scholarly journals Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8+T Cells with Different Specificities

2014 ◽  
Vol 82 (11) ◽  
pp. 4854-4864 ◽  
Author(s):  
Chek Meng Poh ◽  
Shanshan W. Howland ◽  
Gijsbert M. Grotenbreg ◽  
Laurent Rénia
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Synergistic Effects ◽  
Brain Barrier ◽  
High Dose ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Blood Brain

ABSTRACTCD8+T cells play a pathogenic role in the development of murine experimental cerebral malaria (ECM) induced byPlasmodium bergheiANKA (PbA) infection in C57BL/6 mice. Only a limited number of CD8+epitopes have been described. Here, we report the identification of a new epitope from the bergheilysin protein recognized by PbA-specific CD8+T cells. Induction and functionality of these specific CD8+T cells were investigated in parallel with previously reported epitopes, using new tools such as tetramers and reporter cell lines that were developed for this study. We demonstrate that CD8+T cells of diverse specificities induced during PbA infection share many characteristics. They express cytolytic markers (gamma interferon [IFN-γ], granzyme B) and chemokine receptors (CXCR3, CCR5) and damage the blood-brain barrierin vivo. Our earlier finding that brain microvessels in mice infected with PbA, but not with non-ECM-causing strains, cross-presented a shared epitope was generalizable to these additional epitopes. Suppressing the induction of specific CD8+T cells through tolerization with a high-dose peptide injection was unable to confer protection against ECM, suggesting that CD8+T cells of other specificities participate in this process. The tools that we developed can be used to further investigate the heterogeneity of CD8+T cell responses that are involved in ECM.

scholarly journals S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Robyn E. Elphinstone ◽  
Rickvinder Besla ◽  
Eric A. Shikatani ◽  
Ziyue Lu ◽  
Alfred Hausladen ◽  
...  
Keyword(s):  
T Cell ◽  
Cerebral Malaria ◽  
Clinical Outcomes ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

ABSTRACT Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected with Plasmodium berghei ANKA had significantly delayed mortality compared to WT animals (P < 0.0001), despite higher parasite burdens (P < 0.01), and displayed markedly enhanced survival versus the wild type (WT) when treated with the antimalarial drug artesunate (77% versus 38%; P < 0.001). Improved survival was associated with higher levels of protein-bound NO, decreased levels of CD4+ and CD8+ T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival following P. berghei ANKA infection compared to those receiving KO bone barrow (P < 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism.

The effect of interleukin-2 on the blood-brain barrier in the 9L gliosarcoma rat model

1989 ◽  
Vol 70 (1) ◽  
pp. 92-96 ◽  
Author(s):  
Joseph T. Alexander ◽  
Stephen C. Saris ◽  
Edward H. Oldfield
Keyword(s):  
Blood Brain Barrier ◽  
Interleukin 2 ◽  
Brain Barrier ◽  
High Dose ◽  
Normal Brain ◽  
Content Type ◽  
Tumor Bearing ◽  
Blood Brain ◽  
Significant Difference ◽  
Fine Print

✓ Carbon-14-labeled aminoisobutyric acid was used to determine local blood-to-tissue transfer constants in 22 Fischer rats with intracerebral 9L gliosarcomas that received either high-dose parenteral interleukin-2 (IL-2) or a control injection. In tumor and peritumoral tissue, the transfer constants in the IL-2-treated animals (89.6 ± 14.6 and 35.8 ± 6.0, respectively, mean ± standard error of the mean) were larger (p < 0.05) than in control animals (61.4 ± 6.4 and 14.6 ± 2.2, respectively). In contrast, in normal frontal and occipital tissue contralateral to the tumor-bearing hemisphere, there was no significant difference between the transfer constants in IL-2-treated and control animals. Furthermore, treatment of animals with IL-2 excipient caused no change in permeability as compared to animals treated with Hanks' balanced salt solution. Parenteral injection of IL-2 increases blood-brain barrier disruption in tumor-bearing rat brain but does not increase the vascular permeability of normal brain. Methods to prevent this increased tumor vessel permeability are required before parenteral IL-2 can be used safely for the treatment of primary or metastatic brain tumors.

scholarly journals Targeting the CD146/Galectin-9 axis protects the integrity of the blood–brain barrier in experimental cerebral malaria

2020 ◽  
Author(s):  
Hongxia Duan ◽  
Shuai Zhao ◽  
Jianquan Xiang ◽  
Chenhui Ju ◽  
Xuehui Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Immune Cells ◽  
Current Treatment ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Blood Brain ◽  
Infected Rbcs ◽  
Antiparasitic Drugs

AbstractCerebral malaria (CM) is a life-threatening diffuse encephalopathy caused by Plasmodium falciparum, in which the destruction of the blood–brain barrier (BBB) is the main cause of death. However, increasing evidence has shown that antimalarial drugs, the current treatment for CM, do little to protect against CM-induced BBB damage. Therefore, a means to alleviate BBB dysfunction would be a promising adjuvant therapy for CM. The adhesion molecule CD146 has been reported to be expressed in both endothelial cells and proinflammatory immune cells and mediates neuroinflammation. Here, we demonstrate that CD146 expressed on BBB endothelial cells but not immune cells is a novel therapeutic target in a mouse model of experimental cerebral malaria (eCM). Endothelial CD146 is upregulated during eCM development and facilitates the sequestration of infected red blood cells (RBCs) and/or proinflammatory lymphocytes in CNS blood vessels, thereby promoting the disruption of BBB integrity. Mechanistic studies showed that the interaction of CD146 and Galectin-9 contributes to the aggregation of infected RBCs and lymphocytes. Deletion of endothelial CD146 or treatment with the anti-CD146 antibody AA98 prevents severe signs of eCM, such as limb paralysis, brain vascular leakage, and death. In addition, AA98 combined with the antiparasitic drug artemether improved the cognition and memory of mice with eCM. Taken together, our findings suggest that endothelial CD146 is a novel and promising target in combination with antiparasitic drugs for future CM therapies.

scholarly journals Suppression of CD4+Effector Responses by Naturally Occurring CD4+CD25+Foxp3+Regulatory T Cells Contributes to Experimental Cerebral Malaria

2015 ◽  
Vol 84 (1) ◽  
pp. 329-338 ◽  
Author(s):  
Anne-Laurence Blanc ◽  
Tarun Keswani ◽  
Olivier Gorgette ◽  
Antonio Bandeira ◽  
Bernard Malissen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cerebral Malaria ◽  
T Cell Response ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Naturally Occurring ◽  
Cell Enrichment

The role of naturally occurring CD4+CD25+Foxp3+regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4+T cells in an attenuated model ofPlasmodium bergheiANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6)P. bergheiANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4+T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4+T cell response toP. bergheiANKA infectionin vivoin both CM-susceptible (B6) and CM-resistant (B6-CD4−/−) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional duringP. bergheiANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.

Cerebrovascular permeability and delivery of gentamicin to normal brain and experimental brain abscess in rats

1984 ◽  
Vol 61 (3) ◽  
pp. 430-439 ◽  
Author(s):  
Edward A. Neuwelt ◽  
David E. Baker ◽  
Michael A. Pagel ◽  
Nathan K. Blank
Keyword(s):  
Brain Abscess ◽  
Blood Brain Barrier ◽  
Medical Management ◽  
Brain Barrier ◽  
High Dose ◽  
Normal Brain ◽  
Content Type ◽  
Stage Of Development ◽  
Blood Brain ◽  
Brain Abscesses

✓ Antibiotics vary widely in their ability to penetrate the blood-brain barrier. In studies of 70 rats, the permeability of the normal blood-brain barrier to gentamicin was shown to be poor. In experimental brain abscesses, during the cerebritic stage of development, the penetration of intravenous antibiotics was increased compared to normal brain but was very inconsistent. Antibiotic delivery to brain abscess was not significantly altered with the administration of high-dose steroids, but the macrophage and glial response was markedly decreased with high-dose steroid therapy. Reversible osmotic blood-brain barrier modification with mannitol increased the delivery of gentamicin both to brain abscess and to the surrounding brain. It also resulted in more consistent tissue drug levels. The clinical implications of these studies suggest that, because of the inconsistent delivery of gentamicin to brain abscess, the therapeutic efficacy of medical management alone may be quite variable. This mode of therapy could possibly increase the efficacy of medical management of brain abscesses, especially in patients with multiple or surgically inaccessible brain abscesses.

In vivo assessment of the window of barrier opening after osmotic blood—brain barrier disruption in humans

2000 ◽  
Vol 92 (4) ◽  
pp. 599-605 ◽  
Author(s):  
Tali Siegal ◽  
Rina Rubinstein ◽  
Felix Bokstein ◽  
Allan Schwartz ◽  
Alexander Lossos ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Time Course ◽  
Photon Emission ◽  
Brain Barrier ◽  
Therapeutic Window ◽  
Content Type ◽  
Blood Brain ◽  
The Mean ◽  
Fine Print

Object. Osmotic blood—brain barrier (BBB) disruption induced by intraarterial infusion of mannitol is used in conjunction with chemotherapy to treat human brain tumors. The time course to barrier closure, or the so-called therapeutic window, has been examined in animals but little information is available in humans. The authors, therefore assessed the time course to barrier closure after osmotic BBB disruption in humans.Methods. Disruption of the BBB was demonstrated using 99mTc-glucoheptonate (TcGH) single-photon emission computerized tomography (SPECT) scanning in 12 patients who were treated monthly with combination chemotherapy in conjunction with BBB disruption. The primary diagnosis was primary central nervous system lymphoma in seven patients and primitive neuroectodermal tumors in five. The TcGH (20 mCi) was injected at 1- to 480-minute intervals after osmotic BBB disruption, and patients underwent SPECT scanning after 4 hours. A total of 38 studies was performed. Good-to-excellent BBB disruption was obtained in 29 procedures and poor-to-moderate disruption was seen in the other nine studies.The TcGH indices correlated with the degree of BBB disruption as measured postprocedure on contrast-enhanced CT scans (r = 0.852). Mean baseline TcGH indices were 1.02 ± 0.07. For the group of patients with good-to-excellent disruptions the mean indices at 1 minute postdisruption measured 2.19 ± 0.18. After 40 minutes no significant change was noted (mean index 2.13 ± 0.2). Then the indices declined more steeply and at 120 minutes after the disruption the index was 1.36 ± 0.02. A very slow decline was noted between 120 and 240 minutes after mannitol infusion. At 240 minutes the barrier was still open for all good-to-excellent disruptions (index 1.33 ± 0.08) but at 480 minutes the mean indices had returned to the baseline level.Conclusions. Results of these in vivo human studies indicate that the time course to closure of the disrupted BBB for low-molecular-weight complexes is longer than previously estimated. The barrier is widely open during the first 40 minutes after osmotic BBB disruption and returns to baseline levels only after 6 to 8 hours following the induction of good or excellent disruption. These findings have important clinical implications for the design of therapeutic protocols.

scholarly journals Beta Interferon Suppresses the Development of Experimental Cerebral Malaria

2011 ◽  
Vol 79 (4) ◽  
pp. 1750-1758 ◽  
Author(s):  
Craig N. Morrell ◽  
Kalyan Srivastava ◽  
AnneMarie Swaim ◽  
M. Teresa Lee ◽  
Jun Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Vascular Inflammation ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Beta Interferon ◽  
Cxcr3 Expression ◽  
Blood Brain ◽  
The Brain

ABSTRACTCerebral malaria (CM) is a major complication ofPlasmodium falciparuminfection, particularly in children. The pathogenesis of cerebral malaria involves parasitized red blood cell (RBC)-mediated vascular inflammation, immune stimulation, loss of blood-brain barrier integrity, and obstruction of cerebral capillaries. Therefore, blunting vascular inflammation and immune cell recruitment is crucial in limiting the disease course. Beta interferon (IFN-β) has been used in the treatment of diseases, such as multiple sclerosis (MS) but has not yet been explored in the treatment of CM. Therefore, we sought to determine whether IFN-β also limits disease progression in experimental cerebral malaria (ECM).Plasmodium berghei-infected mice treated with IFN-β died later and showed increased survival, with improved blood-brain barrier function, compared to infected mice. IFN-β did not alter systemic parasitemia. However, we identified multiple action sites that were modified by IFN-β administration.P. bergheiinfection resulted in increased expression of chemokine (C-X-C motif) ligand 9 (CXCL9) in brain vascular endothelial cells that attract T cells to the brain, as well as increased T-cell chemokine (C-X-C motif) receptor 3 (CXCR3) expression. The infection also increased the cellular content of intercellular adhesion molecule 1 (ICAM-1), a molecule important for attachment of parasitized RBCs to the endothelial cell. In this article, we report that IFN-β treatment leads to reduction of CXCL9 and ICAM-1 in the brain, reduction of T-cell CXCR3 expression, and downregulation of serum tumor necrosis factor alpha (TNF-α). In addition, IFN-β-treatedP. berghei-infected mice also had fewer brain T-cell infiltrates, further demonstrating its protective effects. Hence, IFN-β has important anti-inflammatory properties that ameliorate the severity of ECM and prolong mouse survival.

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