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Improvement of T cell mediated immunity

A cell and cell group technology, which can be used in medical preparations containing active ingredients, endocrine system diseases, peptide/protein components, etc., and can solve problems such as memory cell deviation

Inactive Publication Date: 2002-08-14
NORWOOD IMMUNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This is further exemplified by the recent work of Timm and Thoman (1999), who showed that although aged mice post-BMT CD4 + T cells regenerate, but they exhibit a bias toward memory cells due to an aging peripheral microenvironment and poor thymic production of naive T cells

Method used

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Examples

Experimental program
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Effect test

Embodiment Embodiment 1

[0071] EXAMPLES Example 1: Reversal of Age-Induced Thymic Atrophy Materials and Methods Animals

[0072] CBA / CAH and C57B16 / J male mice were obtained from CentralAnimal Services, Monash University, and housed under conventional conditions. Ages range from 4-6 weeks to 26 months and are indicated where relevant. castration

[0073] By intraperitoneal injection of 0.3 mL of 0.3 mg xylazine (Xylazine; BayerAustralia Ltd., Botany, New South Wales, Australia) and 1.5 mg of ketamine hydrochloride (Cordamine; Parke-Davis, Caringbah, New South Wales, Australia) Anesthetize the animal with a solution in saline. Surgical castration is performed by incision of the scrotum to expose the testes, which are ligated with sutures and then removed along with the surrounding fatty tissue. Bromodeoxyuridine (BrdU) introduction

[0074] Mice received two intraperitoneal injections (100 mg / kg body weight in 100 microliters of PBS) of BrdU (Sigma Chemical Co., St. Louis, MO) at 4 hour intervals....

Embodiment 2

[0105] Approximately 1% of T cells migrate out of the thymus per day in juvenile mice (Scollay et al., 1980). We found that, although significantly (p≤0.001) less in number, migration occurred at the same rate as normal juvenile mice at 14 months and even 2 years of age ( Figure 5 ). The CD4:CD8 ratio of newly migrated thymic cells increased from about 3:1 at 2 months to about 7:1 at 26 months. By 1 week post-castration, the number of cells migrating to the periphery increased significantly, while the overall migration rate remained unchanged at 1-1.5%. Example 2: Reversal of Chemotherapy or Radiation Induced Thymic Atrophy

[0106] Following radiation or cyclophosphamide treatment, the rate of thymus regeneration was significantly increased in castrated mice (one week before or on the day of treatment).

[0107] In the thymus, the structure of the irradiated mouse thymus was severely disrupted, accompanied by a decrease in rapidly dividing cells. Cortical collapse, remin...

Embodiment 3

[0110] Figure 9 To illustrate the use of chemical castration in promoting T cell regeneration compared to surgical castration. The kinetics of chemical castration are much slower than surgical castration, that is, it takes about 3 more weeks for mice to reduce their circulating steroid levels. However, chemical castration is still effective in regenerating the thymus, as Figure 9 shown. Example 3: Thymus regeneration following sex steroid suppression leads to restoration of deficient peripheral T cell function

[0111] To determine whether castration can enhance the immune response, herpes simplex virus (HSV) immunity was tested, as it allows the study of disease progression and the role of CTL (cytotoxic) T cells. Castrated mice had qualitatively and quantitatively improved reactivity to the virus. Mouse footpads were immunized and popliteal (draining) lymph nodes were analyzed on day 5 post immunization. Additionally, footpads were taken and homogenized to determine v...

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Abstract

The present invention provides a method of modifying the T-cell population makeup or increasing the number of T-cells in a subject having depressed or abnormal T-cell population or function, the method comprising disrupting sex steroid signalling to the thymus in the subject. The invention can be used to treat a subject suffering from a wide array of diseases, for example, cancer, HIV infection, autoimmunity and hypersensitivity. In addition, the present invention provides methods for enhancing an immune response to an antigen, treating an autoimmune disease, and decreasing a host-vs-graft reaction in a transplantation donor.

Description

field of invention [0001] The present invention relates to methods of altering the composition or increasing the number of T cell populations in patients with suppressed or abnormal T cell populations or functions. These methods include disrupting the patient's sex steroid signaling to the thymus. Background of the invention [0002] The thymus is largely influenced by its two-way communication with the neuroendocrine system (Kendall, 1988). Of particular importance is the interaction between the pituitary, adrenal, and gonads on thymic function, both trophic (TSH and GH) and atrophic (LH, FSH, and ACTH) (Kendall, 1988; Homo-Delarche, 1991). Indeed, one of the characteristic features of thymus physiology is a progressive decline in structure and function, which matches the increase in circulating sex steroid production during adolescence (Hirokawa and Makinodan, 1975; Tosi et al., 1982 and Hirokawa et al., 1994). The precise targets of the hormones and the mechanism by whi...

Claims

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Application Information

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IPC IPC(8): A61K31/167A61K31/445A61K38/00A61K38/04A61K39/00A61K38/09A61K39/39A61K45/00A61P5/02A61P5/24A61P15/00A61P31/18A61P35/00A61P37/04A61P37/06
CPCA61K38/09A61K39/39A61P15/00A61P31/18A61P35/00A61P37/04A61P37/06A61P5/02A61P5/24A61K38/00
Inventor 理查德·伦诺克斯·博伊德
Owner NORWOOD IMMUNOLOGY
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