Identification of rejection-associated indirect CD4 T cell epitopes provides a target for donor-specific transplant tolerance
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ABSTRACT: Antibody-mediated rejection, caused by antibodies against the donor human leukocyte antigen (HLA) molecules plays a fundamental role in graft rejection in transplantation. Most significant is transplant patients who generate antibodies against the donor HLA-DQ have the highest risk of rejection. In this study, we investigated the role of indirect CD4 T cell epitopes in the formation of donor-specific antibodies (DSA). Using antigen mapping techniques in kidney and heart transplant recipients with HLA-DQ DSA, we identified two polymorphic hotspots in the HLA-DQ gene that generated alloreactive CD4 T cell responses. To study the functional significance of indirect CD4 T cells, we first mapped epitopes recognised by H2-Kb C57Bl6 mice against a skin graft from H2-Kd Balb/c mice. We identified a CD4 T cell epitope, specific for amino acids 287-301 derived from the H2-Kd protein, that generated tetramer-binding Kd287+ CD4 T cells during rejection. Importantly, the transfer of Kd287+ CD4 T cells into T cell-deficient mice was sufficient to drive an antibody response against the donor H2-Kd molecule. Lastly, we found that administration of systemic high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the formation of Kd287+ CD4 T cells and diminished DSA formation. Together, these findings demonstrate that the identification of donor antigens indicates the potential for inducing donor-specific immune tolerance in transplantation.
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE277075 | GEO | 2024/09/17
REPOSITORIES: GEO
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