Lymphocyte T-Cell Immune Modulator

Lymphocyte T-Cell Immune Modulator (LTCI, Lymphocyte T-Cell Immunomodulator) is an immune regulating polypeptide. 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.

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 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. [Asanuma Y, Goldstein AL, White A. Reduction in the incidence of wasting disease in neonatally thymectomized CBA-W mice by the injection of thymosin. Endocrinology. 1970 Mar;86(3):600-10.] [Stutman O, Yunis EJ, Martinez C, Good RA. Reversal of post-thymectomy wasting disease in mice by multiple thymus grafts. J Immunol. 1967 Jan;98(1):79-87.] 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 [. Roth JA.; Possible association of thymus dysfunction with fading syndromes in puppies and kittens. Vet Clin North Am Small Anim Pract. 1987 May;17(3):603-16. ] , and feline leukemia virus infections [Tshikuka JG, Torres-Anjel MJ, Blenden DC, Elliott SC. The microepidemiology of wasting syndrome, a common link to diarrheal disease, cancer, rabies, animal models of AIDS, and HIV-AIDS YHAIDS). The feline leukemia virus and rabies virus models.Ann N Y Acad Sci. 1992 Jun 16;653:274-96.] . In cases of feline infectious peritonitis, necrotizing lesions in the thymus is often a consequence of early stages of the disease [Kipar A, Köhler K, Leukert W, Reinacher M. A comparison of lymphatic tissues from cats with spontaneous feline infectious peritonitis (FIP), cats with FIP virus infection but no FIP, and cats with no infection. J Comp Pathol. 2001 Aug-Oct;125(2-3):182-91. ] . Additionally, the thymus is a preferred tissue for viral replication of feline immunodeficiency virus, which results in lesions and dysfunction [Woo JC, Dean GA, Pedersen NC, Moore PF. Immunopathologic changes in the thymus during the acute stage of experimentally induced feline immunodeficiency virus infection in juvenile cats. J Virol. 1997 Nov;71(11):8632-41. ] .

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 [Beardsley, et al. "Induction of T-Cell Maturation by a Cloned Line of Thymic Epithelium (TEPI) Immunology 80: pp. 6005-6009, (Oct. 1983).] . 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 [Beardsley, Terry R. Patent # 7,196,060; Method to enhance hematopoiesis. [http://www.google.com/patents?id=wE1_AAAAEBAJ&dq=7,196,060] ] . 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 “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. [Beardsley, Terry R. Patent # 5,616,554; Immune-enhancing agent for therapeutic use in immunocompromised hosts. [http://www.google.com/patents?id=TXMbAAAAEBAJ&dq=5,616,554] ] 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.

Biochemical Properties

Lymphocyte T-Cell Immune Modulator 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. [Beardsley, Terry R. Patent # 7,196,060; Method to enhance hematopoiesis. [http://www.google.com/patents?id=wE1_AAAAEBAJ&dq=7,196,060] ]

Uses in Veterinary Medicine

LTCI is manufactured by T-Cyte Therapeutics, Inc. and is marketed by IMULAN BioTherapeutics, LLC. LTCI 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.

External links

* [http://www.imulan.com/felv-fiv-treatment.html Lymphocyte T-Cell Immunomodulator (LTCI)]
* [http://www.imulan.com/Resources/LTCI_Product_Brochure.pdf LTCI Treatment Aid for FIV/FeLV Infections]

References

1. Asanuma Y, Goldstein AL, White A. Reduction in the incidence of wasting disease in neonatally thymectomized CBA-W mice by the injection of thymosin. Endocrinology. 1970 Mar;86(3):600-10.

2. Stutman O, Yunis EJ, Martinez C, Good RA. Reversal of post-thymectomy wasting disease in mice by multiple thymus grafts. J Immunol. 1967 Jan;98(1):79-87.

3. Roth JA.; Possible association of thymus dysfunction with fading syndromes in puppies and kittens. Vet Clin North Am Small Anim Pract. 1987 May;17(3):603-16.

4. Tshikuka JG, Torres-Anjel MJ, Blenden DC, Elliott SC. The microepidemiology of wasting syndrome, a common link to diarrheal disease, cancer, rabies, animal models of AIDS, and HIV-AIDS YHAIDS). The feline leukemia virus and rabies virus models.Ann N Y Acad Sci. 1992 Jun 16;653:274-96.

5. Kipar A, Köhler K, Leukert W, Reinacher M. A comparison of lymphatic tissues from cats with spontaneous feline infectious peritonitis (FIP), cats with FIP virus infection but no FIP, and cats with no infection. J Comp Pathol. 2001 Aug-Oct;125(2-3):182-91.

6. Woo JC, Dean GA, Pedersen NC, Moore PF. Immunopathologic changes in the thymus during the acute stage of experimentally induced feline immunodeficiency virus infection in juvenile cats. J Virol. 1997 Nov;71(11):8632-41.

7. Beardsley, et al. "Induction of T-Cell Maturation by a Cloned Line of Thymic Epithelium (TEPI) Immunology 80: pp. 6005-6009, (Oct. 1983).

8. Beardsley, Terry R. Patent # 7,196,060; Method to enhance hematopoiesis.
* [http://www.google.com/patents?id=wE1_AAAAEBAJ&dq=7,196,060]

9. Beardsley, Terry R. Patent # 5,616,554; Immune-enhancing agent for therapeutic use in immunocompromised hosts.
* [http://www.google.com/patents?id=TXMbAAAAEBAJ&dq=5,616,554]