Small difference, significant effect: How antibodies influence the defense against infections

Monoclonal antibodies (mabs) against TNFα influence the defense against a leishmania infection at different rates. Source: PEI

Autoimmune diseases are chronic inflammatory diseases in which immune cells erroneously attack the body’s own cells or tissue. In these diseases which, for example, also include rheumatoid arthritis, psoriasis, or chronic inflammatory diseases of the intestine such as Crohn’s disease, TNFα plays an important role. Among other things, it conveys the classic inflammatory symptoms: swelling, redness, and pain. However, TNFα is a versatile cytokine which, in its role as a central regulator of the immune system is also important for the defense of pathogenic agents.

Thus, there is evidence that the treatment with mabs blocking TNFα involves an increased risk of infectious disease. However, the data obtained up to now are contra­dictory. Furthermore, an increased occurrence of the parasitic disease leishmaniosis was reported in patients treated with a particular mab. Leishmaniosis is caused by the single-cell parasite leishmanial transmitted by sand flies. The disease above all occurs in the Mediterranean, tropical regions, and Asia. Around one million people contract the disease world-wide each year.

Do TNFα-blocking mabs differ in their influence on the immune defense of the body? Researchers led by Professor Ger van Zandbergen, head of Division Immunology of the Paul Ehrlich Institut and Dr Katharina Arens have studied the influence of various TNFα-blocking mabs on the immune response of human immune cells against leishmania. The studies were performed by the researchers in vitro – outside the body. For this purpose, they infected macrophages, certain immune cells of the body which are preferably infected by leishmainia, with the parasite. Then they added different mabs and T-lymphocytes.

T-lymphocytes, in their role as important immune cells, are normally able to recognise infected macrophages, to replicate as a result of this contact, and to combat the pathogen directly. The reactions of the T-cells to the parasite in the presence of the different mabs differed greatly. While some mabs markedly reduced T-lymphocyte activity thus enabling the parasites to replicate, the effect was lower with another mab – and replication of the leishmania was prevented.

In a next step, the researchers of the PEI compared the molecular structure of the mab showing the different action profiles. In doing so, they found that polymer polyethylene glycol (PEG) was the molecule that causes a small but significant difference. It primarily extends the half-life of the effect created by the antibody, since it protects from the body’s own digestion of the antibody: PEGylation – the adherence of the PEG to the mab at defined sites reduces the inhibitory effect of TNFα-blocking mabs on the immune defense against leishmanial.

The researchers conclude from these results that only small PEG modifications of TNFα inhibiting mabs are able to reduce effects that weaken the immune defense. In the researcher’s view, the differences between the mabs with regard to immune defense should be further studied in order to gain insights on the road to effective and even safer medicinal products.

Original Publication

Arens K, Filippis C, Kleinfelder H, Goetzee A, Crauwels P, Reichmann G, Waibler Z, Bagola K, van Zandbergen G (2018): Anti-Tumor Necrosis Factor α Therapeutics Differentially Affect Leishmania Infection of Human Macrophages.
Front Immunol 9: Article 1772.
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