Combination Therapy of Acellular Pro-Tolerogenic and Pro-Inflammatory Preparations for Modulating the Immune System

Abstract

This disclosure relates to acellular-based therapies for modulating the level of regulatory T cells (Treg) and/or the level of pro-inflammatory T cells (Th17/Th1). To provide these therapeutic effects, a combination comprising at least one acellular pro-tolerogenic preparation and at least one acellular pro-inflammatory preparation are administered sequentially.

What is claimed is: 
     
         1 . A method of modulating a ratio of the level of regulatory T (Treg) cells to the level of pro-inflammatory T cells in a subject in need thereof, said method comprising administering a therapeutic amount of at least one acellular pro-inflammatory preparation to the subject having received a therapeutic amount of at least one acellular pro-tolerogenic preparation, wherein
 the at least one acellular pro-tolerogenic preparation is obtained by a first process comprising:
 (i) associating a low-immunogenic biocompatible polymer to a cytoplasmic membrane of a first leukocyte to obtain a first modified leukocyte; 
 (ii) contacting the first modified leukocyte with a second leukocyte under conditions to allow a pro-tolerogenic allo-recognition to provide a pro-tolerogenic conditioned preparation, wherein the first modified leukocyte is allogeneic to the second leukocyte; 
 (iii) removing the first modified leukocyte and the second leukocyte from the pro-tolerogenic conditioned preparation under conditions to inhibit RNA degradation so as to obtain a pro-tolerogenic composition enriched in acellular pro-tolerogenic components; and 
 (iv) formulating the pro-tolerogenic composition of step (iii), under conditions to inhibit RNA degradation, in the acellular pro-tolerogenic preparation for administration to the subject; and 
   the at least one pro-inflammatory preparation is obtained by a second process comprising:
 (a) contacting a third leukocyte with a fourth leukocyte under conditions to allow a pro-inflammatory allo-recognition to provide a pro-inflammatory conditioned preparation, wherein the third leukocyte is allogeneic to the fourth leukocyte; 
 (b) removing the third leukocyte and the fourth leukocyte from the pro-inflammatory conditioned preparation under conditions to inhibit RNA degradation so as to obtain a pro-inflammatory composition enriched in acellular pro-inflammatory components; and 
 (c) formulating the pro-inflammatory composition of step (b), under conditions to inhibit RNA degradation, in the acellular pro-inflammatory preparation for administration to the subject. 
   
     
     
         2 . The method of  claim 1 , further comprising identifying that the subject is need of a decrease of the ratio of the level of Treg cells to the level of pro-inflammatory T cells prior to the administration of the at least one acellular pro-inflammatory preparation. 
     
     
         3 . The method of  claim 2 , wherein the need for the decrease of the ratio is for treating, preventing and/or alleviating the symptoms associated with a condition caused or exacerbated by a reduced immune response in the subject. 
     
     
         4 . The method of  claim 3 , wherein the condition is a proliferation-associated disorder. 
     
     
         5 . The method of  claim 4 , wherein the proliferation-associated disorder is cancer. 
     
     
         6 . The method of  claim 3 , wherein the condition is an infection. 
     
     
         7 . The method of  claim 6 , wherein the infection is at least one of a parasitic infection, a viral infection, a bacterial infection and a fungal infection. 
     
     
         8 . The method of  claim 3 , wherein the condition is an immune response to a vaccine. 
     
     
         9 . The method of  claim 1 , further comprising administering to the subject a therapeutic amount of the at least one acellular pro-tolerogenic preparation prior to the administration of the therapeutic amount of the at least one acellular pro-inflammatory preparation. 
     
     
         10 . The method of  claim 9 , further comprising identifying that the subject is need of an increase of the ratio of the level of Treg cells to the level of pro-inflammatory T cells prior to the administration of the at least one acellular pro-tolerogenic preparation. 
     
     
         11 . The method of  claim 10 , wherein the need for the increase of the ratio is for treating, preventing and/or alleviating the symptoms associated to an auto-immune disease afflicting the subject. 
     
     
         12 . The method of  claim 11 , wherein the auto-immune disease is at least one of type I diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, immune thrombocytopenia, experimental autoimmune encephalomyelitis, autoimmune uveitis, inflammatory bowel disease, scleroderma and Crohn's disease. 
     
     
         13 . The method of  claim 10 , wherein the need for the increase of the ratio is for preventing or limiting the rejection of transplanted cells or tissue in the subject. 
     
     
         14 . The method of  claim 13 , wherein the transplanted cells or tissue are allogeneic or xenogeneic to the subject. 
     
     
         15 . A method of modulating a ratio of the level of regulatory T (Treg) cells to the level of pro-inflammatory T cells in a subject in need thereof, said method comprising administering a therapeutic amount of at least one acellular pro-tolerogenic preparation to the subject having received a therapeutic amount of at least one acellular pro-inflammatory preparation, wherein
 the at least one acellular pro-tolerogenic preparation is obtained by a first process comprising:
 (i) associating a low-immunogenic biocompatible polymer to a cytoplasmic membrane of a first leukocyte to obtain a first modified leukocyte; 
 (ii) contacting the first modified leukocyte with a second leukocyte under conditions to allow a pro-tolerogenic allo-recognition to provide a pro-tolerogenic conditioned preparation, wherein the first modified leukocyte is allogeneic to the second leukocyte; 
 (iii) removing the first modified leukocyte and the second leukocyte from the pro-tolerogenic conditioned preparation under conditions to inhibit RNA degradation so as to obtain a pro-tolerogenic composition enriched in acellular pro-tolerogenic components; and 
 (iv) formulating the pro-tolerogenic composition of step (iii), under conditions to inhibit RNA degradation, in the acellular pro-tolerogenic preparation for administration to the subject; and 
   the at least one pro-inflammatory preparation is obtained by a second process comprising:
 (a) contacting a third leukocyte with a fourth leukocyte under conditions to allow a pro-inflammatory allo-recognition to provide a pro-inflammatory conditioned preparation, wherein the third leukocyte is allogeneic to the fourth leukocyte; 
 (b) removing the third leukocyte and the fourth leukocyte from the pro-inflammatory conditioned preparation under conditions to inhibit RNA degradation so as to obtain a pro-inflammatory composition enriched in acellular pro-inflammatory components; and 
 (c) formulating the pro-inflammatory composition of step (b), under conditions to inhibit RNA degradation, in the acellular pro-inflammatory preparation for administration to the subject. 
   
     
     
         16 . The method of  claim 15 , further comprising identifying that the subject is need of an increase of the ratio of the level of Treg cells to the level of pro-inflammatory T cells prior to the administration of the at least one acellular pro-tolerogenic preparation. 
     
     
         17 . The method of  claim 16 , wherein the need for the increase of the ratio is for treating, preventing and/or alleviating the symptoms associated to an auto-immune disease afflicting the subject. 
     
     
         18 . The method of  claim 16 , wherein the need for the increase of the ratio is for preventing or limiting the rejection of transplanted cells or tissue in the subject. 
     
     
         19 . The method of  claim 15 , further comprising administering to the subject a therapeutic amount of the at least one acellular pro-inflammatory preparation prior to the administration of the therapeutic amount of the at least one acellular pro-tolerogenic preparation. 
     
     
         20 . The method of  claim 19 , further comprising identifying that the subject is need of a decrease of the ratio of the level of Treg cells to the level of pro-inflammatory T cells prior to the administration of the at least one acellular pro-inflammatory preparation. 
     
     
         21 . The method of  claim 20 , wherein the need for the decrease of the ratio is for treating, preventing and/or alleviating the symptoms associated with a condition caused or exacerbated by a reduced immune response in the subject.