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 T cell capable of recognizing a subdominant antigen or epitope in a patient for use in a method of altering the immunodominance hierarchy of the patient. 
     
     
         2 . A T cell for the use according to  claim 1 , wherein the T cell is obtained by:
 a. identifying at least one subdominant antigen or epitope in a sample obtained from the patient, and   b. cultivating a T cell capable of recognizing said subdominant antigen or epitope.   
     
     
         3 . A T cell for the use according to  claim 1 , wherein altering the immunodominance hierarchy treats, prevents, or alleviates an infection, cancer, inflammation, organ transplantation rejection, or graft versus host disease in the patient. 
     
     
         4 . Use of a T cell capable of recognizing a subdominant antigen or epitope in a patient in the manufacture of a medicament for altering the immunodominance hierarchy of the patient. 
     
     
         5 . A use according to  claim 4 , wherein the T cell is obtained by:
 a. identifying at least one subdominant antigen or epitope in a sample obtained from the patient, and   b. cultivating a T cell capable of recognizing said subdominant antigen or epitope.   
     
     
         6 . A use according to  claim 4 , wherein altering the immunodominance hierarchy treats/prevents/alleviates an infection, cancer, inflammation, organ transplantation rejection, or graft versus host disease in the patient. 
     
     
         7 . A T cell population for use in altering the immunodominance hierarchy of a patient obtainable by identifying at least one subdominant antigen or epitope in a sample obtained from the patient and cultivating a T cell population capable of recognizing said subdominant antigen or epitope. 
     
     
         8 . A T cell population according to  claim 7  for use in therapy. 
     
     
         9 . A method comprising the steps of:
 a. identifying a dominant antigen or epitope and a subdominant antigen or epitope in a patient sample;   b. cultivating a T cell capable of recognizing said subdominant antigen or epitope; and   c. treating a patient with an effective number of said T cell to alter the immunodominance hierarchy of the patient.   
     
     
         10 . A method comprising the steps of:
 a. identifying at least one subdominant antigen or epitope in a patient sample;   b. cultivating a T cell capable of recognizing said subdominant antigen or epitope; and   c. treating a patient with an effective number of said T cell to alter the immunodominance hierarchy of the patient.   
     
     
         11 . The method of  claim 9 , wherein said subdominant antigen or epitope are antigens or epitopes to which a cellular or humoral immune response is not detectable or is only detectable at a low level. 
     
     
         12 . The method of  claim 9 , wherein said subdominant antigen is a viral antigen, other infectious agent antigen, tumor antigen, or an antigen associated with autoimmunity, allergy, inflammation, organ transplantation rejection, or graft versus host disease. 
     
     
         13 . The method of  claim 9 , wherein step (b) further comprises cultivating a T cell in the absence of a dominant antigen or epitope. 
     
     
         14 . The method of  claim 9 , wherein step (b) further comprises cultivating a T cell in the presence or absence of agents to enrich either suppressive T cells or responsive T cells. 
     
     
         15 . The method of  claim 9 , wherein step (c) further comprises administering the effective number of T-cell via intradermal administration. 
     
     
         16 . The method of  claim 9 , further comprising a step prior to step (c), wherein the patient is pretreated with a conditioning agent to reduce the number of endogenous T cells. 
     
     
         17 . The method of  claim 9 , wherein said T cell is a suppressive T cell, and wherein step (c) further comprises inducing tolerance in the patient to treat or prevent an autoimmune disease, allergy, inflammation, organ transplantation rejection, or graft versus host disease. 
     
     
         18 . The method of  claim 9 , wherein said T cell is a responsive T cell, and wherein step (c) further comprises inducing a cytotoxic immune response to treat or prevent an infection or cancer. 
     
     
         19 . The method of  claim 9 , further comprising profiling the tolerance or humoral or cellular immune response to the subdominant antigen or epitope to determine if the therapy successfully rebalanced the immune response of the patient.