High Doses of GM-CSF Inhibit Antibody Responses in Rectal Secretions and Diminish Modified Vaccinia Ankara/Simian Immunodeficiency Virus Vaccine Protection in TRIM5α-Restrictive Macaques.
High Doses of GM-CSF Inhibit Antibody Responses in Rectal Secretions and Diminish Modified Vaccinia Ankara/Simian Immunodeficiency Virus Vaccine Protection in TRIM5α-Restrictive Macaques.
复制标题
DOI：
10.4049/jimmunol.1600629
复制
发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Amara RR
中科院分区：
文献类型：
--
作者：
Kannanganat S;Wyatt LS;Gangadhara S;Chamcha V;Chea LS;Kozlowski PA;LaBranche CC;Chennareddi L;Lawson B;Reddy PB;Styles TM;Vanderford TH;Montefiori DC;Moss B;Robinson HL;Amara RR
在这里，我们在恒河猴中测试了500倍范围的混合重组修饰的牛痘安卡拉（MVA）表达恒河猴GM-CSF（MVA/GM-CSF）的MVA/猴免疫缺陷猕猴239（SIVmac 239）疫苗引起的免疫原性和保护的效果。高剂量MVA/GM-CSF不影响全身Env特异性Ab的水平，但确实降低了浆细胞样树突状细胞上肠道归巢受体α4β7的表达（p<0.01）以及直肠分泌物中Env特异性伊加（p=0.01）和IgG（p<0.05）的水平。在恒河猴中，采用12周一次的直肠攻毒评价疫苗的保护作用，所述恒河猴按照限制性或允许攻毒病毒SIVsmE 660感染的三重基序蛋白5α（TRIM 5 α）基因型进行亚组。9只TRIM 5 α限制性动物中有8只未接受MVA/GM-CSF或接受最低剂量[1×105空斑形成单位（pfu）] MVA/GM-CSF，对所有12次攻击均产生抵抗。在可比较的TRIM 5 α-允许组中，12只动物中仅1只抵抗了所有12次攻击。在TRIM 5 α限制性而非允许性动物中，感染激发次数与Env特异性直肠IgG（r=0.6）和伊加（r=0.6）、Env特异性血清IgG的亲合力（r=0.5）和抗体依赖性细胞介导的病毒抑制（r=0.6）直接相关。中和抗体滴度与保护作用无关。我们的结论是：（i）MVA/SIVmac 239引起的保护作用强烈依赖于TRIM 5 α限制性的存在，（ii）在TRIM 5 α限制性动物中，非中和性Ab应答有助于对抗SIVsmE 660的保护作用，（iii）高剂量的共表达MVA/GM-CSF抑制粘膜Ab应答和MVA/SIV 239引起的保护作用。
Here, we test in rhesus macaques the effects of a 500-fold range of an admixed recombinant modified vaccinia Ankara (MVA) expressing rhesus GM-CSF (MVA/GM-CSF) on the immunogenicity and protection elicited by an MVA/simian immunodeficiency macaque 239 (SIVmac239) vaccine. High doses of the MVA/GM-CSF did not affect the levels of systemic Env-specific Ab but did decrease the expression of the gut homing receptor α4β7 on plasmacytoid dendritic cells (p<0.01) and the magnitudes of Env-specific IgA (p=0.01) and IgG (p<0.05) in rectal secretions. The protective effect of the vaccine was evaluated using 12 weekly rectal challenges in rhesus subgrouped by tripartite motif-containing protein 5α (TRIM5α) genotypes that are restrictive or permissive for infection by the challenge virus, SIVsmE660. Eight of 9 TRIM5α-restrictive animals receiving no, or the lowest dose [1×105 plaque forming units (pfu)] of MVA/GM-CSF resisted all 12 challenges. In the comparable TRIM5α-permissive group only 1 of 12 animals resisted all 12 challenges. In the TRIM5α restrictive, but not permissive animals, the number of challenges to infection directly correlated with the magnitudes of Env-specific rectal IgG (r=0.6) and IgA (r=0.6), the avidity of Env-specific serum IgG (r=0.5), and antibody dependent cell-mediated virus inhibition (r=0.6). Titers of neutralizing Ab did not correlate with protection. We conclude that (i) protection elicited by MVA/SIVmac239 is strongly dependent on the presence of the TRIM5α restriction, (ii) in TRIM5α restrictive animals, non-neutralizing Ab responses contribute to protection against SIVsmE660, and (iii) high doses of co-expressed MVA/GM-CSF inhibit mucosal Ab responses and MVA/SIV239-elicited protection.
登录
查看更多内容
影响因子：
5.4
作者：
Chavan, R.;Marfatia, K. A.;Feinberg, A. B.
通讯作者：
Feinberg, A. B.
影响因子：
4.4
作者：
Kusakabe, K;Xin, KQ;Okuda, K
通讯作者：
Okuda, K
影响因子：
5.4
作者：
Kwa, Suefen;Lai, Lilin;Amara, Rama Rao
通讯作者：
Amara, Rama Rao
影响因子：
5.5
作者：
Lai, Lilin;Kwa, Sue-Fen;Kozlowski, Pamela A.;Montefiori, David C.;Nolen, Tracy L.;Hudgens, Michael G.;Johnson, Welkin E.;Ferrari, Guido;Hirsch, Vanessa M.;Felber, Barbara K.;Pavlakis, George N.;Earl, Patricia L.;Moss, Bernard;Amara, Rama Rao;Robinson, Harriet L.
通讯作者：
Robinson, Harriet L.
影响因子：
4.2
作者：
Chamcha V;Kannanganat S;Gangadhara S;Nabi R;Kozlowski PA;Montefiori DC;LaBranche CC;Wrammert J;Keele BF;Balachandran H;Sahu S;Lifton M;Santra S;Basu R;Moss B;Robinson HL;Amara RR
通讯作者：
Amara RR