Angewandte Chemie International Edition
Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
For full article and contact information, see Angew. Chem. Int. Ed. 2002, 41 (22), 4241 - 4244
Better Help for Blood Poisoning?
A new approach for fighting endotoxic shock
through active immunization with an endotoxin analogue
Even today, some 50 % of blood poisoning cases are fatal. According to the Center for Disease Control and Prevention, septic shock is one of the ten most common causes of death in the United States. Treatment has thus far been very limited. Now a team of researchers working with Kim D. Janda and Paul Wentworth, Jr. at the Scripps Research Institute in La Jolla has developed a highly promising new therapeutic approach.
The life-threatening state of shock in the course of blood poisoning brought on by gram-negative bacteria is triggered by endotoxins. These are lipopolysaccharides (LPS), building blocks of the bacterial cell membrane that are released as the bacteria die. Lipid A, the lipid component of the LPS, is the primary cause of the toxicity. Lipid A triggers a panic-like immune reaction in the body, which can ultimately lead to circulatory failure and multiple organ failure. The dilemma is this: on the one hand, in order to stop the bacterial growth, antibiotics must be administered; on the other hand, the death of the bacteria through antibiotics leads to increased release of endotoxins. Also, it is not possible to inactivate lipid A, a carbohydrate, by means of passive immunization through the administration of antibodies. The Californian researchers now propose using active immunization. This means that they want the patient’s body itself to produce antibodies for lipid A. For this to work, the immune system must be outsmarted. The scientists have synthesized a slightly altered version of lipid A containing phosphonate groups, which allows for easier production of antibodies. Also, they have coupled this new lipid to keyhole lipid hemocyanin (KLH), a protein that is obtained from a Californian sea snail and a "workhorse" of immunological research. This protein is known to be a strong antigen, which means that antibodies to KLH are easily produced.
Trials have shown that mice do produce antibodies to the conjugate of KLH and the lipid-A derivative. These antibodies can also recognize "real" bacterial lipid A in the mouse’s blood and can take it out of action. This study brings hope that an effective treatment for endotoxic shock can be developed along these lines.