Biomedical subjects

Henri C van der Heyde

Publications and source records attributed to Henri C van der Heyde.

10 recordsLinked to original sources

PubMed2006

Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria.

The role of nitric oxide (NO) in the genesis of cerebral malaria is controversial. Most investigators propose that the unfortunate consequence of the high concentrations of NO produced to kill the parasite is the development of cerebral malaria. Here we have tested this high NO bioavailability hypothesis in the setting of experimental cerebral malaria (ECM), but find instead that low NO bioavailability contributes to the genesis of ECM. Specifically, mice deficient in vascular NO synthase showed parasitemia and mortality similar to that observed in control mice. Exogenous NO did not affect parasitemia but provided marked protection against ECM; in fact, mice treated with exogenous NO were clinically indistinguishable from uninfected mice at a stage when control infected mice were moribund. Administration of exogenous NO restored NO-mediated signaling in the brain, decreased proinflammatory biomarkers in the blood, and markedly reduced vascular leak and petechial hemorrhage into the brain. Low NO bioavailability in the vasculature during ECM was caused in part by an increase in NO-scavenging free hemoglobin in the blood, by hypoargininemia, and by low blood and erythrocyte nitrite concentrations. Exogenous NO inactivated NO-scavenging free hemoglobin in the plasma and restored nitrite to concentrations observed in uninfected mice. We therefore conclude that low rather than high NO bioavailability contributes to the genesis of ECM.

Alkenes↗

PubMed2006

A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction.

A unifying hypothesis for the genesis of cerebral malaria proposes that parasite antigens (released by replication in blood, surface molecules on parasitized erythrocytes, or merozoites) activate platelets that, in turn, contribute to the activation of the inflammatory response and increased levels of endothelial cell adhesion molecules (eCAMs). Increased levels of eCAMs result in further parasitized-erythrocyte sequestration and marked local inflammation that might disrupt the brain microvasculature, which cannot be repaired by the hemostasis system because of its procoagulant state. Disruption of the brain microvasculature can result in vascular leak and/or hemorrhaging into the brain; similar processes can occur in other vascular beds, including the lung. The blockage of functional capillaries by parasitized and/or unparasitized erythrocytes with decreased deformability or rosettes is also a key interaction between hemostasis and mechanical obstruction leading to pathogenesis. The events resulting in the development of cerebral malaria complications are multi-factorial, encompassing a dynamic interaction between three processes, thereby explaining the complexity of this deadly syndrome.

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PubMed2006

Splenic gammadelta T cells regulated by CD4+ T cells are required to control chronic Plasmodium chabaudi malaria in the B-cell-deficient mouse.

Little is known about the function and regulation of splenic gammadelta T cells during chronic Plasmodium chabaudi malaria. The splenic gammadelta T-cell population continues to expand, reaching levels equal to 4 times the number of splenocytes in an uninfected mouse. Splenic gammadelta T cells from J(H)-/- mice with chronic malaria expressed Vgamma1+ or Vdelta4+ in the same ratio as uninfected controls with Vgamma1 cells dominating, but the Vgamma2 ratio declined about twofold. Gammadelta T cells from G8 mice specific for the TL antigen increased only 2-fold in number, compared with 10-fold in BALB/c controls, but G8 gammadelta T cells failed to express the B220 activation marker. Elimination of the parasite by drug treatment caused a slow depletion in the number of splenic gammadelta, CD4+, and CD8+ T cells. Following challenge, drug-cured J(H)-/- mice exhibited nearly identical parasitemia time courses as naïve controls. Depletion of either CD4+ T cells or gammadelta T cells from chronically infected J(H)-/- mice by monoclonal antibody treatment resulted in an immediate and significant (P < 0.05) exacerbation of parasitemia coupled with a marked decrease in splenic gammadelta T-cell numbers. The number of CD4+ T cells, in contrast, did not decrease in mice after anti-T-cell receptor gammadelta treatment. The results indicate that cell-mediated immunity against blood-stage malarial parasites during chronic malaria (i) requires the continued presence of blood-stage parasites to remain functional, (ii) is dependent upon both gammadelta T cells and CD4+ T cells, and (iii) lacks immunological memory.

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PubMed2005

Cell- rather than antibody-mediated immunity leads to the development of profound thrombocytopenia during experimental Plasmodium berghei malaria.

Experimental malarial thrombocytopenia can reach life-threatening levels and is believed to be due to Abs targeting platelets for destruction by the reticuloendothelial system. However, we report that Abs account for at most 15% of platelet destruction as Plasmodium berghei-infected B cell-deficient mice exhibited profound thrombocytopenia (83%) as did C57BL/6 controls (98%). Further, no significant increase in Abs bound to intact platelets was observed during infection. P. berghei infection can enhance the activity of anti-platelet Abs as indicated by a significantly (p < 0.005) increased thrombocytopenia on day 4 of infection in mice that were administered a low dose anti-CD41 mAb compared with rat IgG1-injected controls. RAG1-/- and CD4- plus CD8-deficient mice were markedly protected from thrombocytopenia (p < 0.005) and malarial pathogenesis. CD8- or TCRgammadelta-deficient mice were not protected from thrombocytopenia and CD4-deficient mice were modestly protected. RAG1-/- mice exhibited significantly (p < 0.05) lower levels of plasma TNF, IFN-gamma, and IL-12 during infection. IFNgamma-/- and IL-12-/- mice exhibited increased survival but similar thrombocytopenia to C57BL/6 controls. Collectively, these data indicate that thrombocytopenia is necessary but not sufficient for malarial pathogenesis and Abs are not the major contributors to malarial thrombocytopenia. Rather, we propose that both CD4+ and CD8+ T cell populations play key roles in malarial thrombocytopenia; a complex bidirectional interaction between cell-mediated immunity and platelets exists during experimental severe malaria that regulates both responses.

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PubMed2005

Nitric oxide bioavailability in malaria.

Rational development of adjunct or anti-disease therapy for severe Plasmodium falciparum malaria requires cellular and molecular definition of malarial pathogenesis. Nitric oxide (NO) is a potential target for such therapy but its role during malaria is controversial. It has been proposed that NO is produced at high levels to kill Plasmodium parasites, although the unfortunate consequence of elevated NO levels might be impaired neuronal signaling, oxidant damage and red blood cell damage that leads to anemia. In this case, inhibitors of NO production or NO scavengers might be an effective adjunct therapy. However, increasing amounts of evidence support the alternate hypothesis that NO production is limited during malaria. Furthermore, the well-documented NO scavenging by cell-free plasma hemoglobin and superoxide, the levels of which are elevated during malaria, has not been considered. Low NO bioavailability in the vasculature during malaria might contribute to pathologic activation of the immune system, the endothelium and the coagulation system: factors required for malarial pathogenesis. Therefore, restoring NO bioavailability might represent an effective anti-disease therapy.

Anemia↗

PubMed2005

Hemoglobin serves to protect Plasmodium parasites from nitric oxide and reactive oxygen species.

Our understanding of how the host immune response kills Plasmodium, the causative agent of malaria, is limited and controversial. One widely held belief is that reactive oxygen species are crucial for controlling parasite replication. One of the hallmarks of blood-stage malaria is the cyclic rupture of erythrocytes by the parasite, which releases free hemoglobin into the circulation. We propose that this free hemoglobin, as well as the hemoglobin within the erythrocyte and surrounding the parasite, effectively shields Plasmodium from reactive oxygen species well in excess of those achievable in vivo.

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PubMed2004

Platelet depletion by anti-CD41 (alphaIIb) mAb injection early but not late in the course of disease protects against Plasmodium berghei pathogenesis by altering the levels of pathogenic cytokines.

Accumulating evidence indicates that platelets play a critical role in the pathogenesis of experimental severe malaria (ESM) elicited by infection with Plasmodium berghei. Mice injected on day 1 of P berghei infection (early) with either anti-CD41 or anti-CD61 monoclonal antibodies (mAbs) exhibited significantly (P<.001) increased survival from ESM compared with infection controls, indicating that platelets function early in the disease. In contrast, groups of mice treated on days 4, 5, and 6 (late) with anti-CD41 mAb exhibited similar mortality as controls. Because platelet depletion by anti-CD41 mAb on day 4 of infection did not protect mice, and platelet adherence occurs on day 6, platelet adherence to endothelium is not required to mediate malarial pathogenesis. Few platelet microparticles were detected in the blood during the course of malaria, but large numbers of erythrocyte vesicles, microparticles, and debris were detected. The protective effect of early anti-CD41 mAb treatment was independent of the number of platelets, platelet microparticles, erythrocyte-platelet conjugates, and erythrocyte vesicles. Mice treated early with anti-CD41 mAb exhibited markedly altered cytokine production on day 4 of P berghei infection (increased interleukin 10 [IL-10], IL-1alpha, IL-6, interferon-gamma [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]; decreased IL-2) but no decline in coagulation factors compared with rat immunoglobulin G (IgG)-treated controls, indicating that platelets regulate the levels of pathogenic cytokines.

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PubMed2003

Inhibition of platelet adherence to brain microvasculature protects against severe Plasmodium berghei malaria.

Some patients with Plasmodium falciparum infections develop cerebral malaria, acute respiratory distress, and shock and ultimately die even though drug therapy has eliminated the parasite from the blood, suggesting that a systemic inflammatory response contributes to malarial pathogenesis. Plasmodium berghei-infected mice are a well-recognized model of severe malaria (experimental severe malaria [ESM]), and infected mice exhibit a systemic inflammatory response. Because platelets are proposed to contribute to ESM and other systemic inflammatory responses, we determined whether platelet adherence contributes to experimental malarial pathogenesis. Indeed, a significant (P < 0.005) increase in the number of rolling and adherent platelets was observed by intravital microscopy in brain venules of P. berghei-infected mice compared with the number in uninfected controls. P-selectin- or ICAM-1-deficient mice exhibit increased survival after P. berghei infection. We observed a significant (P < 0.0001) reduction in the morbidity of mice injected with anti-CD41 (alpha(IIb) or gpIIb) monoclonal antibody on day 1 of P. berghei infection compared with the morbidity of infected controls injected with rat immunoglobulin G. Additionally, platelet rolling and adhesion in brain venules were reduced in P. berghei mice lacking either P-selectin or ICAM-1 or when the platelets were coated with anti-CD41 monoclonal antibody. Unlike other inflammatory conditions, we did not detect platelet-leukocyte interactions during P. berghei malaria. Because (i). leukocyte adhesion is not markedly altered in the absence of P-selectin or ICAM-1 and (ii). CD41 is not an adhesion molecule for parasitized erythrocytes, these findings support the hypothesis that inhibition of platelet adhesion to the brain microvasculature protects against development of malarial pathogenesis.

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PubMed2003

P-selectin contributes to severe experimental malaria but is not required for leukocyte adhesion to brain microvasculature.

Plasmodium berghei-infected mice, a well-recognized model of experimental cerebral malaria (ECM), exhibit many of the hallmarks of a systemic inflammatory response, with organ damage in brain, lung, and kidneys. Identification of the molecules mediating pathogenesis of the inflammatory response, such as leukocyte adhesion, may lead to new therapies. Indeed, mice lacking the cell adhesion molecule P-selectin were significantly (P = 0.005) protected from death due to P. berghei malaria compared with C57BL/6 controls despite similar parasitemia (P = 0.6) being found in both groups of mice. P-selectin levels assessed by the quantitative dual radiolabeled monoclonal antibody technique increased significantly (P < 0.05) in several organs in C57BL/6 mice infected with P. berghei, supporting the concept of a systemic inflammatory response mediating malarial pathogenesis. Intravital microscopic analysis of the brain microvasculature demonstrated significant (P < 0.001) leukocyte rolling and adhesion in brain venules of P. berghei-infected mice compared with those found in uninfected controls. The maximum leukocyte adhesion occurred on day 6 of P. berghei infection, when the mice become moribund and exhibit marked vascular leakage into the brain, lung, and heart. However, P-selectin levels were significantly (P < 0.005) increased in brain, lung, and kidneys during P. berghei malaria in ECM-resistant BALB/c mice compared with those found in uninfected BALB/c controls, indicating that increased P-selectin alone is not sufficient to mediate malarial pathogenesis. Leukocyte adhesion to brain microvessels of P-selectin-deficient mice with P. berghei malaria was similar to that observed in control mice. Collectively, these results indicate that P-selectin is important for the development of malarial pathogenesis but is not required for leukocyte adhesion in brain.

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PubMed2003

Intercellular adhesion molecule 1 is important for the development of severe experimental malaria but is not required for leukocyte adhesion in the brain.

Plasmodium berghei-infected mice, a well-recognized model of experimental cerebral malaria (ECM), exhibit a systemic inflammatory response. Most investigators hypothesize that leukocytes bind to endothelial cells via intercellular adhesion molecule 1 (ICAM-1), which causes endothelial damage, increased microvascular permeability, and, ultimately, death. ICAM-1-deficient mice on an ECM-susceptible C57BL/6 background were significantly (p = .04) protected from P. berghei mortality compared with ICAM-1 intact controls. ICAM-1 expression assessed by the dual radiolabeled monoclonal antibody technique was increased in the brain and lung in C57BL/6 mice on day 6 of P. berghei infection compared with uninfected controls (5.3-fold, p = .0003 for brain and 1.8-fold, p = .04 for lung). The increase in ICAM-1 expression coincided with significant (p < .05) increases in microvascular permeability in the brain and lung. In contrast to the hypothesized role for ICAM-1, in vivo analysis by intravital microscopy of leukocyte rolling and adhesion in brain microvasculature of mice revealed markedly increased levels of leukocyte rolling and adhesion in ICAM-1-deficient mice on day 6 of P. berghei infection compared with uninfected controls. In addition, ICAM-1 expression and microvascular permeability were increased in infected ECM-resistant BALB/c mice compared with uninfected BALB/c controls. These results collectively indicate that although ICAM-1 contributes to the mortality of experimental malaria, it is not sufficient for the development of severe experimental malaria. In addition, ICAM-1 expressed on the endothelium or on leukocytes is not required for leukocyte rolling or adhesion to the brain microvasculature of mice during P. berghei malaria. Leukocyte rolling and adhesion in the brain vasculature during P. berghei malaria use different ligands than observed during inflammation in other vascular beds.

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