Methods of treating autoimmune disease via CTLA-4Ig

Abstract

The method of immunotherapy of the present invention involves the regulation of the T cell immune response through the activation or suppression/inactivation of the CD28 pathway. Induction of activated T cell lymphokine production occurs upon stimulatory binding of the CD28 surface receptor molecule, even in the presence of conventional immunosuppressants. Inhibition of CD28 receptor binding to an appropriate stimulatory ligand or inactivation of the CD28 signal transduction pathway through other means down-regulates CD28-pathway related T cell lymphokine production and its resulting effects.

What is claimed is:  
     
         1 . A method of inhibiting CD28 pathway activation associated with an increase in cellular production of a T H CD28 lymphokine in a T cell population, wherein activation occurs by the binding of a stimulatory CD28 ligand to a CD28 receptor stimulatory binding site, the method comprising the steps of: 
 a) selecting an inhibitory ligand capable of binding to the stimulatory CD28 ligand;    b) providing the inhibitory ligand in a biologically compatible form; and    c) administering the inhibitory ligand to the population in an amount sufficient to bind and inhibit the stimulatory ligand from binding the CD28 receptor stimulatory binding site.    
     
     
         2 . The method of  claim 1 , wherein the stimulatory ligand comprises a natural CD28 ligand.  
     
     
         3 . The method of  claim 1 , wherein the inhibitory ligand comprises an antibody or fragment thereof to the stimulatory ligand.  
     
     
         4 . The method of  claim 1 , wherein the inhibitory ligand comprises a soluble form of CTLA-4.  
     
     
         5 . The method of  claim 4 , wherein the ligand comprises CTLA-4lg.  
     
     
         6 . The method of  claim 1 , wherein the inhibitory ligand is of synthetic origin.  
     
     
         7 . The method of  claim 1 , wherein the inhibitory ligand comprises a recombinant molecule.  
     
     
         8 . The method of  claim 1 , further comprising the step of: 
 d) administering a second inhibitory ligand capable of binding but not stimulating the CD28 receptor binding site.    
     
     
         9 . A method of suppressing the production of a T H CD28 lymphokine by a population of T cells, the method comprising the steps of: 
 a) administering an inhibitory ligand which binds a stimulatory ligand for CD28;    b) providing the ligand in biologically compatible form; and    c) administering the provided ligand in an amount sufficient to suppress production of the lymphokine in the population.    
     
     
         10 . The method of  claim 9 , wherein the inhibitory ligand comprises a soluble form of CTLA-4.  
     
     
         11 . The method of  claim 10 , wherein the inhibitory ligand comprises CTLA-4lg.  
     
     
         12 . The method of  claim 9 , wherein the T cell population is in a patient in an autoimmune state.  
     
     
         13 . A method of suppressing T H CD28 lymphokine production in a patient having a population of T cells, the method comprising the steps of: 
 a) providing an inhibitory ligand which binds a natural stimulatory ligand for CD28; and    b) administering the inhibitory ligand in a therapeutically effective amount to the population of T cells.    
     
     
         14 . The method of  claim 13 , wherein the administration of the ligand to the population of T cells is in vivo.  
     
     
         15 . The method of  claim 13 , wherein the administration of the ligand to the population of T cells is in vitro, and further comprising the step of: 
 d) introducing the population of T cells into the patient after administration.    
     
     
         16 . The method of  claim 15 , wherein the T cell population is removed from the patient prior to ligand administration.  
     
     
         17 . The method of  claim 13 , wherein the inhibitory ligand comprises a soluble form of CTLA-4.  
     
     
         18 . The method of  claim 17 , wherein the inhibitory ligand comprises CTLA-4lg.  
     
     
         19 . A method of treating an autoimmune disease in a patient comprising the steps of: 
 a) selecting an inhibitory ligand which binds a natural stimulatory ligand to CD28; and    b) administering atherapeutically effective amount of the ligand to the patient.    
     
     
         20 . The method of  claim 19 , wherein the stimulatory ligand is B7 and the inhibitory ligand comprises a soluble form of CTLA-4.  
     
     
         21 . The method of  claim 19 , wherein the inhibitory ligand comprises CTLA-4lg.  
     
     
         22 . The method of  claim 20 , wherein the administration is in vivo.  
     
     
         23 . The method of  claim 20 , wherein the administration is in vitro to a population of cells removed from the patient, and further comprising the step of: 
 c) reintroducing the cells to the patient after administration.    
     
     
         24 . The method of  claim 20 , wherein the autoimune disease is multiple sclerosis.