Malaria immunology

非洲儿童脑型疟疾治疗方法的探索 恶性疟原虫疟疾是由蚊子传播的寄生虫引起的一种潜在的致命性传染病。去年，恶性疟原虫感染造成2.19亿多例疟疾病例和43.5万人死亡，其中绝大多数是非洲儿童。最致命的感染并发症是脑型疟疾（CM），占疟疾死亡人数的90%以上。CM的死亡率很高，估计为15- 25%，尽管用高效抗疟疾药物治疗。可悲的是，许多儿童幸存下来的CM遭受终身后遗症，包括削弱认知，听力和视力障碍。关键的是，目前还没有将联合收割机与速效抗疟药联合使用的有效CM疗法。鉴于严重疟疾的全球负担，CM疗法的开发是公共卫生和人道主义的优先事项。 目前，我们的知识的细胞和分子机制，CM疾病的病理基础是不完整的。死于CM的儿童的血管系统中的大量iRBC隔离通常伴有血管内和血管周围病理，包括环状血管。这些观察结果导致了普遍接受的假设，即iRBC在血管系统中的隔离和由此产生的后遗症，包括机械性阻塞、炎症、血管调节受损和BBB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（至少17项临床试验的11种疗法）尚未显示出疗效。现有的CM小鼠模型，实验CM（ECM）与人类疾病有许多共同特征。事实上，包括我们自己使用MRI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疝的证据，与MRI在CM儿童中观察到的结果相似。然而，小鼠模型提示了另一种病理机制。ECM需要通过脑血管系统在MHC-I上交叉呈递寄生虫抗原，并通过CD 3 + CD 8 + T细胞靶向该血管系统。然而，免疫细胞浸润到死于CM的儿童的大脑中的存在或性质尚未严格确定。因此，我们对儿童CM知识的一个关键差距是，在死于CM的儿童的大脑中是否存在类似于在CM小鼠模型中观察到的CD 3 + CD 8 + T细胞积聚模式。我们最近提供了明确的证据表明，CD 3 + CD 8 + T细胞存在于死于CM的儿童的大脑中。CD 3 + CD 8 + T细胞存在于与内皮密切相关的静脉血管系统的管腔中以及血管周围空间中的血管的近腔侧。在HIV感染的CM儿童中，CD 3 + CD 8 + T细胞的数量甚至更大，这表明HIV合并感染可以影响这种疾病。这些观察结果为CM的连续治疗开辟了新的途径，其涉及用大量可用的T细胞靶向治疗剂调节CD 3 + CD 8 + T细胞。 一项I/IIa期临床试验，旨在测试DON作为非洲儿童CM有效联合治疗的安全性 基于上述研究结果，我们于2019年启动了一项计划，将DON作为非洲CM儿童的预防性治疗进行I/IIa期临床试验（标题为：DON在小儿脑型疟疾中的应用：I/IIa期剂量递增安全性研究）。我们的临床试验团队包括Louis米勒（高级科学家LMVR），布列塔尼里格尔（研究员LIG）和道格Postels（儿童医院/GW医学院）。我们已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二零二二年八月初开始。我们拥有：在马拉维确定了一个设备齐全的研究中心，由Terrie Taylor领导开展我们的试验;与Postels博士（PI）一起编写并提交了临床方案，供美国和马拉维的IRB批准，并获得了两个IRB的批准;从NCI获得足够量的cGGP DON用于我们的研究，其被成功地填充和完成并运送到马拉维以开始我们的试验，并运送到弗雷德里克的设施，MD用于存储;向FDA提交了一份IND前申请，以批准在我们的方案中使用DON，并收到FDA确认，无需进行额外的临床前研究;向FDA提交了一份IND申请，并获得了继续进行我们研究成人组的许可，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.