Lymphocyte T-Cell Immune Modulator
Encyclopedia
Lymphocyte T-Cell Immune Modulator (LTCI, Lymphocyte T-Cell Immunomodulator) is an immune regulating polypeptide manufactured by T-Cyte Therapeutics and distributed by ProLabs Animal Health. Lymphocyte T-Cell Immune Modulator is a potent regulator of CD-4 lymphocyte
production and function. It has been shown to increase lymphocyte numbers and Interleukin-2 (IL-2) production in animals.
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. 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.
In veterinary medicine, wasting syndrome is also recognized and is thought to be associated with infectious canine hepatitis
virus infection, feline infectious peritonitis
virus infection , and feline leukemia virus infections . In cases of feline infectious peritonitis
, necrotizing lesions in the thymus is often a consequence of early stages of the disease
. Additionally, the thymus is a preferred tissue for viral replication of feline immunodeficiency virus
, which results in lesions and dysfunction .
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 . 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. This protein came to be known as Lymphocyte T-Cell Immunomodulator (LTCI).
” or “cytotoxic” T-cells, because 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. Because LTCI increases the production of CD-4+ T-cells, this immunosuppression
can be overcome by treatment.
Because of its action on CD4+ T-cells, LTCI also promotes hematopoiesis. It is hypothesized that CD4+ T-cells may regulate the production of all blood cell types in the bone marrow
, including red blood cells, platelets, and granulocytes. A deficiency in CD-4+ T-cells thus could lead to the anemia
observed in immune compromised subjects including cancer patients undergoing chemotherapy
, or viral or other chemically induced conditions.
In summary, the primary action of LTCI is directed toward the mature T lymphocyte production and activation, resulting in increased production of IL-2 and interferon
in physiological amounts and ratios. These cytokines stimulate a cascade of events that enhance or potentiate both cell mediated immunity as well as antibody
-mediated responses.
, and is purified with cation exchange resin. Purification of protein from bovine-derived stromal 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.
(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
.
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
production and function. It has been shown to increase lymphocyte numbers and Interleukin-2 (IL-2) production in animals.
Discovery and Characterization
Prior to 1960 the thymus gland, which lies in the cervical thoracic area, was thought to be of little importance. In adult animals the thymusThymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
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
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
, failure to grow, neuromuscular disorders, cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, 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. This suggested that the thymus produces substances important in the development of immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
. It was not until 1971 that it was discovered that thymus-derived lymphocytes (T-cells) were important regulators of bone-marrow-derived antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
-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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
was prepared from the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
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.
In veterinary medicine, wasting syndrome is also recognized and is thought to be associated with infectious canine hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
virus infection, feline infectious peritonitis
Feline infectious peritonitis
Feline infectious peritonitis is a fatal incurable disease that affects cats. It is believed by some to be caused by Feline Infectious Peritonitis Virus , which is a mutation of Feline Enteric Coronavirus - . Although there appears to be a connection between FIP and feline coronavirus, no clear...
virus infection , and feline leukemia virus infections . In cases of feline infectious peritonitis
Feline infectious peritonitis
Feline infectious peritonitis is a fatal incurable disease that affects cats. It is believed by some to be caused by Feline Infectious Peritonitis Virus , which is a mutation of Feline Enteric Coronavirus - . Although there appears to be a connection between FIP and feline coronavirus, no clear...
, necrotizing lesions in the thymus is often a consequence of early stages of the disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
. Additionally, the thymus is a preferred tissue for viral replication of feline immunodeficiency virus
Feline immunodeficiency virus
Feline immunodeficiency virus is a lentivirus that affects domesticated housecats worldwide and is the causative agent of feline AIDS. From 2.5% up to 4.4% of cats worldwide are infected with FIV...
, which results in lesions and dysfunction .
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 . 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. This protein came to be known as Lymphocyte T-Cell Immunomodulator (LTCI).
Biological Properties
Normally a proportion of immature thymus-derived lymphocytes differentiate into mature CD-4+ T-cells which produce a number of cytokines, including interleukin-2 (IL-2) and gamma interferon. CD-4 cells coordinate the overall immune response and help activate CD-8 T-lymphocytes, which attack viruses and tumor cells. CD-8+ T-lymphocytes are often called “effectorEffector
Effector may refer to:*An actuator, in robotics*Effector , a music album by the Experimental Techno group Download*Effector cell, a type of lymphocyte in immunology...
” or “cytotoxic” T-cells, because 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
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
, and consequently fail to coordinate CD-8 responses to viruses. Because LTCI increases the production of CD-4+ T-cells, this immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
can be overcome by treatment.
Because of its action on CD4+ T-cells, LTCI also promotes hematopoiesis. It is hypothesized that CD4+ T-cells may regulate the production of all blood cell types in the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
, including red blood cells, platelets, and granulocytes. A deficiency in CD-4+ T-cells thus could lead to the anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
observed in immune compromised subjects including cancer patients undergoing chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, or viral or other chemically induced conditions.
In summary, the primary action of LTCI is directed toward the mature T lymphocyte production and activation, resulting in increased production of IL-2 and interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
in physiological amounts and ratios. These cytokines stimulate a cascade of events that enhance or potentiate both cell mediated immunity as well as antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
-mediated responses.
Biochemical Properties
Lymphocyte T-Cell Immune Modulator is a single chain polypeptide. It is a strongly cationic glycoproteinGlycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
, and is purified with cation exchange resin. Purification of protein from bovine-derived stromal cell
Stromal cell
In cell biology, stromal cells are connective tissue cells of any organ, for example in the uterine mucosa , prostate, bone marrow, and the ovary. They are cells that support the function of the parenchymal cells of that organ...
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
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
is prepared in a lyophilized 1 microgram dose. Reconstitution in sterile diluent produces a solution for subcutaneous injection.
Uses in Veterinary Medicine
LTCI is manufactured by T-Cyte Therapeutics, Inc. and distributed exclusively by ProLabs Animal Health, a division of AgriLabs, LTD. LTCI has been conditionally approved by the United States Department of AgricultureUnited States Department of Agriculture
The United States Department of Agriculture is the United States federal executive department responsible for developing and executing U.S. federal government policy on farming, agriculture, and food...
(USDA) as an aid in the treatment of cats infected with feline leukemia virus
Feline leukemia virus
Feline leukemia virus is a retrovirus that infects cats. FeLV can be transmitted between infected cats when the transfer of saliva or nasal secretions is involved. If not defeated by the animal’s immune system, the virus can be lethal...
(FeLV) and/or feline immunodeficiency virus
Feline immunodeficiency virus
Feline immunodeficiency virus is a lentivirus that affects domesticated housecats worldwide and is the causative agent of feline AIDS. From 2.5% up to 4.4% of cats worldwide are infected with FIV...
(FIV), and the associated symptoms of lymphopenia, opportunistic infection
Opportunistic infection
An opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system...
, anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, granulocytopenia, or thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
.