Abstract
In pre-sensitizing events, immunological memory is mainly created via indirect allorecognition where CD4+ T cells recognize foreign peptides in the context of self-HLA class II (pHLA) presented on antigen-presenting cells. This recognition makes it possible for naive CD4+ T-helper cells to differentiate into memory cells, resulting in the creation of further antibody memory. These responses contribute to effective secretion of donor-specific anti-HLA antibodies (DSA) after second encounters with the same peptide. Preformed donor-reactive CD4+ memory T cells may induce early immune responses after transplantation; however, the tools to evaluate them are limited. This study evaluated shared T cell epitopes (TEs) between the pre-sensitizing and donor HLA using an in silico assay, an alternative to estimate donor-reactive CD4+ memory T cells before transplantation. In 578 living donor kidney transplants without preformed DSA, 69 patients had anti-HLA antibodies before transplantation. Of them, 40 had shared TEs and were estimated to have donor-reactive CD4+ memory T cells. De novo DSA formation in the early phase was significantly higher in the shared TE-positive group than in the anti-HLA antibody- and shared TE-negative groups (p=0.001 and p=0.02, respectively). In conclusion, evaluation of shared TEs for estimating preformed donor-reactive CD4+ memory T cells may help predict the risk of early de novo DSA formation after kidney transplantation.
Highlights
Adaptive immunity creates immunological memory after the first response to a specific foreign antigen; this memory leads to an enhanced rapid response to subsequent exposure to the same antigen and is important in organ transplantation [1]
This study was the first attempt to use the predicted indirectly recognizable HLA epitopes (PIRCHE)-II algorithm as a tool to estimate preformed memory CD4+ T cells, which may be reactivated by encountering pHLAs derived from the donor HLA via the indirect allorecognition pathway
Anti-HLA antibodies toward a shared BE were reportedly diluted across multiple beads in a single antigen beads (SAB) assay, resulting in lowering the Mean fluorescence intensity (MFI) values compared with antibodies toward a private epitope specific to a single HLA [35]
Summary
Adaptive immunity creates immunological memory after the first response to a specific foreign antigen; this memory leads to an enhanced rapid response to subsequent exposure to the same antigen and is important in organ transplantation [1]. Unlike T cell receptors, B cell receptors recognize fragments on the tertiary structure of proteins, which are in structurally close contact [4] This indirect allorecognition with the foreign-HLA-specific T cell receptor allows naive CD4+ T-helper cells to differentiate into memory cells, thereby helping naïve B cells with the foreign-HLA-specific B cell receptor to differentiate into antibody-producing plasma cells and memory B cells [5, 6]. During this process, memory T cells and B cells memorize the molecular components known as epitope, not the foreign HLA as a whole [4]. These memory cells lead an enhanced, rapid response after second encounters with the same epitopes derived from donor HLA [7,8,9]
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