Yasuo Yagi

Protective activity of thymosin against opportunistic infections in animal models

SummaryAnimal models for opportunistic infections were developed by using mice immunosuppressed by 5-FU. These mice were susceptible to various microorganisms, while normal mice had greater tolerance to such microbial infections. In these models, thymosin α1 was found to protect mice against lethal infections with Candida albicans, Listeria monocytogenes, Pseudomonas aeruginosa, and Serratia marcescens when it was administered during 5-FU treatment prior to the infections. Thymosin α1 was effective in some infections at 0.4–400 μg/kg/day IP, about 1/100 of the dose required for thymosin fraction 5. Activity was also demonstrated against L-monocytogenes and Ps. aeruginosa by counting the viable bacteria in the liver after infection. The protective activity against Candida, elimination of which macrophages were essential, was abrogated by anti-thymocyte serum and/or carrageenan, indicating that thymosin α1 serves to maintain the functions of macrophages by reducing the damage to T cells by 5-FU. On the other hand, the activity against Pseudomonas infection was not affected by anti-thymocyte serum or carrageenan. It is probable that thymosin α1 also exerts its effect on neutrophils without participation of T cells and macrophages.

Thymosin α1 restores NK-cell activity and prevents tumor progression in mice immunosuppressed by cytostatics or X-rays

SummaryThe effect of thymosin against tumor progression was examined in mice immunosuppressed by cytostatics or X-ray irradiation. When pretreated with cytostatic agents, such as 5-fluorouracil (5-FU) or BCNU, or by X-ray, and then inoculated with P388 or L1210 leukemias, mice died rapidly within a few days. In these systems, thymosin α1 given concomitantly with the cytostatic agents or after X-irradiation prevented rapid death and extended survival, although the mice eventually died with leukemia like normal mice inoculated with cells of the same tumor. Rapid death in the 5-FU-treated mice was also prevented by adoptive transfer of spleen cells from the donor mice if these had been treated with 5-FU plus thymosin α1, but not if they had received 5-FU alone. However, the restorative activity of the donor spleen cells was abrogated by treatment with anti-asialo GM1, but not by treatment with anti-Thy 1 or anti-mouse Ig serum, suggesting that the effector cells in the spleen are NK cells. In fact, thymosin α1, when given concomitantly with 5-FU or after X-irradiation, maintained the NK activity of spleen, which was damaged by treatment with 5-FU or X-irradiation alone. The present study indicates that thymosin α1 exerts a preventive activity against progression of leukemias at least in part through an effect on NK cells or their progenitor cells.

Thymosin α1 exerts protective effect against the 5-FU induced bone marrow toxicity

Abstract Thymosin α 1 was shown to prevent the 5-fluorouracil(5-FU)-induced bone marrow toxicity in BDF 1 mice, as determined by the cellularity, haemopoietic stem cells (CFU-s) and granulocyte-macrophage colony forming unit (GM-CFU). Furthermore, thymosin α 1 increased the levels of colony stimulating factor (CSF) in sera or in culture media of spleen cells derived from 5-FU-treated mice. The treatment of spleen cells with anti-Thy 1,2 antibody plus complement abolished completely the CSF production. The in vivo treatment of donor mice with anti-Thy 1,2 antibody following 5-FU abolished completely the capability of their bone marrow cells to save lethally irradiated recipients. Thymosin α 1 treatment prevented the damage by such combined treatment. The present study indicates that thymosin α 1 exerts its protective effect against the 5-FU-induced bone marrow toxicity, at least partially, through its effect on the maturation of immature T cells to functional T cells which produce various kinds of lymphokines including CSF.

Immunomodulating activity of thymosin fraction 5 and thymosin α1 in immunosuppressed mice

SummaryWe found that both thymosin from calf thymus and its constituent peptide α1 prepared by chemical synthesis restore cell-mediated immunity following its suppression in mice by injection of 5-FU. Conditions suitable for assessing the thymosin activity by means of footpad reaction were established in such immunosuppressed mice. In this new animal model, thymosin α1-peptide showed activity at a low dose of 5–50 μg/kg, which was 100–1,000 times less than that required for thymosin F-5 preparations.Further studies utilizing the adoptive transfer technique showed that α1-peptide corrects the 5-FU-induced suppression of mature T cells, transferring the DTH response as well as that of macrophage function responsible for the expression of footpad reaction. Furthermore, regeneration of lymph node and bone marrow cells as well as CFU-c (progenitor cells of macrophages and granulocytes) was enhanced by thymosin α1 in the 5-FU-treated mice. All these results indicate that thymosin α1 accelerates the replenishment and maturation of haematopoietic cells, including not only T cells but also macrophages, when they have been severely damaged by the 5-FU treatment.

Thymosin α1 enhances haemopoietic colony formation by stimulating the production of interleukin 3 in NU/NU mice

Abstract We have studied the action mechanism of thymosin α 1 in modulation of haemopoietic system. The present study demonstrated that thymosin α 1 enhanced the colony formation as determined by CFU-s, GM-CFU and T-CFU, as well as the production of IL-3, when administered twice a week for a total of six or twelve times into nu/nu mice. The incubation of bone marrow cells with thymosin α 1 in vitro did not cause an increase of CFU-s, in contrast to IL-3 which caused a marked increase of CFU-s during the incubation of 72 h. These experiments indicate that thymosin α 1 exerts its effect on colony formation of haemopoietic stem cells (CFU-s) indirectly through the enhancement of the IL-3 production. The present finding may support clinical applications of thymosin α 1 in a wide range, since IL-3 is known to be the growth factor for many kinds of haemopoietic precursor cells including not only CFU-s but also GM-CFU, BFU-E, Eos-CFU, Meg-CFU, Mast cells, Pre B-cells and Pre T-cells.

Protective Activity of Thymosin α1 Against Tumor Progression in Immunosuppressed Mice

Thymus gland has been shown to play an important role in the development, growth and function of lymphoid systems through a hormonal mechanism. One of the thymic hormones, thymosin (1), stimulates T cell development and corrects some immunodeficiency diseases resulting from lack of thymus functions. Considering the importance of T cells in immunoregulatory systems, thymosin is expected to be useful as a pharmaceutical agent for a variety of diseases which are caused by or which accompany the aberration of these systems.

Efficacy of Thymosin α1 in Animal Models

The thymus gland produces many factors which are known to play a major role in the differentiation and maturation of T cells (Trainin et al., 1983). Considering the importance of T cells in immunoregulatory systems, thymic factors are expected to be useful as pharmaceutical agents to counteract immunodeficiency states. Thymic factors have been given in many clinical instances and shown to improve immunodeficiency diseases, particularly those with congenital T-cell defects (Wara et al., 1975). However, their efficacy in patients with the secondary immunodeficiencies has not been fully investigated.