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Why are Artemisia infusions prophylactic (part 2): the role of CD4 and CD8 T cells.

June 6, 2016 - 13:55 -- Pierre Lutgen

ARTEMISIA PLANTS INCREASE THE CD4 AND CD8 CELL COUNT

In vivo trials on the therapeutic effects of encapsulated Artemisia annua and Artemisia afra run by Constant Kansango Tchandema MD, Lubumbashi, RD Congo confirmed that these medicinal herbs indeed increase the immunity. 44 volunteers carrying trophozoites were treated with capsules containing Artemisia afra. The total dose of Artemisia afra powder administered over 10 days was 20 gr. In order to better understand the prophylactic and therapeutic effect of Artemisia herbal medicine on malaria infection it is important to assess the CD4 count and gametocyte carriage before and after treatment. It was found that on day 10 the CD4 count had on the average increased by 20% and the trophozoite carriage was reduced to zero except in a few rare cases (paper accepted for publication).

Dr Patrick Ogwang, Ministry of Health, Uganda, found that after 6 months of consumption of his prophylactic product Artavol the CD4 in numerous HIV patients increased from 300 to 500 cells/µL on an average and their count continues to rise (personal communication). Similar CD4 and CD8 cell boosting effects have been described for Artemisia annua in a PhD thesis in India (MD Islamuddin, Jamia Hamdard University, New Delhi, 2013). The population of these lymphocytes increased 2 weeks after treatment with an Artemisia annua hexane extract (100 mg/kg b.w.) by 18.4% for CD4 cells and 13.9% for CD8 cells. The author found no similar effect for artemisinin and essential oil extracted from the plant.

Of course the question remains open why Artemisia plants stimulate the proliferation of CD4 T and CD8 T cells. Artemisinin and its derivatives exhibit potent immunosuppressive activity on T cells (JX Wang et al., Brit J Pharmacol, 2007, 1-10). Artesunate inhibits proliferation of CD4+ T cells (SH Lee et al., Arch Pharm res 2014Nov 6). Several plants however like Astralagus, Echinacea, Glycyrrhiza have a boosting effect when administered orally. Some of these plants are very rich in pentacyclic triterpenes (I.Krasteva et al., Z.Naturforsch. 2006, 61b, 1166-69). In our opinion the pentacyclic triterpenes like beta-amyrin found in Artemisia annua and Artemisia apiacea (S Lee et al., Arch Pharm Res 2003,26, 902-5) deserve more attention.

THE ROLE OF CD4 AND CD8 CELLS IN MALARIA IMMUNITY AND PROPHYLAXY.

It is widely accepted that CD4 T cells play critical roles during blood stage malaria but the role of CD8 T cells remains controversial. Their action is probably limited to the liver and the silent stage of malaria infection in hepatocytes has so far been neglected in research. Vertebrates maintain T cells for the detection of pathogens. Recognition triggers infection control. The efficiency achieved by this immunosurveillance depends upon the CD4 and CD8 T cell population.

The individual contribution of each set is complex. Mice depleted of CD4 cells had significantly higher parasitemisia on day 7 as well as significantly higher peak parasitemias (JE Podoba et al., Infection and Immunity, 1991, 59, 51-58). Depletion of CD8 lymphocytes was found to have no effect on the early course of infection or on the level of peak parasitemia. However mice depleted of CD8 cells experienced two recurrent bouts of parasitemia during the later stage of the infection and required more than 5 weeks to eliminate the parasites. The results of this study confirm the importance of CD4 T cells in acquired immunity and demonstrate a role for CD8 cells in the resolution of infection. Protective CD8 T cell responses are strongly dependent on the presence of CD4 T cells (SW Tse et al., Mem Inst Oswaldo Cruz 2011, 106, 172-178). Another study showed that CD8+ exhaustion drives chronic malaria (JM Horne-Debets et al., Cell Rep 2013, 12, 1204-13). In patients whose CD4 counts are below 200 cells/µL the delay in parasitemia clearance is longer (J Kirinyet et al., Int J of Advanced Res, 2013, 1, 140-149).

ORGAN SPECIFIC T CELLS

Effective immunity is dependent on long-surviving memory T cells. Various memory subsets make distinct contributions to immune protection, especially in peripheral infection. It recently became clear that a subset, termed tissue resident memory T cells, resides in organs without recirculating (E Steinert et al., Cell 2015, 16, 737-749). It has been suggested that these T cells in nonlymphoid tissues are important during local infection, although their relationship with populations in the circulation remains poorly defined. For immunosurveillance, many CD8 T cells are positioned in solid organs and body surfaces such as the gastrointestinal, respiratory, mucosae and skin that represent common primary sites of pathogen exposure. The majority of memory CD8 T cells that patrol these frontlines are segregated populations that confine their surveillance locally and do not migrate. Organs such as liver and kidney also contain a substantial fraction of the overall memory CD8 T cell population, which may facilitate direct immunosurveillance of the organ.

A study in Japan established a novel system to investigate the cellular and molecular mechanisms underlying the protective immune response against liver-stage infection with malaria parasites using a model malaria antigen (K Kimura et al., Infect Immun. 2013; 81 3825–3834). They found that CD8+ T cells specific for a malaria cytoplasmic antigen form clusters around Infected hepatocytes. Clusters are more efficient in the elimination of the intrahepatic parasites than isolated CD4 or CD8 cells. These features suggest that a novel mechanism might be involved in the protective immune responses of CD8+ T cells against intrahepatic parasites. In vivo imaging has confirmed this cluster formation of CD8 cells around infected hepatocytes (IA Cockburn et al., PNAS, 2013, 110-22). This is consistent with the hypothesis that antigen-specific CD8 T cells themselves drive the recruitment of other CD8 cells to the site of infection in a positive feedback loop. This is also in line with previous work indicating that a large number of Plasmodium-specific CD8 cells are needed to ensure sterile protection (N Schmidt et al., PNAS 2008, 105, 14017-22). Importantly, the number required for liver stage immunity greatly exceeds the number required for resistance to other pathogens. The same authors demonstrate that CD8 T cells specific for the Plasmodium liver-stage are capable of providing long-term immunity, up to 6 months. An increase in CD4 cells may decrease the threshold of CD8 cells required for this protective immunity or prophylaxis. It was also confirmed that CD8 T cell activity is restricted to the immediate microenvironment of the infected hepatocyte and thus the protection depends on each parasite being found and eliminated by cognate CD8 T cells. Parasites which are not recognized because of their location or their genetic nature survive (IA Cockburn et al., Infection and Immunity, 2014, 82, 1460-64). Previous beliefs that IFN-γ and TNF-α cytokines were playing a major role in the elimination of infected hepatocytes seem not to apply.

DIFFERENCE BETWEEN ENDEMIC AND NON ENDEMIC AREAS?

We have overwhelming evidence now that for people leaving in endemic areas and drinking regularly Artemisia tea infusions or taking powdered leaves in capsules the frequency and severity of the malaria disease is drastically reduced.

But we have also the case of a few Caucasians from non-endemic areas whose regular consumption of Artemisia capsules or infusions did not protect them against a malaria crisis when visiting Africa. This also may explain why it is so difficult to develop a vaccine against malaria for European tourists: billions spent over 50 years in an ever-draining Danaids barrel.

A working hypothesis is that most Africans are asymptomatic carriers of Plasmodium falciparum parasites and that the regular tea consumption not only raises their overall number of CD4 and CD8 T cells but also the number of Plasmodium-specific cells in their liver. A Caucasian may be totally naïve and the consumption of Artemisia will eventually strengthen his immune system, but not lead to a proliferation of Plasmodium-specific CD8 cells because they are absent ab initio. Artemisia annua or afra will not be prophylactic for them but still have the strong suppressive and curative effect as confirmed in many trials.

Pierre Lutgen

Constant Kansango Tchandema