Methods of boosting thymic regeneration in patients suffering from a thymic injury by using rankl

Abstract

Cytoablative treatments lead to severe damages on thymic epithelial cells (TECs), which result in delayed de novo thymopoiesis and a prolonged period of T-cell immunodeficiency. Understanding the mechanisms that govern thymic regeneration is of paramount interest for the recovery of a functional immune system notably after bone marrow transplantation (BMT). Here, the inventors show that administration of RANK ligand (RANKL) after total body irradiation and BMT boosts thymic regeneration. Notably, this treatment is also beneficial upon BMT in aged individuals. The inventors show that RANKL can improve thymopoiesis in aged individuals affected by thymic involution. Finally, the inventors show that RANK receptor is conserved in the human thymus. Accordingly, one aspect of the present invention relates to a method of boosting thymic regeneration in a patient suffering from a thymic injury comprising administering to the subject a therapeutically effective amount of a RANKL polypeptide.

1 . A method of boosting thymic regeneration in a patient suffering from a thymic injury comprising administering to the patient a therapeutically effective amount of a RANKL polypeptide. 
     
     
         2 . The method of  claim 1  wherein the thymic injury results from cytoablative therapy, complications related to HIV/AIDS, aging process, malnutrition, and radiation poisoning due to nuclear disaster. 
     
     
         3 . The method of  claim 1  wherein the patient is selected from the group consisting of children, young adults, middle aged adults, and elderly adults. 
     
     
         4 . The method of  claim 1  wherein the patient suffers from a cancer and has undergone a cytoablative therapy which caused thymic injury. 
     
     
         5 . The method of  claim 4  wherein the cytoablative therapy is radiotherapy or chemotherapy. 
     
     
         6 . The method of  claim 4  wherein the administration of the RANKL polypeptide is performed after bone marrow transplantation. 
     
     
         7 . The method of  claim 1  wherein the RANKL polypeptide is a polypeptide comprising an amino acid sequence having at least 80% of identity with SEQ ID NO:1 or SEQ ID NO:2. 
     
     
         8 . The method of  claim 1  wherein the RANKL polypeptide is fused to an immunoglobulin domain to form an immunoadhesin. 
     
     
         9 . The method of  claim 1  wherein the RANKL polypeptide is administered to the patient in combination with bisphosphonate to prevent bone resorption. 
     
     
         10 . The method of  claim 1 , wherein the thymic injury is due to cytoablative conditioning and the step of administering prevents immunodeficiency caused by the cytoablative conditioning. 
     
     
         11 . The method of  claim 1  wherein the thymic injury is thymic involution due to aging. 
     
     
         12 . A method for the prophylactic treatment of infectious diseases, autoimmunity or cancer relapse in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a RANKL polypeptide. 
     
     
         13 . The method according to  claim 1  wherein the patient is a human. 
     
     
         14 . The method of  claim 8 , wherein the immunoglobulin domain is a Fc region 
     
     
         15 . The method of  claim 12 , wherein the step of administering boosts or enhances long-term recovery of T-cell functions.