Failure of low-dose recombinant human IL-2 to support the survival of virus-specific CTL clones infused into severe combined immunodeficient foals: Lack of correlation between in vitro activity and in vivo efficacy
Failure of low-dose recombinant human IL-2 to support the survival of virus-specific CTL clones infused into severe combined immunodeficient foals: Lack of correlation between in vitro activity and in vivo efficacy
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DOI：
10.1016/j.vetimm.2007.07.011
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发表时间：
2008-01-15
影响因子：
1.8
通讯作者：
McGuire, Travis C.
中科院分区：
文献类型：
--
作者：
Mealey, Robert H.;Littke, Matt H.;McGuire, Travis C.
尽管CTL对于控制慢病毒（包括马传染性贫血病毒（EIAV））很重要，但尚不清楚在没有CD4辅助和中和抗体的情况下CTL是否可以限制慢病毒复制。将 EIAV 特异性 CTL 克隆过继转移到严重联合免疫缺陷 (SCID) 马驹中可以解决这个问题，但尚不清楚外源性 IL-2 给药是否足以支持注入免疫缺陷马中的 CTL 克隆的植入和增殖。为了解决这个问题，我们将 EIAV Rev 特异性 CTL 克隆过继转移至四匹 EIAV 攻击的 SCID 小马驹中，同时给予低剂量阿地白介素 (180,000 U/m(2))（一种改良的重组人 IL-2 (rhuIL-2) 产品）。该剂量是根据体外对马 PBMC 的比活性计算的，得出的血浆浓度被认为足以使人类高亲和力 IL-2 受体饱和。尽管对马 PBMC 的特异性活性相当于重组马 IL-2 和另一种形式的 rhuIL-2，但阿地白介素不支持输注的 CTL 克隆的植入和扩增，并且没有发生病毒载量和临床疾病的控制。结论是，本研究中使用的剂量的阿地白介素并没有增强输注到 EIAV 攻击的 SCID 小马驹中的 Rev 特异性 CTL 克隆的存活率，并且体外比活性与体内功效不相关。在免疫缺陷马中使用 CTL 克隆成功进行过继免疫治疗可能需要更高剂量的 rhuIL2、共输注 CD4+ T 淋巴细胞或施用马 IL-2。 (c) 2007 Elsevier B.V. 保留所有权利。
Although CTL are important for control of lentiviruses, including equine infectious anemia virus (EIAV), it is not known if CTL can limit lentiviral replication in the absence of CD4 help and neutralizing antibody. Adoptive transfer of EIAV-specific CTL clones into severe combined immunodeficient (SCID) foals could resolve this issue, but it is not known whether exogenous IL-2 administration is sufficient to support the engraftment and proliferation of CTL clones infused into immunodeficient horses. To address this question we adoptively transferred EIAV Rev-specific CTL clones into four EIAV-challenged SCID foals, concurrent with low-dose aldesleukin (180,000 U/m(2)), a modified recombinant human IL-2 (rhuIL-2) product. The dose was calculated based on the specific activity on equine PBMC in vitro, and resulted in plasma concentrations considered sufficient to saturate high affinity IL-2 receptors in humans. Despite specific activity on equine PBMC that was equivalent to recombinant equine IL-2 and another form of rhuIL-2, aldesleukin did not support the engraftment and expansion of infused CTL clones, and control of viral load and clinical disease did not occur. It was concluded that survival of Rev-specific CTL clones infused into EIAV-challenged SCID foals was not enhanced by aldesleukin at the doses used in this study, and that in vitro specific activity did not correlate with in vivo efficacy. Successful adoptive immunotherapy with CTL clones in immunodeficient horses will likely require higher doses of rhuIL2, co-infusion of CD4+ T lymphocytes, or administration of equine IL-2. (c) 2007 Elsevier B.V. All rights reserved.