Identification of novel HLA class II target epitopes for generation of donor-specific T regulatory cells.
Therapies capable of generating host T regulatory cells (T(R)) responsive to donor-specific HLA-class II minor histocompatibility antigens have the potential to promote tolerance of a transplanted organ. Our group has developed a novel approach for the identification of potentially therapeutic T(R) target antigens. We perform parallel non-synonymous SNP genotyping of HLA-identical subject pairs to identify peptide variations expressed by only one of the two subjects. Variant peptide pairs are then evaluated for binding a shared HLA-class II allele. Minor peptides predicted to bind HLA-class II with greater affinity than the common variant peptide are tested for HLA class II binding and in vitro induction of suppressive CD4+ T cells. Using this approach we have identified multiple pairs of variant peptides capable of differential binding and induction of suppressive CD4+ T cells. These data demonstrate the feasibility of identifying potentially therapeutic HLA class II minor antigens for generation of donor-specific T(R).
Translational Research Program, Benaroya Research Institute, Seattle, Washington, USA. bstone@benaroyaresearch.org
Brad
B
Stone
Mary
M
Rieck
Crystal A
CA
Rawlings
Arnold
A
Kas
Jay
J
Shendure
Hywel
H
Jones
Jane H
JH
Buckner
D000483:Alleles; D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D005838:Genotype; D060005:Genotyping Techniques; D059811:HLA-DRB1 Chains / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008969:Molecular Sequence Data; D016377:Organ Transplantation; D010455:Peptides / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D014019:Tissue Donors
D015704:CD4 Antigens; D018984:Epitopes, T-Lymphocyte; D059811:HLA-DRB1 Chains; D010455:Peptides; D007371:Interferon-gamma