Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig.
Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig.
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DOI：
10.1111/ajt.14400
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Ford ML
中科院分区：
文献类型：
--
作者：
Badell IR;La Muraglia GM 2nd;Liu D;Wagener ME;Ding G;Ford ML
供体特异性抗体（DSA）是肾移植后改善长期结局的障碍。用CTLA-4-IG阻断共刺激已显示出作为控制DSA的潜在治疗策略的前景。滤泡辅助性T细胞（Tfh）是最佳抗体产生所需的CD 4 + T细胞亚群，依赖于CD 28共刺激途径。我们以前已经表明，选择性CD 28阻断通过相对于CTLA-4-IG改善对CD 8 + T细胞的控制而导致上级同种异体移植物存活，但CD 28特异性阻断对CD 4 + Tfh细胞的影响尚不清楚。因此，我们在小鼠皮肤移植模型中鉴定并表征了供体反应性Tfh细胞，然后利用该模型评估用抗CD 28结构域抗体（dAb）选择性CD 28阻断对供体特异性Tfh介导的免疫应答的影响。我们观察到，与CTLA-4-IG相比，抗-CD 28 dAb导致供体反应性CXCR 5 +PD-1 hi Tfh和CD 95 + GL 7+生发中心B细胞以及DSA形成的上级抑制。有趣的是，供体反应性Tfh细胞差异上调CTLA-4表达，表明CTLA-4在介导抗CD 28 dAb观察到的上级抑制中的重要作用。因此，选择性CD 28阻断作为一种新的方法来控制Tfh细胞反应和预防肾移植后DSA值得进一步研究。
Donor-specific antibodies (DSA) are a barrier to improved long-term outcomes following kidney transplantation. Costimulation blockade with CTLA-4-Ig has shown promise as a potential therapeutic strategy to control DSA. T follicular helper (Tfh) cells, a subset of CD4+ T cells required for optimum antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8+ T cells relative to CTLA-4-Ig, but the impact of CD28-specific blockade on CD4+ Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model, and then utilized this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5+PD-1hi Tfh and CD95+GL7+ germinal center B cells, and DSA formation as compared to CTLA-4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA-4 expression, suggesting an important role for CTLA-4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.
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DOI：
10.1111/ajt.12589
发表时间：
2014-02
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：
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作者：
Djamali A;Kaufman DB;Ellis TM;Zhong W;Matas A;Samaniego M
通讯作者：
Samaniego M
影响因子：
64.8
作者：
Crotty, S;Kersh, EN;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
56.9
作者：
LINSLEY, PS;WALLACE, PM;TEPPER, MA
通讯作者：
TEPPER, MA
共刺激阻碍改变了生发中心的反应，并防止抗体介导的排斥反应。
DOI：
10.1111/ajt.12526
发表时间：
2014-01
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：
Kim EJ;Kwun J;Gibby AC;Hong JJ;Farris AB 3rd;Iwakoshi NN;Villinger F;Kirk AD;Knechtle SJ
通讯作者：
Knechtle SJ
DOI：
10.1084/jem.20102065
发表时间：
2011-07-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lee SK;Rigby RJ;Zotos D;Tsai LM;Kawamoto S;Marshall JL;Ramiscal RR;Chan TD;Gatto D;Brink R;Yu D;Fagarasan S;Tarlinton DM;Cunningham AF;Vinuesa CG
通讯作者：
Vinuesa CG