6] is a single chain polypeptide that is a strongly cationic glycoprotein and is purified with cation exchange resin. Purification of protein from bovine-derived type II thymic epithelial cell supernatants produces a substantially homogeneous factor, free of extraneous materials. The bovine protein is homologous with other mammalian species and is a homogeneous 50 kDa glycoprotein with an isoelectric point of 6.5. The protein is prepared in a lyophilized 1 microgram dose. Reconstitution in sterile diluent produces a solution for subcutaneous injection. [5]

It is unknown what LTCI is in terms of its sequence. It is not interleukins 1-7 nor G-CSF. The manufacturer verifies its potency by checking for stimulation of IL-2 production. [7]

Mechanism of action

Generally, a proportion of immature thymus-derived lymphocytes differentiate into mature CD4+ T-cells which produce a certain amount of cytokines, such as interleukin-2 (IL-2) and gamma interferon. To attack tumor cells and viruses, CD-4 cells coordinate the overall immune response and help activate CD8 T-lymphocytes. Often called “effector” or “cytotoxic” T-cells, CD-8+ T-lymphocytes they respond to intracellular pathogens and cancer cells. Under viral attack CD-4+ T-cells fail to mature, fail to produce IL-2 and gamma interferon, and consequently fail to coordinate CD-8 responses to viruses. LTCI increases the production of CD-4+ T-cells and can subsequently overcome this immunosuppression. [5]

Veterinary uses

Viral diseases in cats

LTCI, manufactured by T-Cyte Therapeutics, has been conditionally approved by the United States Department of Agriculture (USDA) as an aid in the treatment of cats infected with feline leukemia virus (FeLV) and/or feline immunodeficiency virus (FIV), and the associated symptoms of lymphopenia, opportunistic infection, anemia, granulocytopenia, or thrombocytopenia. [8]

Peer-reviewed literature disputes the benefit claims from the manufacturer. T-Cyte data as of 2011 does not strongly support the medication's ability to significantly increase the length or quality of life of treated cats. [7]

Canine osteoarthritis

LTCI increases the immune response to foreign antigens and dampens the immune-mediated response to self-antigens by increasing the number of precursors of a regulatory T-Cell population. In a double-blind placebo-controlled study, 11 of the 12 LTCI-treated canines had a 40 percent increase in function while the placebo group had a 17 percent decrease in function. [9] Following the study, LTCI was approved by the USDA to treat osteoarthritis in dogs in 2016. [10]

Related Research Articles

Immune system Biological system protecting an organism against disease

The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

Retrovirus Family of viruses

A retrovirus is a type of virus that inserts a copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus.

Thymus Endocrine gland

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or T cells mature. T cells are critical to the adaptive immune system, where the body adapts specifically to foreign invaders. The thymus is located in the upper front part of the chest, in the anterior superior mediastinum, behind the sternum, and in front of the heart. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.

Cytokine Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research.

T cell Type of lymphocyte

A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

Cytotoxic T cell T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell is a T lymphocyte that kills cancer cells, cells that are infected, or cells that are damaged in other ways.

T helper cell Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system. As their name suggests, they "help" the activity of other immune cells by releasing cytokines, small protein mediators that alter the behavior of target cells that express receptors for those cytokines. These cells help to polarize the immune response into the appropriate kind depending on the nature of the immunological insult (virus vs. extracellular bacterium vs. intracellular bacterium vs. helminth vs. fungus vs. protist). They are generally considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils.

Immunosuppressive drug

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system.

Lymphocyte Subtype of white blood cell

A lymphocyte is a type of white blood cell in the immune system of jawed vertebrates. Lymphocytes include natural killer cells, T cells, and B cells. They are the main type of cell found in lymph, which prompted the name "lymphocyte".

<i>Feline immunodeficiency virus</i> Species of virus

Feline immunodeficiency virus (FIV) is a Lentivirus that affects cats worldwide, with 2.5% to 4.4% of felines being infected. FIV differs taxonomically from two other feline retroviruses, feline leukemia virus (FeLV) and feline foamy virus (FFV), and is more closely related to human immunodeficiency virus (HIV). Within FIV, five subtypes have been identified based on nucleotide sequence differences coding for the viral envelope (env) or polymerase (pol). FIV is the only non-primate lentivirus to cause an AIDS-like syndrome, but FIV is not typically fatal for cats, as they can live relatively healthily as carriers and transmitters of the disease for many years. A vaccine is available, although its efficacy remains uncertain. Cats will test positive for FIV antibodies after vaccination.

<i>Feline leukemia virus</i> Species of virus

Feline leukemia virus (FeLV) is a retrovirus that infects cats. FeLV can be transmitted from infected cats when the transfer of saliva or nasal secretions is involved. If not defeated by the animal's immune system, the virus weakens the cat's immune system which can lead to diseases which can be lethal. Because FeLV is cat-to-cat contagious, FeLV+ cats should only live with other FeLV+ cats.

The regulatory T cells, formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4 cells. Because effector T cells also express CD4 and CD25, Tregs are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine TGFβ is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg homeostasis.

This is a list of AIDS-related topics, many of which were originally taken from the public domain U.S. Department of Health Glossary of HIV/AIDS-Related Terms, 4th Edition.

Interleukin 7 Growth factor secreted by stromal cells in the bone marrow and thymus.

Interleukin 7 (IL-7) is a protein that in humans is encoded by the IL7 gene.

X-linked severe combined immunodeficiency Medical condition

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.

GPR15

GPR15 is a class A orphan G protein-coupled receptor. The GPR15 gene is localized at chromosome 3q11.2-q13.1. It is found in epithelial cells, synovial macrophages, endothelial cells and lymphocytes especially T cells. From the mRNA sequence a 40.8 kD molecular weight of GPR15 is proposed. In an epithelial tumour cell line (HT-29), however, a 36 kD band, composed of GPR15 and galactosyl ceramide, was detected. Protein expression in lymphocytes is strongly associated with hypomethylation of its gene.

The severe combined immunodeficiency (SCID) is a severe immunodeficiency genetic disorder that is characterized by the complete inability of the adaptive immune system to mount, coordinate, and sustain an appropriate immune response, usually due to absent or atypical T and B lymphocytes. In humans, SCID is colloquially known as "bubble boy" disease, as victims may require complete clinical isolation to prevent lethal infection from environmental microbes.

Nef (protein)

Nef is a small 27-35 kDa myristoylated protein encoded by primate lentiviruses. These include Human Immunodeficiency Viruses and Simian Immunodeficiency Virus (SIV). Nef localizes primarily to the cytoplasm but also partially to the Plasma membrane (PM) and is one of many pathogen-expressed proteins, known as virulence factors, which function to manipulate the host's cellular machinery and thus allow infection, survival or replication of the pathogen. Nef stands for "Negative Factor" and although it is often considered indispensable for HIV-1 replication, in infected hosts the viral protein markedly elevates viral titers.

Bovine immunodeficiency virus (BIV) is a retrovirus belonging to the genus Lentivirus. It is similar to the human immunodeficiency virus (HIV) and infects cattle. The cells primarily infected are lymphocytes and monocytes/macrophages.

Mice with severe combined immunodeficiency (SCIDs) are often used in the research of human disease. Human immune cells are used to develop human lymphoid organs within these immunodeficient mice, and many different types of SCID mouse models have been developed. These mice allow researchers to study the human immune system and human disease in a small animal model.

References

  1. ↑ Asanuma Y, Goldstein AL, White A (March 1970). "Reduction in the incidence of wasting disease in neonatally thymectomized CBA-W mice by the injection of thymosin". Endocrinology. 86 (3): 600–10. doi:10.1210/endo-86-3-600. PMID   4391388.
  2. ↑ Stutman O, Yunis EJ, Martinez C, Good RA (January 1967). "Reversal of post-thymectomy wasting disease in mice by multiple thymus grafts". Journal of Immunology. 98 (1): 79–87. PMID   6018772.
  3. ↑ Woo JC, Dean GA, Pedersen NC, Moore PF (November 1997). "Immunopathologic changes in the thymus during the acute stage of experimentally induced feline immunodeficiency virus infection in juvenile cats". Journal of Virology. 71 (11): 8632–41. doi:10.1128/JVI.71.11.8632-8641.1997. PMC   192327 . PMID   9343221.
  4. ↑ Beardsley TR, Pierschbacher M, Wetzel GD, Hays EF (October 1983). "Induction of T-cell maturation by a cloned line of thymic epithelium (TEPI)". Proceedings of the National Academy of Sciences of the United States of America. 80 (19): 6005–9. Bibcode:1983PNAS...80.6005B. doi: 10.1073/pnas.80.19.6005 . PMC   534348 . PMID   6604278.
  5. 1 2 3 US 7196060,Beardsley TR,"Method to enhance hematopoiesis."
  6. ↑ "Immune-enhancing agent for therapeutic use in immunocompromised hosts (US5616554A)". Google Patent. 26 July 1994. Retrieved 4 March 2020.
  7. 1 2 Gingerich D (1 January 2008). "Lymphocyte T-cell immunomodulator (LTCI): Review of the Immunopharmacology of a new Veterinary Biologic" (PDF). International Journal of Applied Research in Veterinary Medicine. 6: 61–68.
  8. ↑ "Feline Immunodeficincy Virus Treatment with Lymphocyte T-Cell Immunomodulator". Vetinfo. Retrieved 18 November 2016.
  9. ↑ "Lymphocyte T-Cell Immunomodulator (LTCI), a Potent Immune Modulating Biologic, Exhibits Safety and Efficacy in the Pain Management of Dogs with Moderate-Severe Osteoarthritis" . Retrieved 18 November 2016.
  10. ↑ "T-Cyte Launches First USDA-Approved Treatment Aid for Canine Osteoarthritis". Marketwired. Retrieved 18 November 2016.
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