Discovery and Characterization
Prior to 1960, the thymus gland was thought to be of little importance. In adult animals, the thymus is almost nonexistent 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 these factors 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 these factors. Thus, purification techniques did not allow appropriate pure fractions to be produced in sufficient quantities.
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 was assigned the true name Lymphocyte T-Cell Immunomodulator (LTCI) by the USDA.
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 “effector” 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 now well established that CD4+ T-cells 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 leads to the anemia observed in immunocompromised subjects including cancer patients undergoing chemotherapy, or viral or other chemically induced conditions.
In summary, the primary action of LTCI is directed toward the production and activation of mature T-lymphocytes, 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.
Lymphocyte T-Cell Immunomodulator is a single chain polypeptide. It is a strongly cationic glycoprotein, 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.