Mou Danny, Espinosa Jaclyn E, Stempora Linda, Iwakoshi Neal N, Kirk Allan D
Department of Surgery, Emory University, Atlanta, Georgia.
Department of Surgery, Emory University, Atlanta, Georgia.
J Surg Res. 2015 Jun 15;196(2):241-6. doi: 10.1016/j.jss.2015.02.033. Epub 2015 Feb 21.
Belatacept, a B7-specific fusion protein, blocks CD28-B7 costimulation and prevents kidney allograft rejection. However, it is ineffective in a sizable minority of patients. Although T-cell receptor and CD28 engagement are known to initiate T-cell activation, many human antigen-experienced T-cells lose CD28, and can be activated independent of CD28 signals. We posit that these cells are central drivers of costimulation blockade resistant rejection (CoBRR) and propose that CoBRR might relate to an accumulation of CD28(-) T-cells resulting from viral antigen exposure.
We infected C57BL/6 mice with polyomavirus (a BK virus analog), murine cytomegalovirus (a human cytomegalovirus analog), and gammaherpesvirus (HV68; an Epstein-Barr virus analog) and assessed for CD28 expression relative to mock infection controls. We then used mixed lymphocyte reaction (MLR) assays to assess the alloreactive response of these mice against major histocompatibility complex-mismatched cells.
We demonstrated that infection with polyomavirus, murine CMV, and HV68 can induce CD28 downregulation in mice. We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic, costimulation blockade resistant, alloreactive response against major histocompatibility complex-mismatched cells without prior alloantigen exposure. Further analysis revealed that gammherpesvirus-induced oligoclonal T-cell expansion is required for the increased alloreactivity.
Virus exposure results in reduced T-cell expression of CD28, the target of costimulation blockade therapy. These viruses also contribute to increased alloreactivity. Thus, CD28 downregulation after viral infection may play a seminal role in driving CoBRR.
贝拉西普是一种B7特异性融合蛋白，可阻断CD28 - B7共刺激并预防肾移植排斥反应。然而，在相当一部分患者中它无效。虽然已知T细胞受体与CD28结合可启动T细胞活化，但许多经历过抗原刺激的人类T细胞会丢失CD28，并且可以独立于CD28信号被激活。我们认为这些细胞是共刺激阻断抵抗性排斥反应（CoBRR）的主要驱动因素，并提出CoBRR可能与病毒抗原暴露导致的CD28(-) T细胞积累有关。
我们用多瘤病毒（一种BK病毒类似物）、鼠巨细胞病毒（一种人类巨细胞病毒类似物）和γ疱疹病毒（HV68；一种爱泼斯坦 - 巴尔病毒类似物）感染C57BL/6小鼠，并相对于模拟感染对照评估CD28表达。然后我们使用混合淋巴细胞反应（MLR）测定法评估这些小鼠对主要组织相容性复合体不匹配细胞的同种异体反应性。
我们证明多瘤病毒、鼠巨细胞病毒和HV68感染可诱导小鼠CD28下调。我们表明，这些临床相关人类病毒的类似物使感染小鼠的淋巴细胞能够在没有预先接触同种异体抗原的情况下，对主要组织相容性复合体不匹配细胞发起记忆性、共刺激阻断抵抗性同种异体反应。进一步分析表明，γ疱疹病毒诱导的寡克隆T细胞扩增是同种异体反应性增加所必需的。
病毒暴露导致共刺激阻断治疗靶点CD28的T细胞表达减少。这些病毒也会导致同种异体反应性增加。因此，病毒感染后CD28下调可能在驱动CoBRR中起关键作用。
