Jankowska Gan Ewa, Agashe Vrushali V, Lema Diego A, Zhou Ying, Gonzalez Bosc Laura, Sullivan Jeremy A, Greenspan Daniel S, Burlingham William J
Department of Surgery, Division of Transplantation, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI.
Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM.
Transplant Direct. 2020 Sep 24;6(10):e607. doi: 10.1097/TXD.0000000000001062. eCollection 2020 Oct.
Individuals harbor preexisting HLA-DR/DQ-restricted responses to collagen type V (ColV) mediated by Th17 cells under Treg control, both specific to peptides that bind to inherited HLA class II antigens. Yet after transplant, the donor-DR type somehow influences graft outcome. We hypothesized that, long after a lung or heart allograft, the particular HLA-DR type of the mismatched transplant donor transforms the specificity of the "anti-self" response. This could explain why, over long term, certain donor DRs could be more immunogenic than others.
We analyzed 7 HLA-DR15 patients who had received a lung allograft from a DR15 donor. To determine the mechanism of acquired specificity in self-reactivity, we analyzed the kinetics of DR1 (host) and DR15 (donor) peptide restriction in a heart transplant model using DR-transgenic mice.
Beyond 1.5 years post-lung transplant, all patients tested had acquired DR15-restricted immune responses to ColV peptides. These responses were either unrestrained Th17 type (n = 4) or Th17 controlled by Treg arising early (<5 y) or late (>7 y) after transplant (n = 4). Treg suppression via conventional (transforming growth factor-β [TGF-β]) and extracellular vesicle-associated (IL-35) cytokines correlated with superior outcomes. Naïve DR1 and DR15 transgenic mice had preexisting DR-restricted responses, exclusively to ColV fragments containing DR1- or DR15-binding peptides. When HLA-DR1 transgenic recipients of a HLA-DR15 heart developed ColV reactivity post-transplant, mice that acutely rejected (20-25 d) responded only to the DR1-restricted ColV peptide epitope. In animals whose grafts survived long term, we could detect acquisition of DR from the transplant donor onto the surface of recipient dendritic cells, and immune responses against a donor DR15-restricted ColV peptide.
These results might explain how certain donor HLA-DR types redirect host immune responses to novel peptides of critical self-antigens. Unless regulated, such responses may predispose the allograft to chronic rejection.
个体在Treg控制下存在由Th17细胞介导的对V型胶原蛋白（ColV）的预先存在的HLA - DR/DQ限制性反应，这两种反应均针对与遗传的HLA II类抗原结合的肽段。然而移植后，供体DR类型不知何故会影响移植结果。我们假设，在肺或心脏同种异体移植很久之后，不匹配的移植供体的特定HLA - DR类型会改变“抗自身”反应的特异性。这可以解释为什么从长期来看，某些供体DR比其他供体更具免疫原性。
我们分析了7名接受来自DR15供体的肺移植的HLA - DR15患者。为了确定自身反应性中获得性特异性的机制，我们在心脏移植模型中使用DR转基因小鼠分析了DR1（宿主）和DR15（供体）肽限制的动力学。
肺移植后超过1.5年，所有接受检测的患者都获得了对ColV肽的DR15限制性免疫反应。这些反应要么是不受抑制的Th17型（n = 4），要么是移植后早期（<5年）或晚期（>7年）由Treg控制的Th17型（n = 4）。通过传统（转化生长因子-β [TGF-β]）和细胞外囊泡相关（IL - 35）细胞因子进行的Treg抑制与更好的结果相关。未接触过抗原的DR1和DR15转基因小鼠预先存在DR限制性反应，仅针对含有DR1或DR15结合肽的ColV片段。当HLA - DR1转基因的HLA - DR15心脏受体在移植后出现ColV反应性时，急性排斥（20 - 25天）的小鼠仅对DR1限制性ColV肽表位有反应。在移植长期存活的动物中，我们可以检测到移植供体的DR在受体树突状细胞表面的获得，以及针对供体DR15限制性ColV肽的免疫反应。
这些结果可能解释了某些供体HLA - DR类型如何将宿主免疫反应重定向至关键自身抗原的新肽段。除非受到调节，否则这种反应可能使同种异体移植易发生慢性排斥反应。
