Methods of Treating Autoimmunity With Engineered HLA Proteins

Abstract

Methods of preventing or treating autoimmune disease are disclosed. In some cases, subjects with having or at risk of developing autoimmune disease are identified as possessing one or more autoimmunity-susceptibility HLA alleles at one or more HLA loci. In many cases, the HLA loci are selected from Class I and Class II loci, for example Class I A, B, and C, and Class II DQ, DR, and DP. In many cases, subjects suffering from or at risk of developing an autoimmune disease may be administered a plurality engineered autologous HSCs modified to carry and express a variant susceptibility allele having at least one mutation in the antigen binding cleft that alters antigen binding and/or specificity of that variant HLA molecule. In many embodiments, the engineered HSCs are CD34+ immune cells that express one or more modified HLA proteins.

What is claimed is: 
     
         1 . A method of treating a subject suffering from or at risk of developing an autoimmune disease, comprising:
 identifying a susceptible HLA allele of the subject, wherein the susceptible HLA allele is associated with susceptibility to the autoimmune disease;   isolating a plurality of CD34+ immune cells from the subject;   modifying the plurality of CD34+ immune cells to create a plurality of engineered CD34+ immune cells, wherein the engineered CD34+ immune cells do not express the susceptible HLA allele, and express an engineered HLA allele, wherein the engineered HLA allele differs from a HLA protein encoded for by the susceptible HLA allele by an identity of at least one target amino acid in an antigen binding cleft, and wherein the HLA protein encoded for by the engineered HLA allele possess altered binding affinity for at least one self-peptide as compared to a protein coded for by the susceptible HLA allele;   isolating the plurality of the engineered CD34+ immune cells; and   administering the plurality of isolated, engineered CD34+ immune cells to the subject; and thereby treating the subject suffering from or at risk of developing the autoimmune disease.   
     
     
         2 . The method of claim  claim 1 , wherein the target amino acid is not at the T-cell receptor binding interface. 
     
     
         3 . The method of claim  claim 2 , wherein the autoimmune disease is selected from celiac disease, Type 1 diabetes, rheumatoid arthritis, ankylosing spondylitis, and multiple sclerosis. 
     
     
         4 . The method of claim  claim 3 , wherein the HLA allele codes for HLA-A, HLA-B, or HLA-C. 
     
     
         5 . The method of claim  claim 4 , wherein the susceptible HLA allele is selected from A*02, A*03, and A*29. 
     
     
         6 . The method of claim  claim 5 , wherein the susceptible HLA allele is selected from A*02:01, A*03:01, and A*29:01. 
     
     
         7 . The method of claim  claim 4 , wherein the susceptible HLA allele is selected from B*07, B*08, B*27, B*51, B*54, and B*57. 
     
     
         8 . The method of claim  claim 7 , wherein the susceptible HLA allele is selected from B*07:02, B*08:01, B*27:03 B*27:05, B*27:09, B*51:01, B*54:01, and B*57:01. 
     
     
         9 . The method of claim  claim 4 , wherein the susceptible HLA allele is selected from C*06 and C*18. 
     
     
         10 . The method of claim  claim 9 , wherein the susceptible HLA allele is selected from C*06:02 and C*18:01. 
     
     
         11 . The method of claim  claim 4 , wherein the HLA gene codes for one of HLA-DPA, HLA-DPB, HLA-DQA, HLA-DQB, HLA-DRA, AND HLA-DRB. 
     
     
         12 . The method of claim  claim 11 , wherein the susceptible HLA allele is DPA*02. 
     
     
         13 . The method of claim  claim 12 , wherein the susceptible HLA allele is DPA*02:01. 
     
     
         14 . The method of claim  claim 11 , wherein the susceptible HLA allele is DPB*13. 
     
     
         15 . The method of claim  claim 14 , wherein the susceptible HLA allele is DPB*13:01. 
     
     
         16 . The method of claim  claim 11 , wherein the susceptible HLA allele is selected from DQA1 *01, DQA1*02, DQA1*03, and DQA1 *05. 
     
     
         17 . The method of claim  claim 16 , wherein the susceptible HLA allele is selected from DQA1*01:01, DQA1*01:02, DQA1 *02:01, DQA1 *03:01, DQA1 *05:01 and DQA1 *05:05. 
     
     
         18 . The method of claim  claim 11 , wherein the susceptible HLA allele is selected from DQB1*02, DQB1*03, DQB1*05, and DQB1*06. 
     
     
         19 . The method of claim  claim 18 , wherein the susceptible HLA allele is selected from DQB1*02:01, DQB1*03:01, DQB1 *03:02, DQB1 *05:01, DQB1 *06:01 and DQB1 *06:02. 
     
     
         20 . The method of claim  claim 11 , wherein the susceptible HLA allele is selected from DRB1 *01, DRB1*03, DRB1*04, DRB1*07, DRB1*08, DRB1*09, DRB1*10, DRB1 *11, DRB1*12, DRB1*13, DRB1*14, DRB1*15, DRB1*16, DRB3*01, DRB3*02, DRB3*03, DRB4*01, and DRB5*01. 
     
     
         21 . The method of claim  claim 20 , wherein the susceptible HLA allele is selected from DRB1*01:01, DRB1*01:03, DRB1*03:01, DRB1*04:01, DRB1*04:02, DRB1*04:03, DRB1*04:04, DRB1*04:05, DRB1*04:08, DRB1*07:01, DRB1 *08:01, DRB1 *09:01, DRB1*10:01, DRB1*11:02, DRB1*11:03, DRB1*12:01, DRB1*13:01, DRB1*14:01, DRB1*15:01, DRB1*15:02, DRB1*16:01, DRB3*01:01, DRB3*02:02, DRB3*03:01, DRB4*01:03, and DRB5*01:01. 
     
     
         22 . A method of treating or preventing an autoimmune disease in a subject, the method comprising:
 modifying a population of the subject’s hematopoietic cells to express an engineered HLA protein containing at least one amino acid substitution as compared to a HLA protein encoded for by a susceptible HLA allele for the autoimmune disease;   wherein the engineered HLA protein has reduced affinity for a self-peptide associated with the autoimmune disease, wherein the at least one amino acid substitution is at a position outside a TCR:HLA interface region of the engineered HLA protein, and wherein the engineered HLA protein does not elicit a graft versus host response in the subject.   
     
     
         23 . The method of claim  claim 22 , wherein the autoimmune disease is rheumatoid arthritis, and the HLA allele encoding the engineered HLA protein selected from is DRB1 *04:01_L67l, DRB1 *04:01 _Q70D, DRB1*04:01_K71 E, DRB1*04:01_K71 R, DRB1*04:01_L67F, DRB1*04:01 _A74L, DRB1*04:01 _A74E, DRB1*04:01_G86L, DRB1*04:01_G86F, DRB1 *04:01_G86V, DRB1 *04:01_G86M, DRB1 *04:05_R71 E, DRB1 *01 :01_L67l, DRB1*01:01 _Q70D, DRB1*01:01_R71E, DRB1*01 :01_V85A, DRB1*01:01_G86A, DRB1 *04:03_R71 E, DRB1*04:04_R71 E, and DRB1 *04:08_R71 E. 
     
     
         24 . The method of claim  claim 23 , wherein the HLA allele encoding the engineered HLA protein is not DRB1 *04:01 _K71 E. 
     
     
         25 . The method of claim  claim 22 , wherein the autoimmune disease is type 1 diabetes, and the HLA allele encoding the engineered HLA protein is selected from DQB1*02:01_A57D and DQB1*03:02_A57D. 
     
     
         26 . The method of claim  claim 22 , wherein the autoimmune disease is ankylosing spondylitis, and the HLA allele encoding the engineered HLA protein is HLA-B*27:05_D116H. 
     
     
         27 . The method of claim  claim 22 , wherein the autoimmune disease is multiple sclerosis, and the HLA allele encoding the engineered HLA protein is selected from DRB1 *15:01_F47Y, DRB1*15:01 _A71R, DRB1*15:01_V86L, and DRB1*15:01_V86F. 
     
     
         28 . The method of claim  claim 22 , wherein the autoimmune disease is celiac disease, and wherein the HLA allele encoding engineered HLA protein is selected from DQB1 *02:01_K71 E and DQB1*02:01_K71T. 
     
     
         29 . The method of claim  claim 22 , wherein the autoimmune disease is neuromyelitis optica, and the HLA allele encoding the engineered HLA protein is selected from DRB1 *03:01_V86L and DRB1*03:01_V86M. 
     
     
         30 . The method of claim  claim 22 , wherein the method does not include immunosuppression or chronic immunosuppression.