Zhanzak Zhuldyz, Johnson Aileen C, Foster Petra, Cardenas Maria A, Morris Anna B, Zhang Joan, Karadkhele Geeta, Badell I Raul, Morris Alanna A, Au-Yeung Byron B, Roversi Fernanda M, Silva Juliete A F, Breeden Cynthia, Hadley Annette, Zhang Weiwen, Larsen Christian P, Kissick Haydn T
Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.
Immunity. 2025 Feb 11;58(2):448-464.e6. doi: 10.1016/j.immuni.2025.01.008. Epub 2025 Jan 30.
Antibodies against the donor human leukocyte antigen (HLA) molecules drive late transplant failure, with HLA-DQ donor-specific antibodies (DSAs) posing the highest rejection risk. Here, we investigated the role of indirect CD4 T cell epitopes-donor-derived peptides presented by recipient major histocompatibility complex (MHC) class II-in DSA formation. Antigen mapping of samples from HLA-DQ DSA-positive kidney and heart transplant recipients revealed two polymorphic hotspots in donor HLA-DQ that generated alloreactive peptides. Antigen mapping of indirect CD4 T cell epitopes in a mouse model of fully MHC mismatched skin graft transplantation (BALB/c to C57BL/6) identified a similar epitope (amino acids 287-301) derived from the donor H2-Kd. Tetramer-binding Kd287 CD4 T cells were detected during rejection and their transfer into T cell-deficient mice induced DSA. Systemic delivery of high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the frequencies of Kd287 CD4 T cells and DSA formation. Thus, targeting a narrow range of donor antigens may prevent DSA formation and improve transplant outcomes.
针对供体人类白细胞抗原（HLA）分子的抗体导致移植后期失败，其中HLA-DQ供体特异性抗体（DSA）带来的排斥风险最高。在此，我们研究了间接CD4 T细胞表位（由受体主要组织相容性复合体（MHC）II类分子呈递的供体来源肽段）在DSA形成中的作用。对HLA-DQ DSA阳性肾移植和心脏移植受者的样本进行抗原定位，发现供体HLA-DQ中有两个多态性热点，可产生同种异体反应性肽段。在完全MHC不匹配的皮肤移植小鼠模型（从BALB/c到C57BL/6）中对间接CD4 T细胞表位进行抗原定位，确定了一个源自供体H2-Kd的相似表位（氨基酸287 - 301）。在排斥反应期间检测到四聚体结合的Kd287 CD4 T细胞，将其转移到T细胞缺陷小鼠中可诱导DSA形成。全身给予高剂量供体H2-Kd肽段并联合CTLA4-Ig可降低Kd287 CD4 T细胞的频率和DSA的形成。因此，靶向范围狭窄的供体抗原可能预防DSA形成并改善移植结局。
