Heterologous immunity triggered by a single, latent virus in Mus musculus: combined costimulation- and adhesion- blockade decrease rejection.
Heterologous immunity triggered by a single, latent virus in Mus musculus: combined costimulation- and adhesion- blockade decrease rejection.
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DOI：
10.1371/journal.pone.0071221
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kean LS
中科院分区：
文献类型：
--
作者：
Beus JM;Hashmi SS;Selvaraj SA;Duan D;Stempora LL;Monday SA;Cheeseman JA;Hamby KM;Speck SH;Larsen CP;Kirk AD;Kean LS
潜伏病毒介导的异源免疫和随后的移植排斥反应的机制，特别是在T细胞共刺激阻断的情况下，仍然不确定。为了解决这个问题，我们利用MHV 68开发了潜伏病毒诱导的异源同种免疫的啮齿动物模型。MHV 68感染与多模式免疫偏离相关，包括CXCL 9和CXCL 10分泌增加，以及CD 8dim T细胞群的扩增。CD 8dim T细胞表现出多种共刺激分子的表达减少和两种粘附分子LFA-1和VLA-4的表达增加。在MHV 68潜伏期的设定中，与未感染动物相比，受体表现出加速的皮肤同种异体移植物的共刺激阻断抗性排斥（感染动物的MST为13.5天，未感染动物的MST为22天，p<0.0001）。相比之下，当用组合抗LFA-1/抗VLA-4粘附阻断剂治疗时，未感染和感染动物之间的移植物接受持续时间相等（未感染的MST为24天，感染的MST为27天，p = n.s.）。 基于CTLA-4-IG/抗CD 154的共刺激阻断剂+基于抗LFA-1/抗VLA-4的粘附阻断剂的组合导致在未感染和感染的群组中延长的移植物接受（两者的MST>100天，p<0.0001对比任一者的共刺激阻断剂）。而在未感染的组群中，单独的CTLA-4-IG或抗CD 154可以有效地与粘附阻断剂配对以延长同种异体移植物的接受，在感染的动物中，皮肤移植物的延长的接受只能在抗LFA-1和抗VLA-4抗体与抗CD 154组合时重现（没有CTLA-4-IG，MST>100 d）。当单独的CTLA-4-IG（无抗CD 154）与粘连阻断剂（MST 41 d）组合时，移植物接受性显著受损。这些结果表明，在MHV 68感染的设置，协同作用主要发生在粘附途径和基于CD 154的共刺激之间，并且可能需要两种途径的组合靶向来克服在潜伏病毒介导的免疫偏离的设置中发生的排斥反应的风险增加。
The mechanisms underlying latent-virus-mediated heterologous immunity, and subsequent transplant rejection, especially in the setting of T cell costimulation blockade, remain undetermined. To address this, we have utilized MHV68 to develop a rodent model of latent virus-induced heterologous alloimmunity. MHV68 infection was correlated with multimodal immune deviation, which included increased secretion of CXCL9 and CXCL10, and with the expansion of a CD8dim T cell population. CD8dim T cells exhibited decreased expression of multiple costimulation molecules and increased expression of two adhesion molecules, LFA-1 and VLA-4. In the setting of MHV68 latency, recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals, p<.0001). In contrast, the duration of graft acceptance was equivalent between non-infected and infected animals when treated with combined anti-LFA-1/anti-VLA-4 adhesion blockade (MST 24 d for non-infected and 27 d for infected, p = n.s.). The combination of CTLA-4-Ig/anti-CD154-based costimulation blockade+anti-LFA-1/anti-VLA-4-based adhesion blockade led to prolonged graft acceptance in both non-infected and infected cohorts (MST>100 d for both, p<.0001 versus costimulation blockade for either). While in the non-infected cohort, either CTLA-4-Ig or anti-CD154 alone could effectively pair with adhesion blockade to prolong allograft acceptance, in infected animals, the prolonged acceptance of skin grafts could only be recapitulated when anti-LFA-1 and anti-VLA-4 antibodies were combined with anti-CD154 (without CTLA-4-Ig, MST>100 d). Graft acceptance was significantly impaired when CTLA-4-Ig alone (no anti-CD154) was combined with adhesion blockade (MST 41 d). These results suggest that in the setting of MHV68 infection, synergy occurs predominantly between adhesion pathways and CD154-based costimulation, and that combined targeting of both pathways may be required to overcome the increased risk of rejection that occurs in the setting of latent-virus-mediated immune deviation.
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影响因子：
2.3
作者：
Lima, M;Teixeira, MD;Justiça, B
通讯作者：
Justiça, B
影响因子：
30.5
作者：
Kaech, SM;Tan, JT;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
4.8
作者：
Ko, J;Jang, SW;Na, DS
通讯作者：
Na, DS
影响因子：
5.4
作者：
Lee, BJ;Giannoni, F;Sarawar, SR
通讯作者：
Sarawar, SR
整合素拮抗剂可防止 CD8(+) 记忆 T 细胞引起的共刺激阻滞抵抗性移植排斥。
DOI：
10.1111/j.1600-6143.2011.03762.x
发表时间：
2012-01
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Kitchens WH;Haridas D;Wagener ME;Song M;Kirk AD;Larsen CP;Ford ML
通讯作者：
Ford ML