Malaria immunology

寻找治疗非洲儿童脑型疟疾的方法 恶性疟疾是一种由蚊子传播的寄生虫引起的潜在致命传染病。去年，恶性疟原虫感染导致超过2.19亿疟疾病例和43.5万人死亡，其中绝大多数是非洲幼儿。感染最致命的并发症是脑型疟疾(CM)，造成90%以上的疟疾死亡。尽管接受了高效的抗疟疾药物治疗，但CM的死亡率很高，估计为15%-25%。可悲的是，许多存活下来的儿童患有终身的后遗症，包括衰弱的认知、听力和视力障碍。关键的是，目前还没有与速效抗疟疾药物相结合的辅助CM疗法。鉴于严重疟疾的全球负担，开发CM疗法是公共卫生和人道主义优先事项。 目前，我们对CM病病理基础的细胞和分子机制的了解还不完全。在死于CM的儿童中，脑血管中大量的红细胞隔离通常伴随着血管内和血管周围的病理，包括环出血。这些观察结果导致了普遍接受的假设，即脑血管中的IRBC隔离和由此导致的后遗症包括机械性阻塞、炎症、血管调节受损和血脑屏障调节失调可能导致这种临床综合征。不幸的是，试图针对这一机制的各种疗法(11种疗法的至少17项临床试验)都没有显示出疗效。作为现有的CM小鼠模型，实验性CM(ECM)与人类疾病有许多相似之处。事实上，包括我们自己使用的MRI在内的几项研究提供了ECM中血管源性脑肿胀、血脑屏障功能障碍和致命性脑干突出的证据，与MRI在CM儿童中观察到的类似。然而，小鼠模型提出了另一种病理机制。ECM需要寄生虫抗原通过脑血管系统在MHC-I上交叉递呈，并由CD3+CD8+T细胞靶向该血管系统。然而，在死于CM的儿童中，免疫细胞的存在或性质是否渗透到大脑中还没有得到严格的确定。因此，我们对儿童CM的认识的一个关键差距是，在死于CM的儿童的大脑中是否存在CD3+CD8+T细胞积累的模式，这种模式类似于在CM小鼠模型中观察到的模式。我们最近提供了确凿的证据，表明死于CM的儿童的大脑中存在CD3+CD8+T细胞。CD3+CD8+T细胞分布于与内皮关系密切的静脉血管管腔和血管周围间隙的血管腔内。在感染HIV的CM患儿中，CD3+CD8+T细胞的数量更多，提示HIV合并感染对本病有一定的影响。这些观察结果为CM的辅助治疗开辟了新的途径，包括用丰富的可用的T细胞靶向疗法来调节CD3+CD8+T细胞。 一项I/IIa期临床试验，以测试DON作为非洲儿童CM有效联合治疗的安全性 基于上述发现，2019年，我们启动了DON作为非洲CM儿童辅助治疗的I/IIa期临床试验(题为：DON在儿童脑型疟疾中的应用：I/IIa期剂量-递增安全性研究)。我们的临床试验团队包括LMVR资深科学家Louis Miller、LIG研究员Brittany Rigger和儿童医院/GW医学院的Doug Postels。我们已经将试验所需的几乎所有必要部件组装在一起，我们相信我们的临床试验将于2022年8月初开始。我们已经：在马拉维确定了一个由Terrie Taylor领导的设备齐全的地点来进行我们的试验；编写并提交了Postels博士作为PI在美国和马拉维进行IRB批准的临床方案，并获得了两个IRBs的批准；从NCI获得了足够数量的cGGP DON，用于我们的研究，并成功地填写和完成了，并运往马拉维开始我们的试验和运往马里兰州弗雷德里克的设施进行储存；向FDA提交了预IND，以批准在我们的方案中使用DON，并获得了FDA的确认，即不需要额外的临床前研究；向FDA提交了IND申请，并获得了继续我们研究的成人部分的许可，并从DMID，NIAID获得了支持临床试验的资金，Postels博士担任PI。

A search for therapies for cerebral malaria in African children Plasmodium falciparum malaria is a potentially fatal infectious disease caused by mosquito-transmitted parasites. Last year P. falciparum infections caused over 219 million cases of malaria and 435 thousand deaths, the vast majority of which were among young African children. The deadliest complication of infection is cerebral malaria (CM), causing greater than 90% of malarial fatalities. The mortality for CM is high, estimated to be 15-25%, despite treatment with highly effective anti-malarial drugs. Tragically, many children that survive CM suffer from life-long sequelae, including debilitating cognitive, hearing, and vision impairments. Critically, there are currently no adjunctive CM therapies to combine with rapid-acting antimalarial drugs. Given the global burden of severe malaria, the development of a CM therapy is a public health and humanitarian priority. At present our knowledge of the cellular and molecular mechanisms that underlie CM disease pathology is incomplete. Heavy iRBC sequestration in the cerebrovasculature of children who died of CM is often accompanied by intra- and perivascular pathology, including ring hemorrhages. These observations led to the generally accepted hypothesis that iRBC sequestration in the cerebrovasculature and the resulting sequelae including mechanical obstruction, inflammation, impaired vasoregulation, and BBB dysregulation may cause this clinical syndrome . Unfortunately, various therapies attempting to target this mechanism (at least 17 clinical trials of 11 therapies) have not shown efficacy. An existing mouse model for CM, experimental CM (ECM) shares many features with the human disease. Indeed, several studies including our own using MRI provided evidence of vasogenic brain swelling, blood-brain barrier dysfunction, and fatal brainstem herniation in ECM, similar to that observed in children with CM by MRI. However, the mouse model suggests an alternative mechanism of pathology. ECM requires cross-presentation of parasite antigens on MHC-I by the brain vasculature and targeting of this vasculature by CD3+CD8+ T cells. However, the presence or nature of immune cell infiltrates into the brains of children who dies of CM has not been rigorously determined. Thus, a critical gap in our knowledge of CM in children is whether a pattern of CD3+CD8+ T cell accumulation, which resembles that observed in the murine model of CM, exists in the brains of children who died of CM. We recently provided definitive evidence that CD3+CD8+ T cells are present in the brains of children who died of CM. CD3+CD8+ T cells were present in both the lumen of the venous vasculature in close association with the endothelium as well as on the abluminal side of vessels in the perivascular spaces. The number of CD3+CD8+ T cells is even greater in HIV-infected children with CM, suggesting that HIV coinfection can influence this disease. These observations open new avenues for adjunctive treatment for CM that involve modulating CD3+CD8+ T cells with a wealth of available T cell targeting therapeutics. A phase I/IIa clinical trial to test the safety of DON as an effective conjunctive therapy for CM in African children Based on the findings described above, in 2019, we initiated plans to carry out a phase I/IIa clinical trial of DON as an adjunctive therapy for African children with CM (entitled: DON in pediatric cerebral malaria: a phase I/IIa dose-escalation safety study). Our clinical trial team included Louis Miller (senior scientist LMVR), Brittany Riggle (Research Fellow LIG) and Doug Postels (Childrens Hospital/GW Medical School). We have put nearly all the necessary pieces together required for our trial and we believe our clinical trial will begin in early August 2022. We have: identified a well-equipped site in Malawi headed by Terrie Taylor to carry out our trial; written and submitted clinical protocols with Dr. Postels as PI for IRB approval in the U.S. and in Malawi and received approval by both IRBs; obtained from NCI a sufficient quantity of cGGP DON for our studies that was successfully filled and finished and shipped to Malawi for the start of our trial and to a facility in Frederick, MD for storage; submitted a pre-IND to the FDA for approval of the use of DON in our protocol and received FDA confirmation that no additional pre-clinical studies were required; submitted an IND application to the FDA and received permission to proceed with the adult arm of our study and obtained funding to support the clinical trial from DMID, NIAID with Dr. Postels as PI.