Modulated immunodominance therapy

Abstract

The invention involves generating a T cell response to subdominant antigens and using the cells to therapeutically change the cellular homeostasis and nature of the immune response. In a preferred embodiment, the cells are generated outside of the patient avoiding the influence of the patient's immunologic milieu. By stimulating and growing the T cells from a patient in a tissue culture to one or more subdominant antigens and the transplanting them into the patient, if enough cells are expanded and transplanted, the transplanted cells overwhelm the endogenous dominant T cells in the response to either break or induce immune tolerance or otherwise modify the immune response to the cells or organism expressing that antigen. When the memory cells are established they are then reflective of this new immunodominance hierarchy so that the desired therapeutic effect is long lasting. In effect, the transplantation exogenously generated T cells reactive to the subdominant antigens is recapitulating priming and rebalancing the patient's immune response to target previously subdominant antigens in the cells or organism to produce a therapeutic benefit.

1 . A method for suppressing an immune response in a patient, the method comprising the steps of:
 a. identifying a dominant and a subdominant antigen in a tissue of the patient;   b. producing a T cell population by cultivating ex vivo T cells capable of recognizing the dominant antigen or the subdominant antigen; and   c. treating the patient with an effective number of cultivated T cells from the population to alter an immunodominance hierarchy in the patient;
 whereby the immune response is suppressed in the patient. 
   
     
     
         2 . The method of  claim 1 , wherein the cultivated T cells are immunosuppressive T cells or regulatory T cells (Treg). 
     
     
         3 . The method of  claim 1 , wherein the immune response in the patient is an inflammation, an autoimmune reaction, an organ transplantation rejection, an allergy, an asthma or a graft versus host disease. 
     
     
         4 . The method of  claim 1 , wherein the dominant or the subdominant antigen is a viral antigen, a cancer related viral antigen, a bacterial antigen, a parasitic antigen, a transplantation rejection antigen, or an autoimmune disease related antigen. 
     
     
         5 . The method of  claim 1 , wherein step (b) further comprises:
 contacting human peripheral blood mononuclear cells (PBMC) ex vivo with a plurality of fragments of the dominant antigen or the subdominant antigen, the fragments representing in the aggregate the full length form of the dominant or the subdominant antigen;   
       contacting the PBMC with agents that expand antigen specific immuno-suppressive T cell growth, the agents comprising growth factors, hormones, inhibitors, cytokines, or any combination thereof to produce antigen specific immunosuppressive T cells;
 expanding the antigen specific immunosuppressive T cells in culture; and 
 enriching for the antigen specific immunosuppressive T cells in culture, 
 thereby producing a population of culture enriched, immunosuppressive T cells which are capable of recognizing the dominant or the subdominant antigen. 
 
     
     
         6 . The method of  claim 5 , wherein the cytokines comprise: IL-2 and IL-10;
 wherein the cytokines are added simultaneously or sequentially during the culture; and   wherein IL-2 is used at a concentration ranging between 2 and 1000 Units/ml.   
     
     
         7 . The method of  claim 5 , further comprising contacting the PBMC with one or more agents selected from the group consisting of: anti-CD23 antibody, anti-CD28 antibody, and rapamycin. 
     
     
         8 . The method of  claim 5 , wherein regulatory T cells are selected and isolated from the PBMC prior to contacting the PBMC with the dominant or the subdominant antigen fragments. 
     
     
         9 . The method of  claim 1 , wherein the T cell population is capable of recognizing more than one dominant or subdominant antigen. 
     
     
         10 . The method of  claim 1 , wherein the T cell population comprises CD4+ and CD8+ T cells. 
     
     
         11 . The method of  claim 1 , wherein the altered immunodominance hierarchy in the patient induces immunotolerance against the dominant antigen or the subdominant antigen in the patient, thereby suppressing the immune response and treating or preventing an autoimmune disease, an allergy, inflammation, organ transplantation rejection or graft versus host disease in the patient. 
     
     
         12 . The method of  claim 1 , wherein step (c) comprises administering the T cells via intradermal administration. 
     
     
         13 . The method of  claim 1 , wherein step (c) comprises administering the T cells via intravenous administration. 
     
     
         14 . The method of  claim 1 , further comprising, wherein at least 5% of the cultivated T cells in the population are capable of recognizing the dominant or the subdominant antigen prior to treating to the patient. 
     
     
         15 . The method of  claim 1 , further comprising confirming the expression of one or more immunosuppressive T cell markers in the cultivated T cell population prior to treating to the patient. 
     
     
         16 . The method of  claim 1 , further comprising profiling a humoral or a cellular immune response to the dominant antigen or the subdominant antigen in the patient after the T cell treatment to determine if the immunodominance hierarchy in the patient is successfully altered. 
     
     
         17 . A method of treating an inflammatory, an autoimmune, an allergic disease or disorder, an organ transplant rejection or graft versus host disease in a patient, the method comprising the steps of:
 contacting human PBMC ex vivo with a plurality of fragments of a dominant or a subdominant antigen, the fragments representing in the aggregate the full length dominant antigen form or the full length subdominant antigen form;   contacting the PBMC with agents that enrich immunosuppressive T cell growth, comprising growth factors, hormones, inhibitors, cytokines, IL-2, IL-10, anti-CD23 antibody, anti-CD28 antibody, rapamycin, or any combination thereof;   enriching for T cells capable of recognizing the dominant or the subdominant antigen to produce an antigen specific immunosuppressive T cell population;   administering to the patient an effective number of T cells from the population, to induce immunosuppression in the patient; and   verifying effective immunosuppression by profiling a humoral or a cellular immune response in the patient,   thereby treating the patient.   
     
     
         18 . The method of  claim 17 , wherein the T cell population is capable of recognizing an inflammation associated antigen. 
     
     
         19 . The method of  claim 17 , wherein the T cell population is capable of recognizing an autoimmunity associated antigen. 
     
     
         20 . The method of  claim 17 , wherein the T cell is capable of recognizing a transplantation rejection associated antigen or an allergic response associated antigen. 
     
     
         21 . The method of  claim 17 , wherein the patient is administered an effective number of immunosuppressive T cells more than once. 
     
     
         22 . The method of  claim 17 , wherein the step of enriching for the T cells capable of recognizing the dominant or the subdominant antigen further comprises sorting the immunosuppressive T cell population based on presence or absence of cell surface activation markers, and isolating an effective number of the T cells to induce immunosuppression in the patient into an isotonic buffer comprising a pharmaceutical composition suitable for intravenous administration to the patient.