Immunopharmacology – University of Copenhagen

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Department of Drug Design and Pharmacology > Research > Pharmacotherapy > Immunopharmacology

Immunopharmacology

The research is focusing at the interface between innate immunology and microbiology such as pyrogen testing of pharmaceuticals and development of in vitro assays for pyrogen testing and evaluation of immunomodulation.

Pyrogen testing and detection of endotoxin and other pyrogens

Pyrogens are substances that when injected into the blood of humans and other mammals will induce fever. Consequently all pharmaceutical products that are injected into the blood must be free of pyrogens. Many cell wall components of bacteria and other microorganisms are known to be pyrogenic.

Traditionally pyrogen testing of pharmaceuticals has been conducted by either the rabbit pyrogen test or the test for bacterial endotoxins (Limulus ameboecyte lysate (LAL) test). However these tests both have limitations and disadvantages. In  example the rabbit test uses animals for routine tests and the LAL test can only detect one pyrogenic substance LPS.

Based on the new knowledge of the innate immune system we focus on development of new in vitro tests for detection of pyrogens. When monocytes, macrophages or neutrophils are exposed to pyrogens or other inflammatory substances they will recognize these and secrete inflammatory mediators like cytokines, chemkines and reactive oxygen species (ROS). Using freshly isolated human immune cells or established cell lines we investigate these mechanisms.

Immunomodulation – the effect of antimicrobial peptides and peptidomimetics

Sepsis, an infection induced inflammatory syndrome, is the most common life-threatening complication in patients admitted to intensive care units due to nosocomial bacterial infections. Sepsis may progress into septic shock - an uncontrolled inflammatory response that may lead to multiple organ syndrome and ultimately death. Despite antibiotic treatment and life-sustaining care, the mortality rate for sepsis patients remains 10-60%. Moreover, the number of deaths by septic shock is increasing due to a rise in the incidence of sepsis. Therefore, a novel therapy against sepsis is needed.

Infections caused by Gram-positive bacteria make up approximately 50% of all sepsis related infections.  Lipoteichoic acid (LTA) is a molecule found in the cell wall of Gram-positive bacteria. LTA is considered to be one of the primary immunostimulating factors in these bacteria. When the immune system is stimulated with LTA, from live as well as dead bacteria, it may result in massive release of proinflammatory cytokines and other factors leading to sepsis.

The inflammatory response in sepsis is complex, and therapies based on inhibition of their effects have failed in clinical trials. Our hypothesis is that neutralization of the immunostimulatory effect of LTA can reduce the release of proinflammatory factors and hereby improve the outcome of sepsis treatment.

The aim is to evaluate peptides and peptidomimetics for the ability to modulate the inflammatory response induced by Gram-positive pathogens. The molecular mechanisms behind the observed modulating effects are investigated.

Collaborations

All research projects are conducted in close co-operation with national as well as international researchers at other Universities, at University Hospitals and in the pharmaceutical industry.