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Antimicrobial Agents and Chemotherapy, May 1999, p. 1027-1033, Vol. 43, No. 5
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Thiolated Recombinant Human Tumor Necrosis Factor-Alpha Protects against Plasmodium berghei K173-Induced Experimental Cerebral Malaria in Mice

Nancy S. Postma,1,dagger Rob C. Hermsen,2,* Daan J. A. Crommelin,1 Wijnand M. C. Eling,2 and Jan Zuidema1

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht,1 and Department of Medical Microbiology, University Hospital Nijmegen, 6500 HB Nijmegen,2 The Netherlands

Received 14 October 1998/Returned for modification 30 December 1998/Accepted 25 February 1999

The introduction of reactive thiol groups in recombinant human tumor necrosis factor (TNF) alpha (rhTNF-alpha ) by the reagent succinimidyl-S-acetylthioacetate resulted in the formation of a chemically stabilized rhTNF-alpha trimer (rhTNFalpha -AT; as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis). rhTNFalpha -AT showed a substantially enhanced protective efficacy against the development of experimental murine cerebral malaria (ECM) after intravenous injection compared to the protective efficacy of nonmodified rhTNF-alpha . Administration of thiolated rhTNF-alpha with protected thiol groups (rhTNFalpha -ATA; no stabilized trimers in vitro) exhibited the same protective efficacy against ECM, while in vitro bioactivity was reduced. Parasitemia was significantly suppressed in rhTNF-treated mice that were protected against ECM but not in treated mice that developed ECM. Protection against ECM was not related to increased concentrations in plasma of soluble TNF receptor 1 and 2 directly after injection or at the moment of development of ECM in nontreated mice. The results indicate that thiolation of rhTNF-alpha leads to the formation of stable trimers with increased potential in vivo.

* Corresponding author. Mailing address: Department of Medical Microbiology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-24-3614664. Fax: 31-24-3540216. E-mail: R.Hermsen{at}mmb.azn.nl.

dagger Present address: ACE Pharmaceuticals BV, 3890 BB Zeewolde, The Netherlands.

Antimicrobial Agents and Chemotherapy, May 1999, p. 1027-1033, Vol. 43, No. 5
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.




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