EDCTP portfolio: Career Development Fellowships

Dr Caroline Kijogi aims a better understanding of macrophage polarisation in placental malaria pathogenesis, ultimately to improve outcomes of malaria in pregnancy.

Malaria in pregnancy and the uterine microenvironment

Macrophages account for one of the most abundant leucocytes infiltrating the uterine lining during pregnancy. They play a key role in the maintenance of a healthy pregnancy by promoting implantation, trophoblast invasion, placentation, tissue remodelling and angiogenesis.

Macrophages are present at all stages of pregnancy unlike other leukocytes and are integral in the immunological adaptations that facilitate tolerance of the semi-allogenic fetus. Due to their plasticity and heterogeneity, they may act as either pro- or anti-inflammatory mediators. The activation state and function of macrophages is dependent on the local tissue microenvironment, enabling their polarisation into either of the two distinct subsets; the classically activated, M1 macrophages which are proinflammatory and the alternatively activated, M2 macrophages which are anti-inflammatory and immunoregulatory.

During the course of pregnancy, an M1 bias is observed transiently at the initial immunological phase then a switch to M2 phenotype ensues till delivery. Secreted cytokines, chemokines, growth factors, hormones as well as interactions with related cells are important in the acquisition of the unique phenotypes and functions of macrophages.

The challenge

Infections during pregnancy can disrupt the uterine microenvironment and have profound effects on macrophage activity and subsequently the pregnancy outcome. Plasmodium falciparum infection during pregnancy causes massive recruitment of monocytes and macrophages to the intervillous space of the placenta, the site of sequestration of infected erythrocytes. Dr Kijogi hypothesises that the accumulation of these cells causes an M1/M2 imbalance that skews polarisation to M1 phenotype possibly with deleterious effects on the growing fetus.

She will test this hypothesis by examining the expression of cell surface markers for M1 and M2 macrophages (CD80, CD86, CD68 for M1 and CD163, CD206, CD209 for M2) by flow cytometry. She will also assess the localisation of placental M1 and M2 macrophages by immunohistochemistry. To assess the functional capacity of these cells, the expression levels of related angiogenic factors and cytokines upon stimulation with PMA-ionomycin will be examined. Also, for in vitro polarisation studies, decidual macrophages will be cultured in the presence of malarial antigens.

The project

Findings from this study will lead to a better understanding of P. falciparum-mediated macrophage polarisation during placental infection and could be probed further in the development of immuno-therapeutic tools to improve outcomes during malaria in pregnancy. Such treatment could be explored to reverse M1 polarisation and may have potential as adjunctive treatment for malaria in pregnancy.

Impact


test the safety and efficacy of this new formulation in young children

Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

EDCTP portfolio: HIV & HIV-associated infections

The challenge

Macrophages account for one of the most abundant leucocytes infiltrating the uterine lining during pregnancy. They play a key role in the maintenance of a healthy pregnancy by promoting implantation, trophoblast invasion, placentation, tissue remodelling and angiogenesis.

Macrophages are present at all stages of pregnancy unlike other leukocytes and are integral in the immunological adaptations that facilitate tolerance of the semi-allogenic fetus. Due to their plasticity and heterogeneity, they may act as either pro- or anti-inflammatory mediators. The activation state and function of macrophages is dependent on the local tissue microenvironment, enabling their polarisation into either of the two distinct subsets; the classically activated, M1 macrophages which are proinflammatory and the alternatively activated, M2 macrophages which are anti-inflammatory and immunoregulatory.

During the course of pregnancy, an M1 bias is observed transiently at the initial immunological phase then a switch to M2 phenotype ensues till delivery. Secreted cytokines, chemokines, growth factors, hormones as well as interactions with related cells are important in the acquisition of the unique phenotypes and functions of macrophages.

Infections during pregnancy can disrupt the uterine microenvironment and have profound effects on macrophage activity and subsequently the pregnancy outcome. Plasmodium falciparum infection during pregnancy causes massive recruitment of monocytes and macrophages to the intervillous space of the placenta, the site of sequestration of infected erythrocytes. Dr Kijogi hypothesises that the accumulation of these cells causes an M1/M2 imbalance that skews polarisation to M1 phenotype possibly with deleterious effects on the growing fetus.

She will test this hypothesis by examining the expression of cell surface markers for M1 and M2 macrophages (CD80, CD86, CD68 for M1 and CD163, CD206, CD209 for M2) by flow cytometry. She will also assess the localisation of placental M1 and M2 macrophages by immunohistochemistry. To assess the functional capacity of these cells, the expression levels of related angiogenic factors and cytokines upon stimulation with PMA-ionomycin will be examined. Also, for in vitro polarisation studies, decidual macrophages will be cultured in the presence of malarial antigens.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

Findings from this study will lead to a better understanding of P. falciparum-mediated macrophage polarisation during placental infection and could be probed further in the development of immuno-therapeutic tools to improve outcomes during malaria in pregnancy. Such treatment could be explored to reverse M1 polarisation and may have potential as adjunctive treatment for malaria in pregnancy.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact

L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.

Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.

WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.

WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing

HIV infection: Recommendations for a public health approach
(second edition). 2016

Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3

Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)

Target population(s): Children with HIV

Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)

Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)

Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)

EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)

Total project funding: €1.2M (CHAPAS-1); €5.0M

About us

The European & Developing Countries Clinical Trials Partnership (EDCTP) is a public–public partnership between 14 European and 16 African countries, supported by the European Union. EDCTP’s vision is to reduce the individual, social and economic burden of poverty-related infectious diseases by affecting sub-Saharan Africa. EDCTP’s mission is to accelerate the development of new or improved medicinal products for the identification, treatment and prevention of infectious diseases, including emerging and re-emerging diseases, through pre- and postregistration clinical studies, with emphasis on phase II and III clinical trials. Our approach integrates conduct of research with development of African clinical research capacity and networking. The second EDCTP programme is implemented by the EDCTP Association supported under Horizon 2020, the European Union’s Framework Programme for Research and Innovation.

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