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Name: Kemp, Kåre
Home country: Denmark
Research country: Ghana
Project period: 1997-2000
Title
Significance of T-cell cytokine production for the development of resistance and disease in human leishmaniasis
Abstract
Leishmaniasis is a relatively unknown disease in Denmark, but annually it affects many millions of people and it is estimated that about 300.000 people are affected by one of the clinical forms of the disease. The Centre for Medical Parasitology has for a number of years conducted research into the mechanisms that lead to the protection against and resistance to infectious diseases, including leishmaniasis.
The clinical symptoms of leishmaniasis vary from small self-healing skin sores to fatal trajectories. Despite the big clinical differences, all symptoms are caused by different forms of the same parasite, Leishmania. Studies from recent years have lead to the recognition that the composition of hormones (cytokines), produced by immune system cells, have fundamental significance for the infection trajectory. The production of certain cytokines in mouse models of Leishmania parasite infections have shown to be crucial in determining whether the mice died of the infection or whether they could establish an immune response, which led to slaughtering the parasites and to a trajectory without clinical symptoms. It was highly significant in some of these models, whether the mice produced so-called Th1 type cytokines (e.g. IFN-g
and IL-2), in which case the mice would survive, or so-called Th2 cytokines (e.g. IL-4, IL-10, IL-13), in which case they would die. In vitro
studies with cells from different groups of individuals have shown that some of the mouse model observations transfer to humans. These studies are based on ELISA measurements of cytokines in culture supernatants. However, these studies leave us with the question, which cell types were responsible for the production of the different cytokines. The purpose of this project has been to extend these studies, including the study of phenotypes of the cytokine producing cells.
The project was financed by RUF (DANIDA) and also involved the application of several techniques to Ghana as part of malaria related research.
Cells from some persons, who have never been exposed to Leishmania parasites, produce IFN-g, when they are incubated with Leishmania antigens. It has been discussed whether the IFN-g
originated from NK cells or T-cells. Our results points in the direction that it is primarily T-cells that make this production, and furthermore that these belong to the CD4+ sub-group. Once the L.major infection is over (the parasite that can lead to the cutaneous form of the disease), it will lead to a life long immunity against the parasite. It is suggested that the IFN-g
is responsible for this immunity and the CD4+ T-cells are also in this case responsible for the majority of the produced cytokine. Together with the production of the IFN-g, these cells will also produce TNF-a, which has shown to act synergetically with the IFN-g
in the act of inducing killings of the parasite into the macrophages. In contrast to the cells from individuals, which have had the cutaneous form of the disease, cells from individuals which have had the visceral form can react by the production of both Th1 and Th2 cytokines. Our studies show that it is two different populations of cells producing these cytokines, both CD4+ T-cells. It is surprising to find these two populations of these cells together, since such populations normally would down regulate each other. One of the reasons is that we find these populations together may be explained by the existence of a group of IL-10 and IFN-g
producing cells, which could create and environment that allows the existence of both IL-4 and IFN-g
producing cells.
The results do not directly lead to a vaccine or form of treatment, but they can increase our understanding of the disease, which in the long term can make for example the development of a vaccine easier.
Involved research institutions
Centre for Medical Parasitology (CMP), University of Copenhagen
Noguchi Memorial Institute for Medical Research, University of Ghana
Supervisor(s)
Thor Theander and Lars Hviid (CMP)
B. D. Akanmori, Noguchi Memorial Institute for Medical Research, University of Ghana
Correspondence
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