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Checkpoint inhibitors prod exhausted immune cells into action

Researchers at the Paul-Ehrlich-Institut succeeded in significantly increasing the killing of Leishmania parasite-infected cells by human immune cells in a new laboratory model using a PD-1 checkpoint inhibitor. The findings offer new insights which may be useful for the development of immunotherapeutic strategies to combat leishmaniasis. The research results are reported in "Frontiers in Immunology" (published 22 Dec. 2017).

Checkpoints of the immune system

Immune checkpoints such as PD-1 (programmed death-1) act as important controls for the immune system. At these binding points for particular immune cells, the T lymphocytes, the decision is made whether an immune reaction should be enhanced or inhibited, i.e. whether or not the T lymphocytes can be activated. The mediator for this mechanism is the appropriate binding partner (ligand) of PD-1. Many cancer cells frequently express the matching binding partner for the inhibiting checkpoint PD-1 on their surface. This allows cancer cells to evade the T lymphocyte-mediated immune response, which otherwise would kill the cancer cells. The passive state of the T-lymphocytes, which is caused, inter alia, by PD-1 signalling, is often described as a state of exhaustion. PD-1 checkpoint inhibitors, a group of monoclonal antibodies for cancer therapy, block the inhibiting checkpoints and again mobilise the immune system against the cancer cells. With checkpoint inhibitors, promising therapy results have been achieved treating cancer.

Research results

Little is known about the influence of immunological checkpoints in chronic infectious parasitic diseases. Prof. Dr. Ger van Zandbergen, Christodoulos Filippis and colleagues of the Division of Immunology at the PEI have examined the immunological processes during an infection with Leishmania parasites in a newly established laboratory in vitro model. Leishmania parasites are transmitted by sandflies and cause leishmaniasis. Increasing attention is paid by Germany and many other industrial nations to the world-wide significance of poverty-associated and neglected tropical diseases (NTDs) such as leishmaniasis. More than one billion people in 149 countries world-wide are suffering from neglected tropical diseases.

At first, the researchers caused the T lymphocytes to attain a stressed-out, quasi exhausted state. Then these cells were brought into contact with other immune cells – dendritic cells and macrophages that had previously been infected with Leishmania parasites. Due to their state at start-up, T cells could hardly be activated, and thus Leishmania parasites in the infected cells were poorly combatted.

In a parallel assay, the researchers added the checkpoint inhibitor nivolumab to the cells. By blocking the inhibitory checkpoint PD-1, the nivolumab antibodies restored T cell immune functions. Nivolumab is an antibody which is, among others, used in the treatment of advanced melanoma. The researchers established that under the circumstances described here, the T-cells became active again and mobilised all immune cells involved against the pathogenic agent. The number of cells infected with Leishmania parasites strongly decreased.

PD-1 checkpoint inhibition in Leishmania-infected primary human cells. PD-1 checkpoint inhibition in Leishmania-infected primary human dendritic cells. In chron. leishmaniasis, PD-1/PD-1 ligand, interactions between cells infected with Leishmania parasites and T cells of the immune system result in impaired T cell function which protects the parasite in the host cell. In the in vitro Leishmania infection model with primary human dendritic cells, the T-cell functionality could be improved by PD-1 checkpoint inhibition, which enhanced parasite killing. Source: PEI


"Our experiments provide insights into the role of the immune checkpoint PD-1 in Leishmania infection of primary human immune cells. In the long run, these findings could be useful for the development of immunotherapeutic strategies to combat leishmaniasis" explained Prof. Dr. van Zandbergen.

Product test related research

Examining checkpoint inhibitors in humans as part of clinical trials in Germany requires the authorization by the Paul-Ehrlich-Institut (PEI), Federal Institute for Vaccines and Biomedicines. The PEI evaluates these therapies also as part of a centralized marketing authorization procedure for the European Medicines Agency (EMA). Furthermore, the PEI records and evaluates reports of adverse effects and grants the official batch release for these medicinal products. An important basis for the professional responsibility of the many and varied regulatory tasks of the PEI is its own experimental research including research in the field of immunology.

Original publication

Filippis C, Arens K, Noubissi Nzeteu GA, Reichmann G, Waibler Z, Crauwels P, van Zandbergen G (2017): Nivolumab Enhances In Vitro Effector Functions of PD-1+ T-Lymphocytes and Leishmania-Infected Human Myeloid Cells in a Host Cell-Dependent Manner.
Front Immunol 22: 1880.

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